Degarelix for Injection

FIRMAGON is a GnRH receptor antagonist indicated for treatment of patients with advanced prostate cancer.

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.

A total of 1325 patients with prostate cancer received FIRMAGON either as a monthly treatment (60-160 mg) or as a single dose (up to 320 mg). A total of 1032 patients (78%) were treated for at least 6 months and 853 patients (64%) were treated for one year or more. The most commonly observed adverse reactions during FIRMAGON therapy included injection site reactions (e.g., pain, erythema, swelling or induration), hot flashes, increased weight, fatigue, 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.

FIRMAGON was studied in an active-controlled trial (N = 610) in which patients with prostate cancer were randomized to receive FIRMAGON (subcutaneous) or leuprolide (intramuscular) monthly for 12 months.Adverse reactions reported in 5% of patients or more are shown in Table 1.

Table 1: Adverse Reactions Reported in ≥ 5% of Patients in an Active Controlled Study

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 degarelix.

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.

In 1-5% of patients the following adverse reactions, not already listed, were considered related to FIRMAGON by the investigator:

Body as a whole: Asthenia, fever, night sweats; Digestive system: Nausea; Nervous system: Dizziness, headache, insomnia.

The following adverse reactions, not already listed, were reported to be drug-related by the investigator in ≥ 1% of patients: erectile dysfunction, gynecomastia, hyperhidrosis, testicular atrophy, and diarrhea.

The safety of FIRMAGON administered monthly was evaluated further in an extension study 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 ½ elevations in hepatic transaminases occurred in 47% of patients and Grade 3 elevations occurred in 1% of patients.

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.

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.

Included as part of the PRECAUTIONS section.

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.

Pharmacodynamics

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)

Pharmacokinetics

FIRMAGON forms a depot upon subcutaneous administration, from which degarelix is released to the circulation. Following administration of FIRMAGON 240 mg at a product concentration of 40 mg/mL, the mean Cmax was 26.2 ng/mL (coefficient of variation, CV 83%) and the mean AUC was 1054 ng·day/mL (CV 35%). Typically Cmax occurred within 2 days after subcutaneous administration. In prostate cancer patients at a product concentration of 40 mg/mL, the pharmacokinetics of degarelix were linear over a dose range of 120 to 240 mg. The pharmacokinetic behavior of the drug is strongly influenced by its concentration in the injection solution.

The distribution volume of degarelix after intravenous ( > 1 L/kg) or subcutaneous administration ( > 1000L) indicates that degarelix is distributed throughout total body water. In vitro plasma protein binding of degarelix is estimated to be approximately 90%.

Degarelix is subject to peptide hydrolysis during the passage of the hepato-biliary system and is mainly excreted as peptide fragments in the feces. No quantitatively significant metabolites were detected in plasma samples after subcutaneous administration. In vitro studies have shown that degarelix is not a substrate, inducer or inhibitor of the CYP450 or p-glycoprotein transporter systems.

Following subcutaneous administration of 240 mg FIRMAGON at a concentration of 40 mg/mL to prostate cancer patients, degarelix is eliminated in a biphasic fashion, with a median terminal half-life of approximately 53 days. The long half-life after subcutaneous administration is a consequence of a very slow release of degarelix from the FIRMAGON depot formed at the injection site(s). Approximately 20-30% of a given dose of degarelix was renally excreted, suggesting that approximately 70-80% is excreted via the hepato-biliary system in humans. Following subcutaneous administration of degarelix to prostate cancer patients the clearance is approximately 9L/hr.

There was no effect of age, weight or race on the degarelix pharmacokinetic parameters or testosterone concentration.

Clinical Studies

The safety and efficacy of FIRMAGON were evaluated in an open-label, multi-center, randomized, parallel-group study in patients with prostate cancer A total of 620 patients were randomized to receive one of two FIRMAGON dosing regimens or leuprolide for one year:

1. FIRMAGON at a starting dose of 240 mg (40 mg/mL) followed by monthly doses of 160 mg (40 mg/mL) subcutaneously,
2. FIRMAGON at a starting dose of 240 mg (40 mg/mL) followed by monthly doses of 80 mg (20 mg/mL) subcutaneously,
3. leuprolide 7.5 mg intramuscularly monthly.

Serum levels of testosterone were measured at screening, on Day 0, 1, 3, 7, 14, and 28 in the first month, and then monthly until the end of the study.

The clinical trial population (n=610) across all treatment arms had an overall median age of approximately 73 (range 50 to 98). The ethnic/racial distribution was 84% white, 6% black and 10% others. Disease stage was distributed approximately as follows: 20% metastatic, 29% locally advanced (T3/T4 Nx M0 or N1 M0), 31% localized (T1 or T2 N0 M0) and 20% classified as other (including patients whose disease metastatic status could not be determined definitively - or patients with PSA relapse after primary curative therapy). In addition, the median testosterone baseline value across treatment arms was approximately 400 ng/dL.

The primary objective was to demonstrate that FIRMAGON is effective with respect to achieving and maintaining testosterone suppression to castration levels (T ≤ 50 ng/dL), during 12 months treatment. The results are shown in Table 2.

Table 2: Medical Castration Rates (Testosterone ≤ 50 ng/dL) from Day 28 to Day 364

Percentage changes in testosterone from baseline to Day 28 (median with interquartile ranges) are shown in Figure 2 and the percentages of patients who attained the medical castration of testosterone ≤ 50 ng/dL are summarized in Table 3.

Figure 2: Percentage Change in Testosterone from Baseline by Treatment Group until Day 28 (Median with Interquartile Ranges)

Table 3: Percentage of Patients Attaining Testosterone ≤ 50 ng/dL within the First 28 Days

In the clinical trial, PSA levels were monitored as a secondary endpoint. PSA levels were lowered by 64% two weeks after administration of FIRMAGON, 85% after one month, 95% after three months, and remained suppressed throughout the one year of treatment. These PSA results should be interpreted with caution because of the heterogeneity of the patient population studied. No evidence has shown that the rapidity of PSA decline is related to a clinical benefit.

FIRMAGON
(FIRM-uh-gahn)
(degarelix for injection)

What is FIRMAGON?

FIRMAGON is a prescription medicine used in the treatment of advanced prostate cancer.

It is not known if FIRMAGON is safe or effective in children.

Who should not receive FIRMAGON?

Do not receive FIRMAGON if you are:

• allergic to degarelix or any ingredient in FIRMAGON. See the end of this leaflet for a complete list of ingredients in FIRMAGON.
• a female who is pregnant or may become pregnant. FIRMAGON can harm your unborn baby.

Talk to your healthcare provider before receiving FIRMAGON if you have any of these conditions.

Before receiving FIRMAGON, tell your healthcare provider about all your medical conditions, including if you:

• have any heart problems including a condition called long QT syndrome.
• have problems with blood levels such as sodium, potassium, calcium, and magnesium
• have kidney or liver problems
• are breastfeeding or plan to breastfeed. It is not known if FIRMAGON passes into your breast milk. You and your healthcare provider should decide if you will receive FIRMAGON or breastfeed. You should not do both.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.

How will I receive FIRMAGON?

You will receive an injection of FIRMAGON from your healthcare provider.

• The injection site will always be in the stomach (abdominal area). The injection site will change within the stomach area each time you receive a dose of FIRMAGON.
• Two injections are given as a first dose. The following monthly doses are one injection.
• Do not rub or scratch the injection site. Make sure your injection site is free of any pressure from belts, waistbands or other types of clothing.
• Always set up an appointment for your next injection.

What are the possible side effects of FIRMAGON?

FIRMAGON can cause serious side effects, including:

• Serious allergic reactions. Get medical help right away if you get any of these symptoms:
  • trouble breathing or wheezing
  • severe itching
  • swelling of your face, lips, mouth, or tongue
• Disorder of the heart's electrical activity. Your healthcare provider may do tests during treatment with FIRMAGON to check your heart for a condition called long QT syndrome.

The common side effects of FIRMAGON include:

• injection site pain, redness, and swelling
• hot flashes
• weight gain
• increase in some liver enzymes

Other side effects include decreased sex drive and erectile function problems.

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General information about the safe and effective use of FIRMAGON.

Medicines are sometimes prescribed for conditions that are not mentioned in a Patient Information leaflet. Do not use FIRMAGON for a condition for which it was not prescribed. Do not give FIRMAGON to other people, even if they have the same symptoms that you have. It may harm them.

You can ask your pharmacist or healthcare provider for information about FIRMAGON that is written for health professionals.

What are the ingredients in FIRMAGON?

Active ingredient: degarelix (as acetate)

Inactive ingredient: mannitol