Firmagon - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology.
  • Россия
  • Украина

Firmagon - Scientific Information

Manufacture: Ferring Pharmaceuticals
Country: Canada
Condition: Prostate Cancer
Class: Gonadotropin-releasing hormone antagonists, Hormones/antineoplastics
Form: Subcutaneous (SC), Powder
Ingredients: Degarelix acetate, mannitol, Prefilled Syringe (sterile water for injectionUSP).

Pharmaceutical Information

Drug Substance

The drug substance is manufactured as its acetate salt by freeze-drying from solutions containing acetic acid. The freeze-dried powder also contains variable amounts of acetic acid (not as a counter ion) and water (not as crystal water) not fully removed in the freeze-drying process. The free base content of the drug substance in the freeze-dried powder is always used for dose calculations since the freeze-drying process gives variations in the content of acetic acid and water. Therefore the drug substance is presented as its free base below.

Common name: Degarelix acetate (degarelix is the free base of the drug substance)
Chemical name: D-Alaninamide, N-acetyl-3-(2-naphthalenyl)-D-alanyl-4-chloro-Dphenylalanyl-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-N6-(1-methylethyl)-Llysyl-L-prolyl
Molecular formula: C82H103N18O16Cl
Molecular mass: 1632.3 Da.
Structural formula:

Physicochemical properties:
Solubility: Degarelix acetate is soluble in water and in aqueous solution containing 5% mannitol.
pKa: Experimental pKa values for degarelix are 10.8 (side-chain of Lys(iPr)), 10.2(hydroorotyl) and 4.4 (side-chain of D-3Pal).
pH: The pH value of 20 mg degarelix/mL in 2.5% mannitol (w/v) at 20°C is approximately 4.

Clinical Trials

Study Demographics and Trial Design

Table 1: Summary of patient demographics for clinical trials in patients with prostate cancer
Study Trial design Dosage, route of administration and duration Study subjects (N=number of patients) Age Gender
Phase III Study Open-label, randomised, active-control parallel group study degarelix s.c.: N=610

degarelix N=409
Male patients with prostate cancer
starting dose 240 mg (40mg/mL) followed by a degarelix 240/160 mg: N =202 degarelix 240/160 mg:
Mean (SD):
72.1 (8.47)
Median (range)
72.0 (50.0-88.0)
monthly maintenance dose of 80mg (20 mg/mL) or 160 mg (40 mg/mL) degarelix 240/80 mg: N=207 degarelix 240/80 mg:
Mean (SD):
71.6 (8.12)
Median (range)
72.0 (51.0-89.0)
leuprolide 7.5 mg i.m. monthly leuprolide 7.5 mg: N=201 leuprolide 7.5 mg:
Mean (SD):
72.5 (8.77)
Median (range)
74.0 (52.0-98.0)

Study Results

The efficacy and safety of FIRMAGON was evaluated in an open-label, multi-centre, randomized, active comparator, parallel-group study. The study investigated the efficacy and safety of two different degarelix monthly dosing regimens; a starting dose of 240 mg (40 mg/mL) followed by monthly doses via subcutaneous administration of 160 mg (40 mg/mL) or 80 mg (20mg/mL) in comparison to monthly intramuscular administration of leuprolide 7.5 mg in patients with prostate cancer requiring androgen deprivation therapy. In total, 620 patients were randomized to one of the three treatment groups, 610 received investigational medicinal product treatment, and 504 (81%) completed the study. In the degarelix 240/80 mg treatment group, 41 (20%) patients discontinued the study as compared to 32 (16%) patients in the leuprolide group. The primary objective of the study was to demonstrate that degarelix is effective with respect to achieving and maintaining testosterone suppression to castrate levels, evaluated as the proportion of patients with testosterone suppression ≤0.5 ng/mL during 12 months treatment. The lowest effective maintenance dose of 80 mg was chosen.

Of the 610 patients treated:

  • 31% had localized prostate cancer (T1 or T2 N0 M0)
  • 29% had locally advanced prostate cancer (T3/T4 Nx M0 or N1 M0)
  • 20 % had metastatic prostate cancer
  • 7% had an unknown metastatic status
  • 13% had previous curative intent surgery or radiation and a rising PSA

Baseline demographics were similar between the treatment arms. The median age was 74 years and the age range was 47 to 98 years of age. The ethnic/racial distribution was 84% white, 6% black and 10% other.

Attainment of Serum Testosterone (T) ≤0.5 ng/mL

FIRMAGON is effective in achieving fast testosterone suppression; see Table 2

Table 2: Percentage of patients attaining T≤0.5 ng/mL after start of treatment
Time Degarelix 240/80 mg s.c. Leuprolide 7.5 mg i.m.
Day 1 52% 0%
Day 3 96% 0%
Day 7 99% 1%
Day 14 100% 18%
Day 28 100% 100%

Avoidance of Testosterone Surge

None of the degarelix treated patients experienced a testosterone surge; there was an average decrease of 96% in testosterone at day 3. Most of the leuprolide treated patients experienced testosterone surge; there was an average increase of 65% in testosterone at day 3. Surge was defined as testosterone exceeding baseline by ≥15% within the first 2 weeks. This difference was statistically significant (p<0.001). The clinical benefit for degarelix compared to leuprolide plus antiandrogen for surge protection in the initial phase of treatment has not been demonstrated.

Figure 2: Percentage Change in Testosterone from Day 0 to 28 (median with interquartile ranges)

Long-Term Testosterone Suppression

Successful response in the study was defined as attainment of medical castration at day 28 and maintenance through day 364 where no single testosterone concentration was greater than 0.5 ng/mL.

Table 3: Cumulative Probability of Testosterone ≤0.5 ng/mL from Day 28 to Day 364
240/80 mg
N =207
7.5 mg
No. of responders 202 194
Response Rate (confidence intervals)* 97.2%
(93.5; 98.8%)
(92.5; 98.2%)

* Kaplan Meier estimates within group

Detailed Pharmacology

Mechanism of Action

Degarelix is a selective GnRH receptor antagonist (blocker) that competitively and reversibly binds to the pituitary GnRH receptors. Degarelix has weak in vitro histamine-releasing activity (effective concentration 50% (EC50) = 170 mg/mL) and its effects on vascular permeability in vivo are very low.

The suppression of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone and estradiol has been demonstrated in rats, dogs, monkeys and humans. It has been shown to suppress tumor growth in several models including androgen–dependent rat prostate tumor Dunning R-3327 and nude mice xenografts of human PAC 120 prostate cancer.

Unlike GnRH agonists, GnRH antagonists do not induce an LH surge with subsequent testosterone surge and potential symptomatic flare after the initiation of treatment.


Degarelix rapidly and reversibly suppresses secretion of gonadotropins, thereby achieving a rapid and sustained suppression of testosterone. This is achieved by the starting dose of FIRMAGON 240 mg followed by a monthly maintenance dose of 80 mg as shown in the pivotal clinical trial.

When injected s.c. at doses 0.3-10 µg/kg, degarelix produced a dose-dependent suppression of plasma testosterone in rats. The minimum effective dose was 1µg/kg, producing 71% suppression of plasma testosterone.

When compared to abarelix, ganirelix, and azaline B, a single s.c. injection of 2 mg/kg degarelix showed a longer duration of action than the other GnRH antagonists, given at a similar dose and concentration. All antagonists decreased plasma testosterone to similar levels at Day 1, but by Day 7 plasma testosterone in the abarelix- and ganirelix-treated groups were already returning to baseline, while in the azaline B-treated groups only three out of eight rats had castrate levels of plasma testosterone at Day 14. In contrast, degarelix suppressed testosterone to castration levels for a total of 42 days in all rats and 56 days in seven out of eight rats, at which time plasma testosterone levels began to increase gradually, returning to baseline levels at Day 77.



After s.c. administration FIRMAGON forms a local depot at the injection site from which degarelix is released to the circulation. Degarelix decreases in a biphasic fashion, with a median terminal half-life (t ½) of approximately 43 days for the starting dose, or 28 days for the maintenance dose, as estimated based on population pharmacokinetics modeling. The long t1/2 observed after s.c. administration, compared to i.v. administration is due to the slow release of degarelix from the depot.

Studies in mice, rats and dogs have demonstrated that increasing the concentration of the dosing solution resulted in increase of time to maximum plasma concentration (tmax) and t1/2, but decrease of maximum plasma concentration (Cmax) and bioavailability.


The distribution volume of degarelix after i.v. administration is approximately 1 L/kg in healthy elderly men. This indicates that degarelix is distributed throughout total body water. Distribution of [3H] degarelix in rats, dogs and monkeys demonstrated highest concentration in tissues related to hepatic and renal excretion (i.e. liver, bile, intestines, kidneys), organs containing specific receptors for LHRH (e.g., pituitary) and organs rich in reticuloendothelial cells (e.g., aorta, and vena cava.

In vitro, degarelix is bound to plasma proteins (90%) in animals and man with a high affinity for albumin and α-acid glycoprotein.

Metabolism and Excretion

In vitro studies have demonstrated that there is negligible degradation of degarelix in human plasma, and when incubated with liver microsomes (rabbit, dog, monkey and human). Only minor degradation was seen in liver microsomes from guinea pig and rat. Degarelix is a poor substrate for the cytochrome P450 (CYP450) enzyme system. Degarelix has not been shown to induce or inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4/5 to any great extent in vitro. In human liver microsomes, the total amount of oxidative metabolites formed was <1%. The main metabolite (approximately 2% of initial amount of degarelix) was not oxidative and probably formed by proteases, post-proline cleaving enzyme.

Degarelix is subject to proteolysis by endopeptidases and unchanged degarelix and metabolites are fully excreted via the hepatic and urinary pathways. Systemic exposure to any metabolic products appears to be very low.

Studies in rats and dogs have shown that degarelix is excreted, both as unchanged degarelix and degarelix metabolites, via the kidneys and bile.

Special Populations and Conditions

Hepatic Insufficiency

Degarelix has been investigated in a pharmacokinetic study in patients with mild to moderate hepatic impairment. No signs of increased exposure in the hepatically impaired subjects were observed compared to healthy subjects. Dose adjustment is not necessary in patients with mild or moderate hepatic impairment. Patients with severe hepatic dysfunction have not been studied and caution is therefore warranted in this group.

Renal Insufficiency

No pharmacokinetic studies in renally impaired patients have been conducted. Approximately 20-30% of a given dose of degarelix is excreted unchanged in the urine. A population pharmacokinetics analysis of the data from the confirmatory Phase III study has demonstrated that the clearance of degarelix in patients with moderate CrCL <50 mL/min renal impairment is reduced by 23% therefore dose adjustment in patients with mild or moderate renal impairment is not recommended. Data on patients with severe renal impairment are scarce and caution is therefore warranted in this patient category.


Single Dose Toxicity

Subcutaneous Administration

Administration of a single subcutaneous dose showed that degarelix was well tolerated and no acute signs of systemic toxicity were seen at the highest dose level tested in single or repeat dose toxicity studies: 100 mg/kg in mice, 100 mg/kg in rats and 50 mg/kg in monkeys.

In a tolerance study in dogs, clinical signs (e.g. s.c. edema) consistent with a histamine reaction were noted following three consecutive daily s.c. doses of 20 mg/kg and higher.

Intravenous Administration

The lowest lethal dose seen after a single i.v. dose in single or repeat dose studies was 12.5 mg/kg in rats. Signs of systemic toxicity in surviving animals were abnormal respiration and lethargy which resolved within 24 hours. No deaths occurred up to and including 6.25 mg/kg. In monkeys there were no deaths following single i.v. doses of up to 6.25 mg/kg/day for 7 days.

Repeat Dose Toxicity

Subcutaneous Administration

Repeat-dose toxicity studies were carried out by s.c. administration with durations of 6 and 12 months in rats and monkeys. A 13 week subcutaneous toxicity study was carried out in mice. Results of the studies showed that the pharmacological effect was evident at the low dose level tested: 1.0 mg/kg/2 weeks s.c. in mice, 0.5 mg/kg/2 weeks s.c. in rats and 0.5 mg/kg/4 weeks s.c. in monkeys.

The injections caused a dosage-related increase in the local reaction which has occasionally been the reason for premature euthanasia and has caused signs of systemic toxicity (decreased body weight development) at high dose levels of 100 mg/kg/2 week s.c. in the 13 week toxicity study in mice, 50 and 100 mg/kg/2 week s.c. in the 26 week toxicity studies in rats, and 50 mg/kg/4 week s.c. in the 12 month toxicity study in monkeys.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Degarelix was administered subcutaneously to mice every 2 weeks for 2 years at doses of 2, 10 and 50 mg/kg/2 weeks (about 3, 15 and 75 times the recommended human maintenance dose on a mg/kg basis; or about 1, 4.6 and 17 times human exposure at the recommended dose). Sarcomas related to the injection sites were seen in about 3% of the treated animals, which is not considered relevant in humans given the species specific high susceptibility of mice to foreign body carcinogenesis. This is considered to be a rodent specific effect, as rodents are known to be susceptible to foreign body carcinogenesis.

Degarelix was administered subcutaneously to rats every 2 weeks for 2 years at doses of 2, 10 and 25 mg/kg/2 weeks (about 3, 15 and 38 times the recommended human maintenance dose on a mg/kg basis; or about 1.8, 6.2 and 12.4 times human exposure at the recommended dose). The incidence of combined hemangiomas and hemangiosarcomas was increased in female rats treated with the 25 mg/kg/2 week dose.

Degarelix was not mutagenic. Degarelix was embryotoxic. 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 on a mg/m2 basis), 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 on a mg/m2 basis) 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 on a mg/m2 basis), 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 on a mg/m2 basis), there was an increase in the number of minor skeletal abnormalities and variants.

Degarelix produces reversible infertility in both male and female rats. A single subcutaneous dose caused reversible infertility at ≥1 mg/kg and ≥0.1 mg/kg in males and females, respectively.