FIRMAGON is a gonadotrophin releasing hormone (GnRH) antagonist indicated for treatment of adult male patients with advanced hormone-dependent prostate cancer.

Posology

The first maintenance dose should be given one month after the starting dose.
The therapeutic effect of degarelix should be monitored by clinical parameters and prostate specific antigen (PSA) serum levels. Clinical studies have shown that testosterone (T) suppression occurs immediately after administration of the starting dose with 96% of the patients having serum testosterone levels corresponding to medical castration (T≤0.5 ng/ml) after three days and 100% after one month. Long term treatment with the maintenance dose up to 1 year shows that 97% of the patients have sustained suppressed testosterone levels (T≤0.5 ng/ml).
In case the patient's clinical response appears to be sub-optimal, it should be confirmed that serum testosterone levels are remaining sufficiently suppressed.Since degarelix does not induce a testosterone surge it is not necessary to add an anti-androgen as surge protection at initiation of therapy.

Special populations

Elderly, hepatically or renally impaired patients:
There is no need to adjust the dose for the elderly or in patients with mild or moderate liver or kidney function impairment (see section 5.2). Patients with severe liver or kidney impairment have not been studied and caution is therefore warranted (see section 4.4).
Paediatric population
There is no relevant use of FIRMAGON in children and adolescents in the treatment of adult male patients with advanced hormone-dependent prostate cancer.

Method of administration

administration, please see section 6.6.
FIRMAGON is for subcutaneous use ONLY, not to be administered intravenously.
Intramuscular administration is not recommended as it has not been studied.
FIRMAGON is administered as a subcutaneous injection in the abdominal region. The injection site should vary periodically. Injections should be given in areas where the patient will not be exposed to pressure e.g. not close to waistband or belt and not close to the ribs.

Effect on QT/QTc interval
Long-term androgen deprivation therapy may prolong the QT interval. In the confirmatory study comparing FIRMAGON to leuprorelin periodic (monthly) electrocardiograms (ECGs) were performed; both therapies showed QT/QTc intervals exceeding 450 msec in approximately 20% of the patients, and 500 msec in 1% and 2% of the degarelix and leuprorelin patients, respectively (see section 5.1).
FIRMAGON has not been studied in patients with a history of a corrected QT interval over 450 msec, in patients with a history of or risk factors for torsades de pointes and in patients receiving concomitant medicinal products that might prolong the QT interval. Therefore in such patients, the benefit/risk ratio of FIRMAGON must be thoroughly appraised (see sections 4.5 and 4.8).
A thorough QT study showed that there was no intrinsic effect of degarelix on QT/QTc interval (see section 4.8).

Hepatic impairment
Patients with known or suspected hepatic disorder have not been included in long-term clinical trials with degarelix. Mild, transient increases in ALT and AST have been seen, these were not accompanied by a rise in bilirubin or clinical symptoms. Monitoring of liver function in patients with known or suspected hepatic disorder is advised during treatment. The pharmacokinetics of degarelix has been investigated after single intravenous administration in subjects with mild to moderate hepatic impairment (see section 5.2).

Renal impairment
Degarelix has not been studied in patients with severe renal impairment and caution is therefore warranted.

Hypersensitivity
Degarelix has not been studied in patients with a history of severe untreated asthma, anaphylactic reactions or severe urticaria or angioedema.

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 testosterone suppression in men will have effects on bone density. Bone density has not been measured during treatment with degarelix

Glucose tolerance
A reduction in glucose tolerance has been observed in men who have had orchiectomy or who have been treated with a GnRH agonist. Development or aggravation of diabetes may occur; therefore diabetic patients may require more frequent monitoring of blood glucose when receiving androgen deprivation therapy. The effect of degarelix on insulin and glucose levels has not been studied.

Cardiovascular disease
Cardiovascular disease such as stroke and myocardial infarction has been reported in the medical literature in patients with androgen deprivation therapy. Therefore, all cardiovascular risk factors should be taken into account.

No formal drug-drug interaction studies have been performed.

Since androgen deprivation treatment may prolong the QTc interval, the concomitant use of degarelix with medicinal products known to prolong the QTc interval or medicinal products able to induce torsades de pointes such as class IA (e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicinal products, methadone, moxifloxacin, antipsychotics, etc. should be carefully evaluated (see section 4.4).

Degarelix is not a substrate for the human CYP450 system and has not been shown to induce or inhibit CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4/5 to any great extent in vitro. Therefore, clinically significant pharmacokinetic drug-drug interactions in metabolism related to these isoenzymes are unlikely.

Pregnancy and breast-feeding
There is no relevant indication for use of FIRMAGON in women.
Fertility
FIRMAGON may inhibit male fertility as long as the testosterone is suppressed.

FIRMAGON has no or negligible influence on the ability to drive and use machines. Fatigue and dizziness are common adverse reactions that might influence the ability to drive and use machines.

Summary of the safety profile
The most commonly observed adverse reactions during degarelix therapy in the confirmatory phase III study (N=409) were due to the expected physiological effects of testosterone suppression, including hot flushes and weight increase (reported in 25% and 7%, respectively, of patients receiving treatment for one year), or injection site adverse reactions. Transient chills, fever or influenza like illness were reported to occur hours after dosing (in 3%, 2% and 1% of patients, respectively).
The injection site adverse reactions reported were mainly pain and erythema, reported in 28% and 17% of patients, respectively, less frequently reported were swelling (6%), induration (4%) and nodule (3%). These events occurred primarily with the starting dose whereas during maintenance therapy with the 80 mg dose, the incidence of these events pr 100 injections was: 3 for pain and <1 for erythema, swelling, nodule and induration. The reported events were mostly transient, of mild to moderate intensity and led to very few discontinuations (<1%). Serious injection site reactions were very rarely reported such as injection site infection, injection site abscess or injection site necrosis that could require surgical treatment/drainage.

Tabulated list of adverse reactions
The frequency of undesirable effects listed below is defined using the following convention:
Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to <1/1,000) and very rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Blood and lymphatic system disorders:
Common: Anaemia*. Rare: Neutropenic fever

Immune system disorders:
Uncommon: Hypersensitivity. Rare: Anaphylactic reactions

Metabolism and nutrition disorders:
Common: Weight increase*.
Uncommon: Hyperglycemia/Diabetes mellitus, cholesterol increased, weight decreased, appetite decreased, changes in blood calcium.

Psychiatric disorders:
Common: Insomnia. Uncommon: Depression, libido decreased*.

Nervous system disorders:
Common: Dizziness, headache. Uncommon: Mental impairment, hypoaesthesia,

Eye disorders:
Uncommon: Vision blurred

Cardiac disorders:
Uncommon: Cardiac arrhythmia (incl. atrial fibrillation), palpitations, QT prolongation Rare: Myocardial infarction , cardiac failure

Vascular disorders:
Very Common: Hot flush. Uncommon: Hypertension, vasovagal reaction (incl. Hypotension)

Respiratory, thoracic and mediastinal disorders:

Uncommon: Dyspnoea

Gastrointestinal disorders:
Common: Diarrhoea, nausea. Uncommon: Constipation, vomiting, abdominal pain, abdominal discomfort, dry mouth

Hepatobiliary disorders:
Common: Liver transaminases increased.Uncommon: Bilirubin increased, alkaline phosphatase increased

Skin and subcutaneous tissue disorders:
Common: Hyperhidrosis (incl. night sweats)*, rash. Uncommon: Urticaria, skin nodule, alopecia, pruritus, erythema

Musculoskeletal, connective tissue and bone disorders:
Common: Musculoskeletal pain and discomfort. Uncommon: Osteoporosis/osteopenia, arthralgia muscular weakness, muscle spasms, joint swelling/stiffness
Rare: Rhabdomyolysis

Renal and urinary disorders:
Uncommon: Pollakiuria, micturition urgency, dysuria, nocturia, renal impairment, incontinence,

Reproductive system and breast disorders:
Common: Gynaecomastia*, testicular atrophy*, erectile dysfunction*. Uncommon: Testicular pain, breast pain, pelvic pain, genital irritation, ejaculation failure

General disorders and administration site conditions:
Very Common: Injection site adverse reactions. Common: Chills, pyrexia, fatigue*, Influenza-like illness.
Uncommon: Malaise, peripheral oedema.

*Known physiological consequence of testosterone suppression

Description of selected adverse reactions
Changes in laboratory parameters
Changes in laboratory values seen during one year of treatment in the confirmatory phase III study (N=409) were in the same range for degarelix and a GnRH-agonist (leuprorelin) used as comparator. Markedly abnormal (>3*ULN) liver transaminase values (ALT, AST and GGT) were seen in 2-6% of patients with normal values prior to treatment, following treatment with both medicinal products. Marked decrease in haematological values, hematocrit (≤0.37) and hemoglobin (≤115 g/l) were seen in 40% and 13-15%, respectively, of patients with normal values prior to treatment, following treatment with both medicinal products. It is unknown to what extent this decrease in haematological values was caused by the underlying prostate cancer and to what extent it was a consequence of androgen deprivation therapy. Markedly abnormal values of potassium (≥5.8 mmol/l), creatinine (≥177 μmol/l) and BUN (≥10.7 mmol/l) in patients with normal values prior to treatment, were seen in 6%, 2% and 15% of degarelix treated patients and 3%, 2% and 14% of leuprorelin treated patients, respectively.
Changes in ECG measurements
Changes in ECG measurements seen during one year of treatment in the confirmatory phase III study (N=409) were in the same range for degarelix and a GnRH-agonist (leuprorelin) used as comparator. Three (<1%) out of 409 patients in the degarelix group and four (2%) out of 201 patients in the leuprorelin 7.5 mg group, had a QTcF ≥ 500 msec. From baseline to end of study the median change in QTcF for degarelix was 12.0 msec and for leuprorelin was 16.7 msec The lack of intrinsic effect of degarelix on cardiac repolarisation (QTcF), heart rate, AV conduction, cardiac
depolarisation, or T or U wave morphology was confirmed in a thorough QT study in healthy subjects
(N=80) receiving an i.v. infusion of degarelix over 60 min, reaching a mean Cmax of 222 ng/mL, approx. 3-4-
fold the Cmax obtained during prostate cancer treatment.

There is no clinical experience with the effects of an acute overdose with degarelix. In the event of an
overdose the patient should be monitored and appropriate supportive treatment should be given, if considered
necessary.

Pharmacotherapeutic group: Endocrine therapy, Other hormone antagonists and related agents,

ATC code:
L02BX02
Mechanism of action
Degarelix is a selective gonadotrophin releasing-hormone (GnRH) antagonist that competitively and
reversibly binds to the pituitary GnRH receptors, thereby rapidly reducing the release of the gonadotrophins,
luteinizing hormone (LH) and follicle stimulating hormone (FSH), and thereby reducing the secretion of
testosterone (T) by the testes. Prostatic carcinoma is known to be androgen sensitive and responds to
treatment that removes the source of androgen. Unlike GnRH agonists, GnRH antagonists do not induce a
LH surge with subsequent testosterone surge/tumour stimulation and potential symptomatic flare after the
initiation of treatment.
A single dose of 240 mg degarelix, followed by a monthly maintenance dose of 80 mg, rapidly causes a
decrease in the concentrations of LH, FSH and subsequently testosterone. The serum concentration of
dihydrotestosterone (DHT) decreases in a similar manner to testosterone.
Degarelix is effective in achieving and maintaining testosterone suppression well below medical castration
level of 0.5 ng/ml. Maintenance monthly dosing of 80 mg resulted in sustained testosterone suppression in
97% of patients for at least one year. No testosterone microsurges were observed after re-injection during
degarelix treatment. Median testosterone levels after one year of treatment were 0.087 ng/ml (interquartile
range 0.06-0.15) N=167.

Results of the confirmatory Phase III study
The efficacy and safety of degarelix was evaluated in an open-label, multi-centre, randomised, active
comparator controlled, parallel-group study. The study investigated the efficacy and safety of two different
degarelix monthly dosing regimens with a starting dose of 240 mg (40 mg/ml) followed by monthly doses 7
subcutaneous administration of 160 mg (40 mg/ml) or 80 mg (20 mg/ml), in comparison to monthly intramuscular administration of 7.5 mg leuprorelin in patients with prostate cancer requiring androgen deprivation therapy. In total 620 patients were randomised to one of the three treatment groups, of which 504 (81%) patients 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 leuprorelin group.
Of the 610 patients treated
• 31% had localised prostate cancer
• 29% had locally advanced prostate cancer
• 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 arms. The median age was 74 years (range 47 to 98 years). The primary objective was to demonstrate that degarelix is effective with respect to achieving and maintaining testosterone suppression to below 0.5 ng/ml, during 12 months of treatment.
The lowest effective maintenance dose of 80 mg degarelix was chosen.

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.

Avoidance of testosterone surge
Surge was defined as testosterone exceeding baseline by ≥15% within the first 2 weeks.
None of the degarelix-treated patients experienced a testosterone surge; there was an average decrease of 94% in testosterone at day 3. Most of the leuprorelin-treated patients experienced testosterone surge; there was an average increase of 65% in testosterone at day 3. This difference was statistically significant (p<0.001).
The primary end-point in the study was testosterone suppression rates after one year of treatment with degarelix or leuprorelin. The clinical benefit for degarelix compared o leuprorelin plus anti-androgen in the initial phase of treatment has not been demonstrated.
Testosterone reversibility
In a study involving patients with rising PSA after localised therapy (mainly radical prostatectomy and radiation) were administered FIRMAGON for seven months followed by a seven months monitoring period. The median time to testosterone recovery (>0.5 ng/mL, above castrate level) after discontinuation of treatment was 112 days (counted from start of monitoring period, i.e 28 days after last injection). The median time to testosterone >1.5 ng/mL (above lower limit of normal range) was 168 days.
Long‑term effect
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.

* Kaplan Meier estimates within group

Attainment of prostate specific antigen (PSA) reduction:
Tumour size was not measured directly during the clinical trial programme, but there was an indirect beneficial tumour response as shown by a 95% reduction after 12 months in median PSA for degarelix.
The median PSA in the study at baseline was:
• for the degarelix 240/80 mg treatment group 19.8 ng/ml (interquartile range: P25 9.4 ng/ml, P75 46.4 ng/ml)
• for the leuprorelin 7.5 mg treatment group 17.4 ng/ml (interquartile range: P25 8.4 ng/ml, P75 56.5 ng/ml)
This difference was statistically significant (p<0.001) for the pre-specified analysis at day 14 and day 28.
Prostate specific antigen (PSA) levels are lowered by 64% two weeks after administration of degarelix, 85% after one month, 95% after three months, and remained suppressed (approximately 97%) throughout the one year of treatment.
From day 56 to day 364 there were no significant differences between degarelix and the comparator in the percentage change from baseline.

Effect on prostate volume
Three months therapy with degarelix (240/80 mg dose regimen) resulted in a 37% reduction in prostate volume as measured by trans-rectal ultrasound scan (TRUS) in patients requiring hormonal therapy prior to radiotherapy and in patients who were candidates for medical castration. The prostate volume reduction was similar to that attained with goserelin plus anti-androgen protection.

Effect on the QT/QTc intervals
In the confirmatory study comparing FIRMAGON to leuprorelin periodic electrocardiograms were performed. Both therapies showed QT/QTc intervals exceeding 450 msec in approximately 20% of the patients. From baseline to end of study the median change for FIRMAGON was 12.0 msec and for leuprorelin it was 16.7 msec.
Anti-degarelix antibody
Anti-degarelix antibody development has been observed in 10% of patients after treatment with FIRMAGON for one year and 29% of patients after treatment with FIRMAGON for up to 5.5 years. There is no indication that the efficacy or safety of FIRMAGON treatment is affected by antibody formation after up to 5.5 years of treatment.
Pediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with FIRMAGON in all subsets of the paediatric population (see section 4.2 for information on paediatric use).

Absorption
Following subcutaneous administration of 240 mg degarelix at a concentration of 40 mg/ml to prostate cancer patients in the pivotal study CS21, AUC0-28 days was 635 (602-668) day*ng/ml, Cmax was 66.0 (61.0-71.0) ng/ml and occurred at tmax at 40 (37-42) hours. Mean trough values were approximately 11-12 ng/ml after the starting dose and 11-16 ng/ml after maintenance dosing of 80 mg at a concentration of 20 mg/ml. Cmax degarelix plasma concentration decreases in a biphasic fashion, with a mean terminal half-life (t½) of 29 days for the maintenance dose. The long half-life after subcutaneous administration is a consequence of a very slow release of degarelix from the depot formed at the injection site(s). The pharmacokinetic behavior of the medicinal product is influenced by its concentration in the solution for injection. Thus, Cmax and bioavailability tend to decrease with increasing dose concentration while the half-life is increased. Therefore, no other dose concentrations than the recommended should be used.
Distribution:

The distribution volume in healthy elderly men is approximately 1 l/kg. Plasma protein binding is estimated to be approximately 90%.

Biotransformation:

Degarelix is subject to common peptidic degradation during the passage of the hepato-biliary system and is mainly excreted as peptide fragments in the faeces. No significant metabolites were detected in plasma samples after subcutaneous administration. In vitro studies have shown that degarelix is not a substrate for the human CYP450 system.

Elimination:

In healthy men, approximately 20-30% of a single intravenously administered dose is excreted in the urine, suggesting that 70-80% is excreted via the hepato-biliary system. The clearance of degarelix when administered as single intravenous doses (0.864-49.4 μg/kg) in healthy elderly men was found to be 35-50 ml/h/kg.

Special populations

Patients with renal impairment
No pharmacokinetic studies in renally impaired patients have been conducted. Only about 20-30% of a given dose of degarelix is excreted unchanged by the kidneys. A population pharmacokinetics analysis of the data from the confirmatory Phase III study has demonstrated that the clearance of degarelix in patients with mild to moderate renal impairment is reduced by approximately 23%; therefore, dose adjustment in patients with mild or moderate renal impairment is not recommended. Data on patients with severe renal impairment is scarce and caution is therefore warranted in this patient population.
Patients with hepatic impairment
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.

N/A

Powder: Mannitol (E421).
Solvent: Water for injections.

In the absence of compatibility studies,this medicinal product must not be mixed with other medicinal products.

Store below 30ºC.
For storage conditions of the reconstituted medicinal product, see section 6.3.

FIRMAGON 80 mg powder and solvent for solution for injection
Glass (type I) vial with bromobutyl rubber stopper and aluminium flip-off seal containing 80 mg powder for solution for injection.
Pre-filled glass (type I) syringe with elastomer plunger stopper, tip cap and line-marking at 4 ml containing 4.2 ml solvent.
Plunger rod.
Vial adapter.
Injection needle (25G 0.5 x 25 mm).
FIRMAGON 120 mg powder and solvent for solution for injection
Glass (type I) vial with bromobutyl rubber stopper and aluminium flip-off seal containing 120 mg powder for solution for injection.
Pre-filled glass (type I) syringe with elastomer plunger stopper, tip cap and line-marking at 3 ml containing 3 ml solvent.
Plunger rods.
Vial adapters.
Injection needles (25G 0.5 x 25 mm).

Pack sizes
FIRMAGON 80 mg powder and solvent for solution for injection
Pack-size of 1 tray containing 1 powder vial, 1 solvent pre-filled syringe, 1 plunger rod, 1 vial adapter and 1 needle.Pack-size of 3 trays containing 3 powder vials, 3 solvent pre-filled syringes, 3 plunger rods, 3 vial adapters and 3 needles.

FIRMAGON 120 mg powder and solvent for solution for injection
Pack-size of 2 trays containing 2 powder vials, 2 solvent pre-filled syringes, 2 plunger rods, 2 vial adapters and 2 needles.
Not all pack sizes may be marketed.

The instructions for reconstitution must be followed carefully.
Administration of other concentrations is not recommended because the gel depot formation is influenced by the concentration. The reconstituted solution should be a clear liquid, free of undissolved matter.
NOTE: THE VIALS SHOULD NOT BE SHAKEN
The pack contains one vial of powder and one pre-filled syringe with solvent that must be prepared for subcutaneous injection.

No special requirements for disposal.
Prescription only.