4.1. Therapeutic indications

FIRMAGON is a gonadotrophin releasing hormone (GnRH) antagonist indicated:

- for treatment of adult male patients with advanced hormone-dependent prostate cancer.

- for treatment of high-risk localised and locally advanced hormone dependent prostate cancer in combination with radiotherapy.

- as neo-adjuvant treatment prior to radiotherapy in patients with high-risk localised or locally advanced hormone dependent prostate cancer.

4.2. Posology and method of administration

Posology

Starting dose

Maintenance dose – monthly administration

240 mg administered as two consecutive subcutaneous injections of 120 mg each

80 mg administered as one subcutaneous injection

The first maintenance dose should be given one month after the starting dose.

FIRMAGON may be used as neo-adjuvant or adjuvant therapy in combination with radiotherapy in high-risk localised and locally advanced prostate cancer.

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

FIRMAGON must be reconstituted prior to administration. For instructions on reconstitution and 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.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.

4.4. Special warnings and precautions for use

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.

4.5. Interaction with other medicinal products and other forms of interaction

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.

4.6. Fertility, pregnancy and lactation

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.

4.7. Effects on ability to drive and use machines

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.

4.8. Undesirable effects

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.

Table 1: Frequency of adverse drug reactions reported in 1,259 patients treated for a total of 1781 patient years (phase II and III studies) and from post-marketing reports

MedDRA System Organ Class (SOC)

Very common

Common

Uncommon

Rare

Blood and lymphatic system disorders

Anaemia*

Neutropenic fever

Immune system disorders

Hypersensitivity

Anaphylactic reactions

Metabolism and nutrition disorders

Weight increase*

Hyperglycemia/Diabetes mellitus, cholesterol increased, weight decreased, appetite decreased, changes in blood calcium

Psychiatric disorders

Insomnia

Depression, libido decreased*

Nervous system disorders

Dizziness, headache

Mental impairment, hypoaesthesia

Eye disorders

Vision blurred

Cardiac disorders

Cardiac arrhythmia (incl. atrial fibrillation), palpitations, QT prolongation*(see sections 4.4 and 4.5)

Myocardial infarction, cardiac failure

Vascular disorders

Hot flush*

Hypertension, vasovagal reaction (incl. hypotension)

Respiratory, thoracic and mediastinal disorders

Dyspnoea

Gastrointestinal disorders

Diarrhoea, nausea

Constipation, vomiting, abdominal pain, abdominal discomfort, dry mouth

Hepatobiliary disorders

Liver transaminases increased

Bilirubin increased, alkaline phosphatase increased

Skin and subcutaneous tissue disorders

Hyperhidrosis (incl. night sweats)* , rash

Urticaria, skin nodule, alopecia, pruritus, erythema

Musculoskeletal, connective tissue and bone disorders

Musculoskeletal pain and discomfort

Osteoporosis/osteopenia, arthralgia, muscular weakness, muscle spasms, joint swelling/stiffness

Rhabdomyolysis

Renal and urinary disorders

Pollakiuria, micturition urgency, dysuria, nocturia, renal impairment, incontinence

Reproductive system and breast disorders

Gynaecomastia*, testicular atrophy*, erectile dysfunction*

Testicular pain, breast pain, pelvic pain, genital irritation, ejaculation failure

General disorders and administration site conditions

Injection site adverse reactions

Chills, pyrexia, fatigue*, Influenza-like illness

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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, website: www.mhra.gov.uk/yellowcard.

4.9. Overdose

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.