FIRMAGON 80 mg powder and solvent for solution for injection

Each vial contains 80 mg degarelix (as acetate). After reconstitution, each ml of solution contains 20 mg of degarelix.

For a full list of excipients, see section 6.1.

Powder and solvent for solution for injection (Powder for injection and solvent)

Powder: White to off-white powder

Solvent: Clear, colourless solution

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 plasma testosterone levels corresponding to medical castration (T0.5 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 (T0.5 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.

Method of administration

FIRMAGON must be reconstituted prior to administration. For instructions on reconstitution and administration, please see section 6.6.

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. As with other medicinal products administered by subcutaneous injection, 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.

Special patient 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).

There is no relevant indication for use of FIRMAGON in women, children and adolescents.

Hypersensitivity to the active substance or to any of the excipients.

The data available on efficacy and safety experience with degarelix is limited to a one year treatment.

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) 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).

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.

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, cisapride, moxifloxacine, antipsychotics, etc. should be carefully eva luated (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.

There is no relevant indication for use of FIRMAGON in women.

No studies on the effects of degarelix on the ability to drive and use machines have been performed. However, fatigue and dizziness are common adverse reactions that might influence the ability to drive and use machines.

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 events. 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 events 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%).

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). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 1: Frequency of adverse drug reactions reported in 1259 patients treated for a total of 1781 patient years (phase II and III studies).

*Known physiological consequence of testosterone suppression

The following events have been reported as being related to treatment in single patients: Febrile neutropenia, myocardial infarction and congestive heart failure.

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.

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: Other hormone antagonists and related agents, ATC code: L02BX02

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 plasma 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. 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 eva luated 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 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 T0.5 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).

Figure 1: Percentage change in testosterone from baseline by treatment group until day 28 (median with interquartile ranges).

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 to leuprorelin plus anti-androgen in the initial phase of treatment has not been demonstrated.

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.

Table 3: Cumulative probability of testosterone 0.5 ng/ml from Day 28 to Day 364.

* 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)

Figure 2: Percentage change in PSA from baseline by treatment group until day 56 (median with interquartile ranges).

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.

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 development has been observed in 10% of patients after treatment with FIRMAGON for one year. There is no indication that the efficacy or safety of FIRMAGON treatment is affected by antibody formation after one year of treatment. Efficacy and safety data in relation to antibody development beyond one year is not available.

Absorption

Following subcutaneous administration of 240 mg degarelix at a concentration of 40 mg/ml to prostate cancer patients in the pivotal study CS21, AUC_{0-28 days} was 635 (602-668) day*ng/ml, C_max was 66.0 (61.0-71.0) ng/ml and occurred at t_max 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. Degarelix is eliminated 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 modelling. 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, C_max 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%.

Metabolism

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.

Excretion

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.

Animal reproduction studies showed that degarelix caused infertility in male animals. This is due to the pharmacological effect; and the effect was reversible.

In female reproduction toxicity studies degarelix revealed findings expected from the pharmacological properties. It caused a dosage dependent prolongation of the time to mating and to pregnancy, a reduced number of corpora lutea, and an increase in the number of pre- and post-implantation losses, abortions, early embryo/foetal deaths, premature deliveries and in the duration of parturition.

Preclinical studies on safety pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential revealed no special hazard for humans. Both in vitro and in vivo studies showed no signs of QT prolongation.

No target organ toxicity was observed from acute, subacute and chronic toxicity studies in rats and monkeys following subcutaneous administration of degarelix. Drug-related local irritation was noted in animals when degarelix was administered subcutaneously in high doses.

Powder

Mannitol (E421)

Solvent

Water for injections

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

3 years.

After reconstitution

Chemical and physical in-use stability has been demonstrated for 2 hours at 25ºC. From a microbiological point of view, unless the method of reconstitution precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.

This medicinal product does not require any special storage conditions.

For storage conditions of the reconstituted medicinal product, see section 6.3.

Vials of glass Type I with bromobutyl rubber stopper and aluminium flip-off seal.

1 vial containing 80 mg powder for solution for injection

1 vial containing 6 ml solvent

1 syringe (5 ml with dual-line marking 4.0 and 4.2 ml)

2 vial adapters

1 injection needle (25G 0.5 x 25 mm)

Pack sizes

1 pack containing 1 powder vial, 1 solvent vial, 1 syringe, 2 vial adapters and 1 needle.

3 pack containing 3x (1 powder vial, 1 solvent vial, 1 syringe, 2 vial adapters and 1 needle).

Not all pack sizes may be marketed.

No special requirements for disposal.

Instructions for use:

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 1 set of powder and solvent that must be prepared for subcutaneous injection.

Please be aware:

• No injections should be given in areas where the patient will be exposed to pressure, e.g. around the belt or waistband or close to the ribs.

* Chemical and physical in-use stability has been demonstrated for 2 hours at 25ºC. From a microbiological point of view, unless the method of reconstitution precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.

Ferring Pharmaceuticals A/S

Kay Fiskers Plads 11

DK-2300 Copenhagen S

Denmark

Tel: +45 88 33 88 34

EU/1/08/504/001

EU/1/08/504/003

17/02/2009

{18/06/2010}

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu/.