FIRMAGON 80mg powder + solvent for injection medication leaflet

FIRMAGON 80 mg powder and solvent for solution for injection

FIRMAGON 120 mg powder and solvent for solution for injection

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 ofdegarelix.

FIRMAGON 120 mg powder and solvent for solution for injection

Each vial contains 120 mg degarelix (as acetate). After reconstitution, each ml of solution contains 40 mg ofdegarelix.

For the full list of excipients, see section 6.1.

Powder and solvent for solution for injection

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.

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

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

Starting dose Maintenance dose - monthlyadministration240 mg administered as two consecutive 80 mg administered as one subcutaneoussubcutaneous injections of 120 mg each 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-risklocalised 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 afteradministration of the starting dose with 96% of the patients having serum testosterone levels correspondingto medical castration (T≤0.5 ng/ml) after three days and 100% after one month. Long term treatment with themaintenance 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 serumtestosterone levels are remaining sufficiently suppressed.

Since degarelix does not induce a testosterone surge it is not necessary to add an anti-androgen as surgeprotection at initiation of therapy.

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 kidneyfunction impairment (see section 5.2). Patients with severe liver or kidney impairment have not been studiedand caution is therefore warranted (see section 4.4).

There is no relevant use of FIRMAGON in children and adolescents in the treatment of adult male patientswith advanced hormone-dependent prostate cancer.

FIRMAGON must be reconstituted prior to administration. For instructions on reconstitution andadministration, 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 shouldvary 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.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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; boththerapies showed QT/QTc intervals exceeding 450 msec in approximately 20% of the patients, and 500 msecin 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, inpatients with a history of or risk factors for torsades de pointes and in patients receiving concomitantmedicinal 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 section4.8).

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

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

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

Decreased bone density has been reported in the medical literature in men who have had orchiectomy or whohave been treated with a GnRH agonist. It can be anticipated that long periods of testosterone suppression inmen 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 beentreated with a GnRH agonist. Development or aggravation of diabetes may occur; therefore diabetic patientsmay require more frequent monitoring of blood glucose when receiving androgen deprivation therapy. Theeffect of degarelix on insulin and glucose levels has not been studied.

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

No formal drug-drug interaction studies have been performed.

Since androgen deprivation treatment may prolong the QTc interval, the concomitant use of degarelix withmedicinal products known to prolong the QTc interval or medicinal products able to induce torsades depointes 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 becarefully 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 theseisoenzymes are unlikely.

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

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 dizzinessare 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 flushesand weight increase (reported in 25% and 7%, respectively, of patients receiving treatment for one year), orinjection site adverse reactions. Transient chills, fever or influenza like illness were reported to occur hoursafter 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% ofpatients, respectively, less frequently reported were swelling (6%), induration (4%) and nodule (3%). Theseevents 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 andinduration. The reported events were mostly transient, of mild to moderate intensity and led to very fewdiscontinuations (<1%). Serious injection site reactions were very rarely reported such as injection siteinfection, injection site abscess or injection site necrosis that could require surgical treatment/drainage.

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 inorder of decreasing seriousness.

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

MedDRA Very common Common Uncommon Rare

System Organ

Class (SOC)

Blood and Anaemia* Neutropeniclymphatic feversystem disorders

Immune system Hypersensitivity Anaphylacticdisorders reactions

Metabolism and Weight Hyperglycemia/Diabetesnutrition increase* mellitus, cholesteroldisorders increased, weightdecreased, appetitedecreased, changes in bloodcalcium

Psychiatric Insomnia Depression, libidodisorders decreased*

Nervous system Dizziness, Mental impairment,disorders headache hypoaesthesia

Eye disorders Vision blurred

Cardiac Cardiac arrhythmia (incl. Myocardialdisorders atrial fibrillation), infarction,palpitations, cardiac failure

QT prolongation*(seesections 4.4 and 4.5)

Vascular Hot flush* Hypertension, vasovagaldisorders reaction (incl. hypotension)

Respiratory, Dyspnoeathoracic andmediastinaldisorders

Gastrointestinal Diarrhoea, Constipation, vomiting,disorders nausea abdominal pain, abdominaldiscomfort, dry mouth

Hepatobiliary Liver Bilirubin increased,disorders transamina alkaline phosphataseses increasedincreased

Skin and Hyperhidro Urticaria, skin nodule,subcutaneous sis (incl. alopecia, pruritus, erythematissue disorders nightsweats)*,rash

Musculoskeletal Musculosk Osteoporosis/osteopenia, Rhabdomyo-, connective eletal pain arthralgia muscular lysistissue and bone and weakness, muscle spasms,disorders discomfort joint swelling/stiffness

Renal and Pollakiuria, micturitionurinary urgency, dysuria, nocturia,disorders renal impairment,incontinence

Reproductive Gynaecom Testicular pain, breast pain,system and astia*, pelvic pain, genitalbreast disorders testicular irritation, ejaculation failureatrophy*,erectiledysfunction

*

General Injection site Chills, Malaise, peripheral oedemadisorders and adverse pyrexia,administration reactions fatigue*,site conditions Influenza-like illness

*Known physiological consequence of testosterone suppression

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. Markedlyabnormal (>3*ULN) liver transaminase values (ALT, AST and GGT) were seen in 2-6% of patients withnormal values prior to treatment, following treatment with both medicinal products. Marked decrease inhaematological 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 medicinalproducts. It is unknown to what extent this decrease in haematological values was caused by the underlyingprostate cancer and to what extent it was a consequence of androgen deprivation therapy. Markedlyabnormal values of potassium (≥5.8 mmol/l), creatinine (≥177 μmol/l) and BUN (≥10.7 mmol/l) in patientswith 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 mggroup, had a QTcF ≥ 500 msec. From baseline to end of study the median change in QTcF for degarelix was12.0 msec and for leuprorelin was 16.7 msec.

The lack of intrinsic effect of degarelix on cardiac repolarisation (QTcF), heart rate, AV conduction, cardiacdepolarisation, 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 suspected adverse reactions after authorisation of the medicinal product is important. It allowscontinued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are askedto report any suspected adverse reactions via the national reporting system listed in Appendix V.

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

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

L02BX02

Degarelix is a selective gonadotrophin releasing-hormone (GnRH) antagonist that competitively andreversibly 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 oftestosterone (T) by the testes. Prostatic carcinoma is known to be androgen sensitive and responds totreatment 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 theinitiation of treatment.

A single dose of 240 mg degarelix, followed by a monthly maintenance dose of 80 mg, rapidly causes adecrease in the concentrations of LH, FSH and subsequently testosterone. The serum concentration ofdihydrotestosterone (DHT) decreases in a similar manner to testosterone.

Degarelix is effective in achieving and maintaining testosterone suppression well below medical castrationlevel of 0.5 ng/ml. Maintenance monthly dosing of 80 mg resulted in sustained testosterone suppression in97% of patients for at least one year. No testosterone microsurges were observed after re-injection duringdegarelix treatment. Median testosterone levels after one year of treatment were 0.087 ng/ml (interquartilerange 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, activecomparator controlled, parallel-group study. The study investigated the efficacy and safety of two differentdegarelix monthly dosing regimens with a starting dose of 240 mg (40 mg/ml) followed by monthly dosessubcutaneous administration of 160 mg (40 mg/ml) or 80 mg (20 mg/ml), in comparison to monthlyintramuscular administration of 7.5 mg leuprorelin in patients with prostate cancer requiring androgendeprivation 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%) patientsdiscontinued 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 andmaintaining 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.

Time Degarelix 240/80 mg Leuprorelin 7.5 mg

Day 1 52% 0%

Day 3 96% 0%

Day 7 99% 1%

Day 14 100% 18%

Day 28 100% 100%

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 of94% in testosterone at day 3. Most of the leuprorelin-treated patients experienced testosterone surge; therewas 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 withinterquartile ranges).

The primary end-point in the study was testosterone suppression rates after one year of treatment withdegarelix or leuprorelin. The clinical benefit for degarelix compared to leuprorelin plus anti-androgen in theinitial phase of treatment has not been demonstrated.

Testosterone Reversibility

In a study involving patients with rising PSA after localised therapy (mainly radical prostatectomy andradiation) 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 oftreatment was 112 days (counted from start of monitoring period, i.e 28 days after last injection). The mediantime 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 maintenancethrough 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.

Degarelix 240/80 mg Leuprorelin 7.5 mg

N=207 N=201

No. of responders 202 194

Response Rate 97.2% 96.4%(confidence intervals)* (93.5; 98.8%) (92.5; 98.2%)

* 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 indirectbeneficial 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, P7546.4 ng/ml)

* for the leuprorelin 7.5 mg treatment group 17.4 ng/ml (interquartile range: P25 8.4 ng/ml, P7556.5 ng/ml)

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

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 oneyear of treatment.

From day 56 to day 364 there were no significant differences between degarelix and the comparator in thepercentage change from baseline.

Effect on prostate volume, disease related mortality and increased disease free survival

Neo-adjuvant androgen deprivation therapy prior to radiotherapy has been shown to impact prostate volumereduction, reduced disease related mortallity and increased disease free survival in patients with high-risklocalised or locally advanced prostate cancer (RTOG 86-10, TROG 96-01, RTOG 92-02, and Mason M et al.

Clinical Oncology 2013).

In a randomised parallel-arm, active-controlled, open-label trial, conducted in 244 men with a UICC prostatecancer TNM category T2 (b or c)/T3/T4, N0, M0, Gleason score >7, or prostate specific antigen >10ng/mLand a total prostate volume >30, three months therapy with degarelix (240/80 mg dose regimen) resulted in a37% reduction in prostate volume as measured by trans-rectal ultrasound scan (TRUS) in patients requiringhormonal therapy prior to radiotherapy and in patients who were candidates for medical castration. Theprostate volume reduction was similar to that attained with goserelin plus anti-androgen protection (Mason

M et al. Clinical Oncology 2013).

Combination with radiotherapy

The effect of degarelix in combination with radiotherapy is based on an indirect comparison to the LHRHagonists efficacy data by using the clinical efficacy surrogate endpoints; testosterone suppression and PSAreduction demonstrating non-inferiority to LHRH agonists and indirectly establish efficacy.

In patients with locally advanced prostate cancer several randomised long-term clinical trials provideevidence for the benefit of androgen deprivation therapy (ADT) in combination with radiotherapy (RT)compared to RT alone (RTOG 85-31, RTOG 86-10, EORTC 22863).

Clinical data from a phase III clinical trial (EORTC 22961) in 970 patients with locally advanced prostatecancer (mainly T2c-T4 with some T1c to T2b patients with pathological regional nodal disease) have shownthat radiotherapy followed by long-term therapy (3 years) is preferable to short-term therapy (6 months).

Overall total mortality at 5 years in the short-term hormonal treatment and long-term hormonal treatmentgroups was 19.0% and 15.2% respectively, with a relative risk of 1.42 (an upper one sided 95.71% CI = 1.79;or two sided 95.71% CI = [1.09; 1.85], p = 0.65 for non-inferiority and p = 0.0082 for post-hoc test ofdifference between groups of treatment). The 5-year mortality specifically related to the prostate cancer inthe short-term hormonal treatment and long-term hormonal treatment groups was 4.78% and 3.2%respectively, with a relative risk of 1.71 (95% CI = [1.14 to 2.57], p = 0.002).

The recommended duration of androgen deprivation therapy in medical guidelines for T3-T4 patientsreceiving radiotherapy is 2-3 years.

Evidence for the indication of high-risk localized prostate cancer is based on a number of published studiesof radiotherapy combined with GnRH analogues. Clinical data from five published studies were analyzed(EORTC 22863, RTOG 85-31, RTOG 92-02, RTOG 86-10 and D’Amico et al., JAMA 2004), which alldemonstrate a benefit for the combination of GnRH analogue with radiotherapy.

Clear difference of the respective study populations for the indications locally advanced prostate cancer andhigh-risk localized prostate cancer was not possible in the published studies.

Effect on QT/QTc intervals

In the confirmatory study comparing FIRMAGON to leuprorelin periodic electrocardiograms wereperformed. Both therapies showed QT/QTc intervals exceeding 450 msec in approximately 20% of thepatients. From baseline to end of study the median change for FIRMAGON was 12.0 msec and forleuprorelin it was 16.7 msec.

Anti-degarelix antibodies

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 isno indication that the efficacy or safety of FIRMAGON treatment is affected by antibody formation after upto 5.5 years of treatment.

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).

Following subcutaneous administration of 240 mg degarelix at a concentration of 40 mg/ml to prostatecancer 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/mlafter 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 29days for the maintenance dose. The long half-life after subcutaneous administration is a consequence of avery slow release of degarelix from the depot formed at the injection site(s). The pharmacokinetic behaviorof the medicinal product is influenced by its concentration in the solution for injection. Thus, Cmax andbioavailability tend to decrease with increasing dose concentration while the half-life is increased. Therefore,no other dose concentrations than the recommended should be used.

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

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

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 whenadministered as single intravenous doses (0.864-49.4 µg/kg) in healthy elderly men was found to be 35-50 ml/h/kg.

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

Degarelix has been investigated in a pharmacokinetic study in patients with mild to moderate hepaticimpairment. No signs of increased exposure in the hepatically impaired subjects were observed compared tohealthy 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 thisgroup.

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

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

Nonclinical studies on safety pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potentialrevealed 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 ratsand monkeys following subcutaneous administration of degarelix. Drug-related local irritation was noted inanimals when degarelix was administered subcutaneously in high doses.

Mannitol (E421)

Water for injections

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

3 years.

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

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 forsolution for injection.

Pre-filled glass (type I) syringe with elastomer plunger stopper, tip cap and line-marking at 4 ml containing4.2 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 powderfor solution for injection.

Pre-filled glass (type I) syringe with elastomer plunger stopper, tip cap and line-marking at 3 ml containing3 ml solvent.

Plunger rods.

Vial adapters.

Injection needles (25G 0.5 x 25 mm).

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 1needle.

Pack-size of 3 trays containing 3 powder vials, 3 solvent pre-filled syringes, 3 plunger rods, 3 vial adaptersand 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 adaptersand 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 bythe 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 forsubcutaneous injection.

1. Remove the cover from the vial adapter pack.

Attach the adapter to the powder vial by pressingthe adapter down until the spike pushes throughthe rubber stopper and the adapter snaps in place.

2. Prepare the pre-filled syringe by attaching the plunger rod.

3. Remove the cap of the pre-filled syringe. Attachthe syringe to the powder vial by screwing it onto the adapter. Transfer all solvent to thepowder vial.

4. With the syringe still attached to the adapter,swirl gently until the liquid looks clear and withoutundissolved powder or particles. If the powderadheres to the side of the vial above the liquidsurface, the vial can be tilted slightly. Avoid shakingto prevent foam formation.

A ring of small air bubbles on the surface of theliquid is acceptable. The reconstitution procedureusually takes a few minutes, but may take up to 15minutes in some cases.

5. Turn the vial upside down and draw up to the linemark on the syringe for injection.

Always make sure to withdraw the precisevolume and adjust for any air bubbles.

FIRMAGON 80 mg powder and solvent for solution forinjection: withdrawn until the line marking at 4 ml.

FIRMAGON 120 mg powder and solvent for solutionfor injection: withdrawn until the line marking at3 ml.

6. Detach the syringe from the vial adapter and attach the needle for deep subcutaneousinjection to the syringe.

7. Perform a deep subcutaneous injection. To do so:grasp the skin of the abdomen, elevate thesubcutaneous tissue and insert the needle deeply atan angle of not less than 45 degrees.

FIRMAGON 80 mg powder and solvent for solution forinjection: Inject 4 ml of FIRMAGON 80 mg slowly,immediately after reconstitution.

FIRMAGON 120 mg powder and solvent for solutionfor injection: Inject 3 ml of FIRMAGON 120 mgslowly, immediately after reconstitution.

8. 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.

Do not inject directly into a vein. Gently pull back the plunger to check if blood isaspirated. If blood appears in the syringe, the medicinal product can no longer be used.

Discontinue the procedure and discard the syringe and the needle (reconstitute a new dosefor the patient).

9. FIRMAGON 120 mg powder and solvent for solution for injection

Repeat the reconstitution procedure for the second dose. Choose a different injection siteand inject 3 ml.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Ferring Pharmaceuticals A/S

Amager Strandvej 4052770 Kastrup

Denmark

Tel: +45 88 33 88 34

FIRMAGON 80 mg powder and solvent for solution for injection

EU/1/08/504/001

EU/1/08/504/003

FIRMAGON 120 mg powder and solvent for solution for injection

EU/1/08/504/002

Date of first authorisation:17/02/2009

Date of latest renewal: 13/11/2013

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu/.