Firmagon

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FIRMAGON® (FIRMAGON®)

Composition:

Active substance: degarelix;

1 vial contains degarelix (as acetate) 80 mg or 120 mg,

after reconstitution, the concentration is 40 mg/mL or 20 mg/mL;

Excipients: mannitol (E 421);

1 pre-filled syringe with solvent contains 4.2 mL or 3.0 mL of water for injections.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties:

powder: white or almost white lyophilisate in the form of a cake;

solvent: clear, colorless liquid.

Pharmacotherapeutic group. Hormone antagonists and related agents.

ATC code L02B X02.

Pharmacological Properties.

Pharmacodynamics.

Degarelix is a selective gonadotropin-releasing hormone (GnRH) antagonist that competitively and reversibly binds to pituitary GnRH receptors, rapidly reducing the release of gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and thereby decreasing testicular testosterone secretion. Prostate carcinoma is androgen-sensitive and responds to treatment that removes the source of androgens. Unlike GnRH agonists, GnRH blockers do not induce an initial LH surge followed by a testosterone surge/tumor growth stimulation, which may potentially exacerbate symptoms after the initiation of therapy.

A single 240 mg dose of Firmagon, followed by monthly maintenance doses of 80 mg, rapidly reduces serum levels of LH, FSH, and consequently testosterone. Serum dihydrotestosterone (DHT) concentration decreases in parallel with testosterone concentration.

Firmagon is effective in achieving and maintaining suppression of testosterone secretion below the level of medical castration of 0.5 ng/mL. The monthly maintenance dose of 80 mg results in sustained suppression of testosterone secretion in 97% of patients for at least one year.

No testosterone "flare" effect after repeated injections during Firmagon treatment has been observed. The mean testosterone level after one year of treatment was 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 were evaluated in an open-label, multicenter, randomized, parallel-group study with an active control. The study assessed the efficacy and safety of two different monthly dosing regimens of degarelix with a loading dose of 240 mg (40 mg/mL), followed by monthly subcutaneous injections of either 160 mg (40 mg/mL) or 80 mg (20 mg/mL), compared to monthly intramuscular administration of 7.5 mg leuprorelin in patients with prostate cancer requiring antiandrogen therapy. A total of 620 patients were randomized into one of three treatment groups, of whom 504 (81%) completed the study. In the degarelix 240/80 mg treatment group, 41 (20%) patients discontinued the study compared to 32 (16%) in the leuprorelin group.

Among the 610 treated patients:

• 31% had localized prostate cancer;
• 29% had locally advanced prostate cancer;
• 20% had metastatic prostate cancer;
• 7% had an undefined metastatic status;
• 13% had a history of surgery or radiotherapy aimed at cure and had a rising prostate-specific antigen (PSA) level.

Baseline patient characteristics were similar across all groups. The mean age was 74 years (range 47 to 98 years). The primary objective was to demonstrate the efficacy of degarelix in achieving and maintaining testosterone suppression below 0.5 ng/mL over 12 months of treatment.

The lowest effective maintenance dose of degarelix, 80 mg, was selected.

Achievement of serum testosterone (T) level ≤ 0.5 ng/mL

Firmagon is effective in achieving rapid testosterone suppression, see Table 1.

Table 1

Percentage of patients achieving T level ≤ 0.5 ng/mL after initiation of treatment

Avoidance of Testosterone Fluctuations

Fluctuation was defined as testosterone levels exceeding baseline by ≥ 15% during the first 2 weeks.

No patients receiving degarelix treatment experienced testosterone fluctuations; a mean decrease in testosterone level of 94% was observed on day 3. In contrast, most patients receiving leuprorelin experienced testosterone fluctuations; a mean increase in testosterone level of 65% was observed on day 3. This difference was statistically significant (p < 0.001).

Figure 1. Percentage change in testosterone from baseline in treatment groups up to day 28 (median with interquartile ranges)

The primary endpoint of the study was testosterone suppression levels after one year of treatment with degarelix or leuprorelin. A clinical benefit of degarelix compared to leuprorelin and antiandrogen in the initial treatment phase has not been demonstrated.

Testosterone Recovery

A study was conducted in patients with rising PSA levels after local therapy (mainly radical prostatectomy and radiation therapy), who received Firmagon for seven months followed by a seven-month observation period. The median time to testosterone recovery (> 0.5 ng/mL, exceeding castration levels) after treatment discontinuation was 112 days (counted from the start of the observation period, i.e., 28 days after the last injection). The median time to reach testosterone levels > 1.5 ng/mL (exceeding the lower limit of the normal range) was 168 days.

Long-term Effects

Successful response during the study was defined as achieving medical castration by day 28 and maintaining it until day 364, with no single testosterone concentration exceeding 0.5 ng/mL.

Table 2

Cumulative probability of achieving testosterone levels ≤ 0.5 ng/mL from day 28 to day 364

* Kaplan-Meier estimates within group

Prostate-specific antigen (PSA) reduction

Tumour size was not directly measured during the clinical study, but an indirect response of benign tumours was observed, as indicated by a 95 % reduction in mean PSA levels after 12 months of degarelix treatment.

The mean PSA level at baseline during the study 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 in treatment groups up to Day 56 (median with interquartile ranges)

This difference was statistically significant (p < 0.001) for the pre-specified variable analysis according to the study plan on Day 14 and Day 28.

PSA levels decreased by 64 % within two weeks after degarelix administration, by 85 % after one month, by 95 % after three months, and remained suppressed (approximately 97 %) throughout one year of treatment.

From Day 56 to Day 364, there were no significant differences between degarelix and the comparator drug in percentage change from baseline.

Effect on prostate volume

After 3 months of therapy with degarelix (240/80 mg regimen), a 37 % reduction in prostate volume was observed based on measurements obtained by transrectal ultrasound (TRUS) in patients requiring hormonal therapy prior to radiation therapy and in patients eligible for medical castration. The reduction in prostate volume was similar to that achieved with goserelin and antiandrogen protection.

Effect on QT/QTc intervals

During confirmatory studies comparing Firmagon and leuprorelin, ECGs were performed periodically. Both treatment options demonstrated QT/QTc intervals exceeding 450 ms in approximately 20 % of patients. Compared to baseline, the mean change in QTc at the end of the study was 12.0 ms for Firmagon and 16.7 ms for leuprorelin.

Antibodies to degarelix

Development of antibodies to degarelix was observed in 10 % of patients after one year of treatment with Firmagon and in 29 % of patients after up to 5.5 years of treatment with Firmagon. There is no evidence that the formation of antibodies affects the efficacy or safety of Firmagon treatment after up to 5.5 years of therapy.

Pharmacokinetics.

Absorption

After subcutaneous administration of 240 mg degarelix at a concentration of 40 mg/mL to patients with prostate cancer, AUC0-28 days was 635 (602–668) day*ng/mL, maximum concentration (Cmax) was 66 (61–71) ng/mL, observed at tmax 40 (37–42) hours. Mean trough levels were 11–12 ng/mL after the first dose and 11–16 ng/mL after maintenance doses of 80 mg at a concentration of 20 mg/mL. The Cmax of degarelix in plasma decreases in a biphasic manner with a mean terminal half-life (t1/2) of approximately 29 days for the maintenance dose. The prolonged half-life after subcutaneous administration is due to the very slow release of degarelix from the depot formed at the injection sites. The pharmacokinetic parameters of the drug depend on its concentration in the injection solution. Thus, with increasing concentration, Cmax and bioavailability tend to decrease, while the half-life increases. Therefore, concentrations other than those specified should not be used.

Distribution

The volume of distribution in elderly healthy volunteers was approximately 1 L/kg. Plasma protein binding was approximately 90 %.

Metabolism

Degarelix undergoes normal peptide degradation during passage through the hepatobiliary system, with the majority being excreted as peptide fragments in faeces. After subcutaneous administration, no pharmacologically active metabolites were detected in plasma. In vitro studies have shown that degarelix is not a substrate for the human cytochrome CYP450 system.

Elimination

In healthy men, approximately 20–30 % of a single intravenous dose of degarelix is excreted by the kidneys. It is assumed that 70–80 % is eliminated via the hepatobiliary system. The clearance of degarelix after a single intravenous dose of 0.864–49.4 μg/kg in elderly healthy men was 35–50 mL/h/kg body weight.

Special patient groups

Patients with renal impairment

Pharmacokinetic studies have not been conducted in patients with renal impairment. Only 20–30 % of the administered dose of degarelix is excreted unchanged by the kidneys. Population pharmacokinetic analysis based on Phase III study data showed that degarelix clearance is reduced by 23 % in patients with mild to moderate renal impairment; therefore, dose adjustment in patients with mild to moderate renal impairment is not recommended. Data in patients with severe renal impairment are limited, so caution should be exercised in such patients.

Patients with hepatic impairment

Degarelix was studied in a pharmacokinetic study involving patients with mild to moderate hepatic impairment. No evidence of increased effect in patients with hepatic impairment compared to healthy volunteers was observed. Dose adjustment in patients with mild to moderate hepatic impairment is not required. Use in patients with severe hepatic impairment has not been studied; therefore, caution should be exercised in this patient group.

Clinical characteristics.

Indications. Treatment of adult males with advanced hormone-dependent prostate cancer.

Contraindications. Hypersensitivity to degarelix or to any other component of the medicinal product.

Firmagon is not intended for use in women and children.

Interaction with other medicinal products and other forms of interaction.

Studies on interaction with other medicinal products have not been conducted.

Since androgen deprivation therapy may prolong the QTc interval, concomitant administration of Firmagon with medicinal products that prolong the QTc interval or may induce torsades de pointes ventricular tachycardia, such as class IА antiarrhythmics (quinidine, disopyramide) or class III antiarrhythmics (amiodarone, sotalol, dofetilide, ibutilide), as well as methadone, moxifloxacin, and antipsychotic agents, requires careful evaluation.

Degarelix is not a substrate of the human cytochrome CYP450 system and does not activate or inhibit CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4/5 at any clinically significant levels in vitro.

Therefore, clinically significant pharmacokinetic interactions with other medicinal products involving metabolism mediated by these isoenzymes are unlikely.

Special precautions for use.

Firmagon is intended for subcutaneous administration only.

QT/QTc interval prolongation

Long-term androgen deprivation therapy may lead to QT interval prolongation.

During studies comparing Firmagon and leuprorelin, ECGs were performed monthly. With both treatment regimens, QT/QTc intervals exceeding 450 ms were observed in 20% of patients, and exceeding 500 ms in 1% and 2% of patients receiving degarelix and leuprorelin, respectively.

The effect of Firmagon has not been studied in patients with QT interval greater than 450 ms, in patients with torsades de pointes or at risk of developing it, or in patients receiving concomitant medications that may prolong the QT interval. Therefore, the risk-benefit ratio of using Firmagon in such patients requires careful evaluation.

A dedicated QT study demonstrated that degarelix itself has no effect on the QT/QTc interval.

Hepatic impairment

Patients with known or suspected liver disease were not included in long-term clinical studies of degarelix. Transient, mild elevations in AST and ALT levels have been observed, without concomitant increases in bilirubin levels or clinical symptoms. Monitoring of liver function during therapy is recommended in patients with known or suspected hepatic impairment. The pharmacokinetics of degarelix were studied after a single intravenous dose in patients with mild to moderate hepatic impairment.

Renal impairment

Firmagon should be administered with caution in patients with severe renal impairment.

Hypersensitivity

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

Bone density changes

Decreased bone density has been reported in the medical literature in patients who have undergone orchidectomy or received GnRH agonist therapy, indicating the impact of testosterone suppression in men on bone mineral density. Bone density has not been measured during treatment with Firmagon.

Glucose tolerance

Reduced glucose tolerance has been observed in patients who have undergone orchidectomy or received GnRH agonist therapy. Development or worsening of diabetes may occur. Therefore, more frequent monitoring of blood glucose levels is necessary in diabetic patients receiving androgen deprivation therapy. The effect of Firmagon on insulin and glucose levels has not been studied.

Cardiovascular diseases

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

Fertility

Firmagon may suppress male fertility for as long as testosterone secretion remains suppressed.

Use during pregnancy or breastfeeding.

The drug is not intended for use in women.

Ability to affect reaction speed when driving or operating machinery.

Firmagon has no or negligible influence on the ability to drive vehicles or operate machinery. Fatigue and dizziness are the most common adverse reactions that may affect the ability to drive or operate machinery.

Method of administration and dosage.

Dosage

The first maintenance dose should be administered 1 month after the initial dose.

The therapeutic effect of Firmagon should be monitored based on clinical parameters and by measuring serum PSA levels. Clinical studies have demonstrated that testosterone suppression occurs immediately after administration of the initial dose: serum testosterone levels reach castration levels (T ≤ 0.5 ng/mL) within three days in 96% of patients and in 100% of patients within one month. Long-term treatment up to 1 year with maintenance dosing shows that 97% of patients maintain a consistently suppressed testosterone level (T ≤ 0.5 ng/mL).

If the clinical response is inadequate, it is important to confirm that serum testosterone levels are adequately reduced.

Since Firmagon does not induce an increase in testosterone levels, there is no need to administer antiandrogenic agents to prevent a testosterone surge at the beginning of therapy.

Administration

Firmagon is intended for subcutaneous use only and must not be administered intravenously. Intramuscular administration has not been studied and is therefore not recommended.

The drug should be administered as subcutaneous injections in the abdominal area. The injection site should be rotated regularly. Injections should be given in areas not compressed by clothing (specifically avoiding the waistband or belt area) and not too close to the ribs.

Dose adjustment in specific patient populations

Elderly patients and patients with hepatic or renal impairment

Dose adjustment is not required for elderly patients or for patients with mild to moderate hepatic or renal impairment. The use of the drug in patients with severe renal or hepatic impairment has not been studied; therefore, caution should be exercised in such cases.

Instructions for administration

Administration of concentrations other than those specified is not recommended, as concentration affects depot formation.

The reconstituted solution should be clear and free of insoluble particles.

Precautions

Do not shake the vials.

Firmagon 120 mg

Since the package contains 2 vials of powder and 2 pre-filled syringes of solvent, the reconstitution procedure must be repeated twice.

Firmagon 80 mg

The pack contains 1 vial with powder and 1 pre-filled syringe with solvent for preparation of solution for subcutaneous injection.

After reconstitution, the preparation should be administered immediately. Chemical and physical stability of the diluted solution is maintained for 2 hours after dilution.

Children. The drug is not used in children.

Overdose.

There is no clinical experience regarding the consequences of acute overdosage with Firmagon.

In every case of overdose, the patient should be closely monitored and, if necessary, supportive therapy should be administered.

Side effects.

The side effects most commonly observed during degarelix therapy in the confirmatory Phase III study (N = 409) were either related to the expected physiological effects of testosterone secretion suppression, including hot flushes and increased body weight (reported in 25% and 7% of patients, respectively, receiving treatment for one year), or were injection site reactions. Transient chills, fever, or flu-like symptoms were reported within several hours after drug administration (in 3%, 2%, and 1% of patients, respectively).

Injection site reactions, primarily manifested as pain and erythema, were observed in 28% and 17% of patients, respectively; less frequently reported were swelling (6%), induration (4%), and nodule formation (3%). These events occurred most commonly following the initial loading dose, whereas during maintenance therapy with the 80 mg dose, the frequency per 100 injections was 3 for pain and < 1 for erythema, swelling, induration, and nodule formation. These reactions were predominantly transient, mild to moderate in severity, and very rarely led to treatment discontinuation (< 1%). Serious injection site reactions, such as injection site infections, abscess, or necrosis requiring surgical intervention or drainage, occurred very rarely.

Adverse reactions are categorized by organ systems and frequency of occurrence: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000). Within each frequency group, adverse reactions are listed in decreasing order of severity.

Frequency of adverse reactions reported in 1259 patients treated over a total of 1781 patient-years in Phase II and III studies, and during the post-marketing period.

Blood and lymphatic system disorders.
Common: anemia*. Rare: neutropenic fever.

Immune system disorders.
Uncommon: hypersensitivity. Rare: anaphylactic reactions.

Metabolism and nutrition disorders.
Common: weight gain*. Uncommon: hyperglycemia/diabetes mellitus, increased cholesterol levels, weight loss, decreased appetite, changes in blood calcium levels.

Psychiatric disorders.
Common: insomnia. Uncommon: depression, decreased libido*.

Nervous system disorders.
Common: dizziness, headache. Uncommon: decreased cognitive function, hypoesthesia.

Eye disorders.
Uncommon: blurred vision.

Cardiac disorders.
Uncommon: cardiac arrhythmias (including atrial fibrillation), palpitations, QT interval prolongation*. Rare: myocardial infarction, heart failure.

Vascular disorders.
Very common: hot flushes*. Uncommon: arterial hypertension, vasovagal reaction (including hypotension).

Respiratory, thoracic and mediastinal disorders.
Uncommon: dyspnea.

Gastrointestinal disorders.
Common: diarrhea, nausea. Uncommon: constipation, vomiting, abdominal pain, discomfort in the abdominal area, dry mouth.

Hepatobiliary disorders.
Common: increased liver transaminase levels. Uncommon: increased bilirubin levels, increased alkaline phosphatase levels.

Skin and subcutaneous tissue disorders.
Common: hyperhidrosis (including night sweats)*, rash. Uncommon: urticaria, nodular rash, alopecia, pruritus, erythema.

Musculoskeletal and connective tissue disorders.
Common: musculoskeletal pain and discomfort. Uncommon: osteoporosis/osteopenia, arthralgia, muscle weakness, muscle spasms, joint swelling/stiffness.

Renal and urinary disorders.
Uncommon: pollakiuria, urgency, dysuria, nocturia, renal failure, urinary incontinence.

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

General disorders and administration site conditions.
Very common: injection site reactions. Common: chills, fever, fatigue*, flu-like symptoms. Uncommon: malaise, peripheral edema.

*Physiological consequences of testosterone secretion suppression.

Description of selected adverse reactions

Laboratory test abnormalities.

Laboratory test changes were evaluated over one year of treatment in the confirmatory Phase III study (N = 409) and were within the same range for both degarelix and the GnRH agonist leuprorelin, which was used as the comparator. Marked increases (three times above the upper limit of normal) in liver transaminases (ALT, AST, and GGT) during treatment with either drug were observed in 2–6% of patients who had normal baseline values. Significant decreases in hematological parameters—hematocrit (≤ 0.37) and hemoglobin (≤ 115 g/L)—were observed in 40% and 13–15% of patients with normal baseline values, respectively. The extent to which these hematological changes were due to prostate cancer itself versus androgen blockade remains unclear. Abnormalities in potassium (≥ 5.8 mmol/L), creatinine (≥ 177 µmol/L), and blood urea nitrogen (≥ 10.7 mmol/L) levels in patients with normal baseline values were observed in 6%, 2%, and 15% of patients receiving degarelix, and in 3%, 2%, and 14% of patients receiving leuprorelin, respectively.

ECG changes.

ECG changes observed over one year of treatment in the confirmatory Phase III study (N = 409) were within the same range for both degarelix and the comparator GnRH agonist leuprorelin. QTcF prolongation ≥ 500 ms was observed in three (< 1%) of 409 patients receiving degarelix and in four (2%) of 201 patients receiving leuprorelin 7.5 mg. Compared to baseline, mean increase in QTcF duration at the end of the study was 12 ms for degarelix and 16.7 ms for leuprorelin.

The absence of a direct effect of degarelix on cardiac repolarization (QTcF), heart rate, AV conduction, cardiac depolarization, or T- or U-wave morphology was confirmed in a thorough QT study in healthy volunteers (N = 80) who received a 60-minute intravenous infusion of degarelix, achieving a mean Cmax of 222 ng/mL—approximately 3–4 times higher than the Cmax observed in prostate cancer treatment.

Shelf life. 3 years.

Do not use after the expiry date stated on the packaging.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C. Do not freeze. Keep out of the reach of children.

Incompatibilities.

Due to lack of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Packaging. 1 vial containing 80 mg powder supplied with 1 pre-filled syringe containing 5 mL solvent (water for injections) (marked 4.0 mL, filled volume 4.2 mL), 1 vial adapter, 1 administration needle, and 1 plunger rod in a cardboard carton.

2 vials containing 120 mg powder each, supplied with 2 pre-filled syringes containing 5 mL solvent (water for injections) each (marked 3.0 mL, filled volume 3.0 mL), 2 vial adapters, 2 administration needles, and 2 plunger rods in a cardboard carton.

Prescription status. Prescription only.

Manufacturer.

Ferring GmbH, Germany.

Manufacturer's address and place of business.

Wittland 11, 24109 Kiel, Germany.