Firmagon powder for solution for injection 80 mg + solvent No. 1

Instructions Firmagon powder for solution for injection 80 mg + solvent No. 1

Composition

active ingredient: degarelix;

1 vial contains degarelix (as acetate) 80 mg;

after dissolution, the concentration is 40 mg/ml;

excipients: mannitol (E 421);

1 pre-filled syringe with solvent contains 4.2 ml of water for injections.

Dosage 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 similar agents. ATX code L02B X02.

Pharmacological properties

Pharmacodynamics

Degarelix is a selective gonadotropin-releasing hormone antagonist that competitively and reversibly binds to pituitary gonadotropin-releasing hormone (GnRH) receptors, rapidly reducing the release of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and thus reducing testicular testosterone secretion. Prostate cancer is androgen-sensitive and responds to treatment that removes the source of androgens. Unlike GnRH agonists, GnRH blockers do not induce LH release with subsequent testosterone release/stimulation of tumor growth, potentially worsening symptoms after initiation of therapy.

A single dose of 240 mg of Firmagon, followed by a monthly maintenance dose of 80 mg, rapidly reduces LH, FSH and, consequently, testosterone levels. Serum dihydrotestosterone (DHT) concentrations are reduced in a similar manner to testosterone concentrations.

Firmagon is effective in achieving and maintaining suppression of testosterone secretion below the level of medical castration of 0.5 ng/ml. A maintenance dose of 80 mg per month results in sustained suppression of testosterone secretion in 97% of patients for at least a year.

No micro-fluctuations in testosterone were observed after repeated injections during Firmagon treatment. The median 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, active-controlled study. The study investigated the efficacy and safety of two different monthly dosing regimens of degarelix with an initial dose of 240 mg (40 mg/mL) followed by monthly subcutaneous doses of 160 mg (40 mg/mL) or 80 mg (20 mg/mL) compared with monthly intramuscular administration of 7.5 mg leuprorelin in patients with prostate cancer requiring androgen deprivation therapy. A total of 620 patients were randomized to one of three treatment groups, of whom 504 (81%) completed the study. In the degarelix 240/80 mg group, 41 (20%) patients withdrew from the study compared with 32 (16%) in the leuprorelin group.

Of the 610 patients who received treatment:

31% had localized prostate cancer; 29% had locally advanced prostate cancer; 20% had metastatic prostate cancer; 7% had indeterminate metastatic status; 13% had a history of curative surgery or radiotherapy and present with elevated prostate-specific antigen (PSA) levels.

Baseline personal characteristics were similar in 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 chosen.

Achieving serum testosterone (T) levels ≤ 0.5 ng/mL

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

Percentage of patients who achieved T ≤ 0.5 ng/mL after starting treatment

Avoiding testosterone fluctuations

Fluctuation was defined as testosterone levels ≥ 15% above baseline within the first 2 weeks.

None of the patients treated with degarelix had testosterone fluctuations; there was a mean decrease in testosterone of 94% on day 3. Most of the patients treated with leuprorelin had testosterone fluctuations; there was a mean increase in testosterone of 65% on day 3. This difference was statistically significant (p < 0.001).

The primary endpoint of the study was testosterone suppression levels after one year of treatment with degarelix or leuprorelin. No clinical benefit was demonstrated for degarelix compared to leuprorelin and antiandrogen in the initial treatment phase.

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

Long-term impact

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

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

* Kaplan–Meier estimates within the group

Decreased PSA levels

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

The mean PSA level during the study at baseline was:

for the degarelix 240/80 mg treatment group – 19.8 ng/ml (interquartile range: P25 9.4 ng/ml, P75 46.4 ng/ml); for the leuprorelin 7.5 mg treatment group – 17.4 ng/ml (interquartile range: P25 8.4 ng/ml, P75 56.5 ng/ml).

This difference was statistically significant (p< 0.001) for analysis by pre-specified variables at days 14 and 28.

PSA levels were reduced by 64% two weeks after degarelix administration, by 85% after one month, by 95% after three months, and remained suppressed (about 97%) for one year of treatment.

From days 56 to 364, there were no significant differences between degarelix and comparator in percent change from baseline.

Effect on prostate volume

Three months of treatment with degarelix (240/80 mg regimen) resulted in a 37% reduction in prostate volume, as measured by transrectal ultrasound (TRUS), in patients requiring hormone therapy prior to radiotherapy and in patients eligible for medical castration. The reduction in prostate volume was similar to that seen with goserelin and antiandrogen protection.

Effect on QT/QTc intervals

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

Antibodies to degarelix

Antibody development 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 efficacy or safety of Firmagon treatment is affected by antibody development after up to 5.5 years of treatment.

Pharmacokinetics

Absorption

Following subcutaneous administration of 240 mg degarelix at a concentration of 40 mg/ml to patients with prostate cancer, the AUC0-28 days was 635 (602–668) day*ng/ml, the maximum concentration (Cmax) was 66 (61–71) ng/ml and occurred at a tmax of 40 (37–42) hours. Mean trough values 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 plasma Cmax of degarelix declines in a biphasic manner with a mean terminal half-life (t1/2) of approximately 29 days for the maintenance dose. The long 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 prescribed should not be used.

Distribution

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

Metabolism

Degarelix is subject to normal peptide degradation during its passage through the hepatobiliary system, most of it is excreted in the form of peptide fragments with feces. After subcutaneous administration, pharmacologically active metabolites were not detected in plasma. In vitro studies have shown that degarelix is not a substrate for the human cytochrome CYP450 system.

Breeding

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

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. A population pharmacokinetic analysis from a phase III study showed that degarelix clearance is reduced by 23% in patients with mild to moderate renal impairment, therefore dose adjustment is not recommended for patients with mild to moderate renal impairment. Data in patients with severe renal impairment are limited, therefore special caution should be exercised in such patients.

Patients with liver dysfunction

Degarelix was studied in a pharmacokinetic study in patients with mild to moderate hepatic impairment. There was no evidence of increased exposure in patients with hepatic impairment compared to healthy volunteers. No dose adjustment is necessary in patients with mild to moderate hepatic impairment. Use in patients with severe hepatic impairment has not been studied and caution should be exercised in this patient population.

Indication

Treatment of adult men with advanced hormone-dependent prostate cancer.

Contraindication

Hypersensitivity to degarelix or to any other component of the drug.

Firmagon is not intended for use in women and children.

Interaction with other medicinal products and other types of interactions

Interaction studies with other drugs have not been conducted.

Since androgen deprivation therapy may prolong the QTc interval, the concomitant use of Firmagon with drugs that prolong the QTc interval or can induce torsades de pointes, such as class IA (quinidine, disopyramide) or class III (amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmics, as well as methadone, moxifloxacin, antipsychotics, requires careful evaluation.

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

Therefore, clinically significant pharmacokinetic interactions with other drugs in metabolism associated with these isoenzymes are unlikely.

Application features

Firmagon is intended for subcutaneous administration only.

Effect on QT/QTc interval

Prolonged androgen deprivation therapy may cause prolongation of the QT interval.

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

Firmagon has not been studied in patients with a QT interval longer than 450 ms, in patients with or at risk of developing torsades de pointes, or in patients receiving concomitant medications that may prolong the QT interval. Therefore, the risk/benefit ratio of Firmagon in such patients requires careful evaluation.
A detailed QT study demonstrated that degarelix had no intrinsic effect on the QT/QTc interval.

Liver damage

Patients with known or suspected liver disease were not included in long-term clinical studies of degarelix. Transient, mild elevations of AST and ALT were observed, not accompanied by elevations in bilirubin or clinical symptoms. Monitoring of liver function during therapy is recommended in patients with known or suspected liver disease. The pharmacokinetics of degarelix have been studied after a single intravenous dose in patients with mild to moderate hepatic impairment.

Kidney damage

The drug should be prescribed with caution to 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.

Change in bone density

Decreased bone density has been reported in the medical literature in patients who have undergone orchiectomy or who have been treated with GnRH agonists, suggesting an effect of testosterone suppression in men on bone density. Bone density was not measured during treatment with Firmagon.

Glucose tolerance

In patients who have undergone orchiectomy, as well as in those who have received treatment with GnRH agonists, a decrease in glucose tolerance was observed. The development or complication of diabetes is possible. Therefore, more frequent monitoring of blood glucose levels is necessary in diabetic patients receiving 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 receiving androgen deprivation therapy. Therefore, all cardiovascular risk factors should be considered.

Fertility

Firmagon can suppress male fertility as long as there is suppression of testosterone secretion.

Ability to influence reaction speed when driving vehicles or other mechanisms

Firmagon has no or negligible influence on the ability to drive and use machines. Fatigue and dizziness are the most common adverse reactions that could affect the ability to drive and use machines.

Use during pregnancy or breastfeeding

The drug is not used in women.

Method of administration and doses

Dosage

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

The therapeutic effect of Firmagon should be monitored by clinical parameters and by measuring serum PSA levels. Clinical studies have shown that testosterone (T) suppression occurs immediately after the initial dose: in 96% of patients, serum testosterone levels correspond to the level after medical castration (T ≤ 0.5 ng/ml) after three days and in 100% - after one month. Long-term treatment for up to 1 year with a maintenance dose shows that 97% of patients have stable suppressed testosterone levels (T ≤ 0.5 ng/ml).

If the clinical effect is insufficient, it should be ensured that the serum testosterone level is sufficiently reduced.

Since Firmagon does not induce an increase in testosterone levels, there is no need to prescribe antiandrogen drugs to protect against testosterone surges at the beginning of therapy.

Introduction

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

The drug is administered as a subcutaneous injection into the abdomen. The injection site should be changed periodically. Injections should be given in areas that are not compressed by clothing (in particular, do not inject into the area of the waist belt or belt), and not too close to the ribs.

Dose selection for individual patient groups

Elderly patients, with hepatic and renal insufficiency

No dose adjustment is necessary for elderly patients or those with mild to moderate hepatic or renal impairment. The use of the drug in severe renal or hepatic insufficiency has not been studied, therefore special caution should be exercised in such cases.

Rules for administering the drug

The administration of concentrations other than those prescribed is not recommended, as the concentration affects the formation of depots.

The diluted solution should be clear, without undissolved particles.

Reservation

Do not shake the vials.

Firmagon 80 mg

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

Remove the cap from the vial. Attach the adapter to the powder vial by pressing the adapter down until the needle pierces the rubber stopper and the adapter is in the indicated position. Prepare the pre-filled syringe by attaching the plunger rod. Remove the cap from the pre-filled syringe. Attach the syringe to the powder vial and screw it onto the adapter. Inject all the solvent into the powder vial. Without separating the syringe from the adapter, gently shake until the liquid is clear, free of impurities and undissolved particles. If the powder sticks to the wall of the vial above the liquid level, you can tilt the vial slightly. Do not shake the vial to avoid foaming. A ring of small air bubbles on the surface of the liquid is allowed. The dissolution procedure usually takes several minutes, but in some cases it may take up to 15 minutes. Turn the vial upside down and draw the drug up to the mark line into the syringe for injection. Always check the accuracy of the drawn volume and the absence of any air bubbles. Disconnect the syringe from the vial adapter and attach a needle for deep subcutaneous injection to the syringe. Make a deep subcutaneous injection. To do this, fold the skin of the abdomen, slightly lift the subcutaneous tissue and insert the needle deeply at an angle of at least 45 degrees. Slowly inject 4 ml of Firmagon 80 mg immediately after dilution. Do not inject into areas that will be subject to pressure, such as under a belt or waistband or close to the ribs. Do not inject directly into a vein. Carefully pull the plunger towards you to make sure that there is no blood in the syringe. If blood appears, the drug should not be used further. Stop the procedure and remove the syringe with the needle and drug (dilute a new dose for the patient).

After reconstitution, the product should be administered immediately. Chemical and physical in-use stability of the diluted solution has been demonstrated for 2 hours after reconstitution.

Children

The drug is not used in children.

Overdose

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

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

Adverse reactions

The most common adverse reactions observed with degarelix therapy in the confirmatory phase III study (N = 409) were either related to the expected physiological effects of testosterone suppression, including hot flashes and weight gain (occurring in 25% and 7% of patients treated for one year, respectively), or were injection site reactions. Transient chills, fever, or flu-like symptoms were reported within a few hours of dosing (occurring in 3%, 2%, and 1% of patients, respectively).

Injection site reactions, mainly pain and erythema, occurred in 28% and 17% of patients, respectively, with less frequent events being swelling (6%), induration (4%) and nodule formation (3%). These events were most common with the initial dose, while during maintenance therapy with 80 mg the incidence of these events per 100 injections was 3 for pain and < 1 for erythema, swelling, induration and nodule formation. These events were mostly transient, mild to moderate in severity and very rarely led to treatment discontinuation (< 1%). Serious injection site reactions, such as injection site infections, abscesses or necrosis at the injection site requiring surgical treatment or drainage, occurred very rarely.

Adverse reactions are listed by system organ class and frequency: 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). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

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

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

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

Metabolic disorders: Common: weight gain*. Uncommon: hyperglycaemia/diabetes, 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 mental performance, hypoaesthesia.

Eye disorders: Uncommon: blurred vision.

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

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

Respiratory and thoracic disorders: Uncommon: dyspnoea.

Gastrointestinal disorders: Common: diarrhoea, nausea. Uncommon: constipation, vomiting, abdominal pain, abdominal discomfort, dry mouth.

Hepatobiliary disorders: Common: increased hepatic transaminases. Uncommon: increased bilirubin, increased alkaline phosphatase.

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

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

Urinary system disorders: Uncommon: pollakiuria, urinary urgency, dysuria, nocturia, renal failure, urinary incontinence.

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

General disorders and administration site conditions Very common: injection site reactions Common: chills, fever, fatigue*, influenza-like illness Uncommon: malaise, peripheral oedema

*Physiological consequences of suppression of testosterone secretion.

Description of selected adverse reactions

Changes in laboratory parameters.

ECG changes.

ECG changes observed during one year of treatment in the confirmatory phase III study (N = 409) were in the same range for both degarelix and the GnRH agonist leuprorelin, which was used as a comparator. Three (< 1%) of 409 patients treated with degarelix and four (2%) of 201 patients treated with leuprorelin 7.5 mg had QTcF prolongations ≥ 500 ms. The mean increase in QTcF from baseline to the end of the study was 12 ms for degarelix and 16.7 ms for leuprorelin.

The lack of effect of degarelix itself 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 obtained in the treatment of prostate cancer.

Expiration date

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.

Packaging

1 vial of 80 mg powder complete with 1 pre-filled syringe of solvent (water for injections) of 5 ml (marked 4.0 ml and filled with 4.2 ml), 1 vial adapter, 1 injection needle and 1 plunger rod in a cardboard box.

Vacation category

According to the recipe.

Producer

Ferring GmbH, Germany.

Location of the manufacturer and its business address

Witland 11, 24109 Kiel, Germany.