Firmagon

Firmagon

degarelix

Manufacturer:

Ferring

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Degarelix.
Description
Each 80-mg vial contains degarelix (as acetate) 80 mg. After reconstitution with clear, colourless solvent, each mL of solution contains 20 mg of degarelix.
Each 120-mg vial contains degarelix (as acetate) 120 mg. After reconstitution with clear, colourless solvent, each mL solution contains 40 mg of degarelix.
Firmagon also contains the following excipients: Powder: Mannitol (E421). Solvent: Water for injections.
Action
Pharmacology: Pharmacodynamics: Degarelix is a selective gonadotrophin-releasing hormone (GnRH) blocker 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 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 blockers do not induce a LH surge with subsequent testosterone surge/tumour stimulation and potential symptomatic are after the initiation of treatment.
A single dose of degarelix 240 mg, 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 1 year. Median testosterone levels after 1 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 evaluated in an open-label, multicentre, randomised, active comparator controlled, parallel-group study. The study investigated the efcacy and safety of 2 different degarelix monthly dosing regimens with a starting dose of 240 mg (40 mg/mL) followed by monthly doses SC administration of 160 mg (40 mg/mL) or 80 mg (20 mg/mL), in comparison to monthly IM administration of 7.5 mg leuprorelin in patients with prostate cancer requiring androgen deprivation therapy. In total, 620 patients were randomised to 1 of the 3 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 prostate specific antigen (PSA).
Baseline demographics were similar between the arms. The median age was 74 years (range 47-98 years). The primary objective was to demonstrate that degarelix is effective with respect to achieving and maintaining testosterone suppression to <0.5 ng/mL, during 12 months of treatment.
The lowest effective maintenance dose of degarelix 80 mg was chosen.
Attainment of Serum Testosterone ≤0.5 ng/mL: Firmagon is effective in achieving fast testosterone suppression (see Table 1).

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Avoidance of Testosterone Surge: Surge was defined as testosterone exceeding baseline by ≥15% within the 1st 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) (see Figure 1).

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The primary end-point in the study was testosterone suppression rates after 1 year of treatment with degarelix or leuprorelin. The clinical benefit for degarelix compared to leuprorelin plus antiandrogen 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 >0.5 ng/mL (see Table 2).

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Attainment of Prostatic 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 for the degarelix 240/80 mg treatment group was 19.8 ng/mL (interquartile range: P25 9.4 ng/mL, P75 46.4 ng/mL) and for the leuprorelin 7.5-mg treatment group was 17.4 ng/mL (interquartile range: P25 8.4 ng/mL, P75 56.5 ng/mL) (see Figure 2).

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This difference was statistically significant (p<0.001) for the pre-specified analysis at day 14 and day 28.
Prostate specific antigen levels are lowered by 64% 2 weeks after administration of degarelix, 85% after 1 month, 95% after 3 months and remained suppressed (approximately 97%) throughout the 1 year of treatment.
From day 56-364, 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 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 1 year. There is no indication that the efficacy or safety of Firmagon treatment is affected by antibody formation after 1 year of treatment. Efficacy and safety data in relation to antibody development beyond 1 year is not available.
Pharmacokinetics: Absorption: Following SC administration of degarelix 240 mg at a concentration of 40 mg/mL to prostate cancer patients in the pivotal study CS21, AUC0-28 days was 635 (602-668) day*ng/mL, Cmax was 66 (61-71) ng/mL and occurred at tmax at 40 (37-42) hrs. 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 half-life of approximately 43 days for the starting dose or 28 days for the maintenance dose, as estimated based on population pharmacokinetics modelling. The long t½ after SC administration is a consequence of a very slow release of degarelix from the depot formed at the injection site(s). The pharmacokinetic behavior of Firmagon is influenced by its concentration in the solution for injection. Thus, Cmax and bioavailability tend to decrease with increasing dose concentration while the t½ 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 hepatobiliary system and is mainly excreted as peptide fragments in the faeces. No significant metabolites were detected in plasma samples after SC 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 IV administered dose is excreted in the urine, suggesting that 70-80% is excreted via the hepatobiliary system. The clearance of degarelix when administered as single IV doses (0.864-49.4 mcg/kg) in healthy elderly men was found to be 35-50 mL/hr/kg.
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.
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.
Indications/Uses
Firmagon is a gonadotrophin-releasing hormone (GnRH) blocker indicated for treatment of adult male patients with advanced hormone-dependent prostate cancer.
Dosage/Direction for Use
Starting Dose: 240 mg administered as 2 SC inj of 120 mg each. Monthly Maintenance Dose: 80 mg administered as 1 SC inj.
The 1st maintenance dose should be given 1 month after the starting dose.
The therapeutic effect of degarelix should be monitored by clinical parameters and PSA serum levels. Clinical studies have shown that testosterone suppression occurs immediately after administration of the starting dose with 96% of the patients having plasma testosterone levels corresponding to medical castration (T≤0.5 ng/mL) after 3 days and 100% after 1 month. Long-term treatment with the maintenance dose up to 1 year shows that 97% of the patients have sustained suppressed testosterone levels (T≤0.5 ng/mL).
In case the patient's clinical response appears to be sub-optimal, it should be confirmed that serum testosterone levels are remaining sufficiently suppressed.
Since degarelix does not induce a testosterone surge, it is not necessary to add an antiandrogen as surge protection 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 kidney function impairment (see Pharmacology: Pharmacokinetics under Actions). Patients with severe liver or kidney impairment have not been studied and caution is therefore warranted (see Precautions).
There is no relevant indication for use of Firmagon in women, children and adolescents.
Administration: Firmagon must be reconstituted prior to administration. For instructions on reconstitution and administration, see Instructions for Use under Cautions for Usage.
SC use only, not to be administered IV.
Intramuscular administration is not recommended as it has not been studied.
Firmagon is administered as a SC injection in the abdominal region. As with other medicinal products administered by SC injection, the injection site should vary periodically. Injections should be given in areas where the patient will not be exposed to pressure eg, not close to waistband or belt and not close to the ribs.
Overdosage
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.
Contraindications
Hypersensitivity to degarelix or to any of the excipients of Firmagon.
Special Precautions
The data available on efficacy and safety experience with degarelix is limited to a 1 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 Pharmacology: Pharmacodynamics under Actions).
Firmagon has not been studied in patients with a history of a corrected QT interval >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 Adverse Reactions and Interactions).
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 IV administration in subjects with mild to moderate hepatic impairment (see Pharmacology: Pharmacokinetics under Actions).
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.
Effects on the Ability to Drive or Operate Machinery: 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.
Use in pregnancy & lactation: There is no relevant indication for use of Firmagon in women.
Use In Pregnancy & Lactation
There is no relevant indication for use of Firmagon in women.
Adverse Reactions
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 increased weight (reported in 25% and 7%, respectively, of patients receiving treatment for 1 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 per 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 as follows is defined using the following convention: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness (see Table 3).

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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 1 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 x 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 micromol/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 1 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 4 (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 msec and for leuprorelin was 16.7 msec.
Drug Interactions
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 eg, class IA (eg, quinidine, disopyramide) or class III (eg, amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicinal products, methadone, cisapride, moxifloxacine, antipsychotics, etc should be carefully evaluated (see Precautions).
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.
Incompatibilities: In the absence of compatibility studies, Firmagon must not be mixed with other medicinal products.
Caution For Usage
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.
The vials should not be shaken.
Firmagon 80 mg: The pack contains 1 set of powder and solvent that must be prepared for SC inj. Firmagon 120 mg: The pack contains 2 sets of powder and solvent that must be prepared for SC inj. Hence, the instructions as follows need to be repeated for a 2nd time.
1. Remove the cover from the vial adapter pack. Attach the adapters to both the solvent and powder vial by pressing the adapter down until the spike pushes through the rubber stopper and the adapter snap in place.
2. Remove the cover from the syringe pack. Attach the syringe to the solvent vial by screwing it on to the adapter.
3. Turn the vial upside down and draw 4.2 mL solvent of Firmagon 80 mg or 3 mL solvent of Firmagon 120 mg into the syringe. Always make sure to withdraw the precise volume, as the amount of solvent affects the reconstitution. Detach the syringe from the adapter and discard the vial with the remaining solvent.
4. Attach the syringe to the powder vial by screwing it on to the adapter. Transfer the solvent to the powder vial. With the syringe still attached to the adapter, swirl very gently until the liquid looks clear and without undissolved powder or particles. In case the powder adheres to the vial over the liquid surface, the vial can be tilted slightly. Avoid shaking to prevent foam formation.
A ring of small air bubbles on the surface of the liquid is acceptable. The reconstitution procedure may take, in some cases, up to 15 min, but usually takes a few minutes.
5. Turn the vial upside down and, holding it vertically, draw 4 mL of Firmagon 80 mg or 3 mL of Firmagon 120 mg solution into the syringe for injection. Always make sure to withdraw the precise volume. It can be necessary to tilt the vial slightly.
6. Detach the syringe from the vial adapter and attach the needle for deep SC inj to the syringe. Carefully remove any air bubbles.
7. Grasp the skin of the abdomen, elevate the subcutaneous tissue. Perform a profound SC inj. To do so, insert the needle deeply at an angle of not less than 45 degrees.
8. Inject 4 mL of Firmagon 80 mg or 3 mL of Firmagon 120 mg immediately after reconstitution.
9. Do not inject directly into a vein. Gently pull back the plunger to check if blood is aspirated. If blood appears in the syringe, Firmagon can no longer be used. Discontinue the procedure and discard the syringe and the needle (reconstitute a new dose for the patient).
10. Firmagon 120 mg: Repeat the reconstitution procedure for the 2nd dose. Choose a different injection site and inject 3 mL.
No injections should be given in areas where the patient will be exposed to pressure eg, around the belt or waistband or close to the ribs.
After Reconstitution: Chemical and physical in-use stability has been demonstrated for 2 hrs at 25ºC. From a microbiological point of view, unless the method of reconstitution precludes the risk of microbial contamination, Firmagon should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.
Storage
Store below 30°C. Do not freeze.
Shelf-Life: 3 years.
ATC Classification
L02BX02 - degarelix ; Belongs to the class of other hormone antagonists and related agents. Used in the treatment of advanced prostate cancer.
Presentation/Packing
Powd for soln for inj (vial) (white to off-white powd) 80 mg + 4.2 mL solvent x 1's. 120 mg + 3 mL solvent x 2's.
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