Active ingredients: Degarelix
FIRMAGON 80 mg powder and solvent for solution for injection
Firmagon package inserts are available for pack sizes:- FIRMAGON 80 mg powder and solvent for solution for injection
- FIRMAGON 120 mg powder and solvent for solution for injection
Why is Firmagon used? What is it for?
FIRMAGON contains degarelix. Degarelix is a chemically synthesized hormone blocker used in the treatment of prostate cancer in adult male patients. Degarelix mimics a natural hormone (gonadotropin releasing hormone, GnRH) and directly blocks its effect. By doing this, degarelix immediately reduces the level of the male hormone testosterone which stimulates prostate cancer.
Contraindications When Firmagon should not be used
Do not use FIRMAGON - If you are allergic to degarelix or any of the other ingredients of this medicine.
Precautions for use What you need to know before taking Firmagon
Tell your doctor if you have the following conditions:
- You have any cardiovascular or heart rhythm problems (arrhythmia) or are using medicines to treat this problem. Heart rhythm problems can be aggravated with the use of FIRMAGON.
- You suffer from diabetes mellitus. Worsening or the onset of diabetes may occur. If you are diabetic, you need to have your blood glucose measured more frequently.
- Suffering from liver problems. You may need to check your liver function.
- You suffer from kidney disease. The use of FIRMAGON has not been studied in patients with severe kidney disease.
- You have osteoporosis or any other condition that affects the strength of your bones. Reduced testosterone levels can cause a decrease in calcium in the bones (thinning of the bones).
- Suffers from severe hypersensitivity. The use of FIRMAGON has not been studied in patients with severe hypersensitivity reactions.
Children and adolescents
Do not give this medicine to children or adolescents.
Interactions Which drugs or foods can modify the effect of Firmagon
FIRMAGON may interfere with some medicines used for heart rhythm problems (e.g. quinidine, procainamide, amiodarone and sotalol) or with other medicines that can affect heart rhythm (e.g. methadone (used for pain relief and as part of drug addiction detox treatments), moxifloxacin (an antibiotic), antipsychotics).
Tell your doctor if you are taking or have recently taken or might take any other medicines, including medicines obtained without a prescription.
Warnings It is important to know that:
For those who carry out sports activities
The use of the drug without therapeutic necessity constitutes doping and can in any case determine positive anti-doping tests.
Driving and using machines
Feeling tired and dizzy are common side effects that can affect the ability to drive and use machines. These effects may be due to the treatment or the disease itself.
Dose, Method and Time of Administration How to use Firmagon: Posology
This medicine must usually be administered by a doctor or nurse.
The recommended starting dose is two consecutive 120 mg injections. You will then be given an injection of 80 mg per month. The injected liquid forms a gel which releases degarelix over a period of one month.
FIRMAGON should ONLY be injected under the skin (subcutaneously). FIRMAGON must NOT be injected into a blood vessel (intravenously). Precautions should be used to avoid accidental injection into a vein. The injection point must be varied within the abdominal area.
If you forget to use FIRMAGON
If you think you have forgotten your monthly dose of FIRMAGON, please inform your doctor. If you have any further questions on the use of this medicine, ask your doctor.
Instructions for proper use
NOTE:
DO NOT SHAKE THE VIALS
The pack contains a vial of powder and a pre-filled syringe of solvent which must be prepared for subcutaneous injection.
- Remove the cover from the vial adapter package. Attach the adapter to the powder vial by pressing down until the tip passes through the rubber stopper and the adapter clicks into place.
- Prepare the pre-filled syringe by inserting the plunger
- Remove the pre-filled syringe cap. Attach the syringe to the powder vial by screwing it onto the adapter. Transfer all the solvent to the powder vial.
- Keeping the syringe inserted into the adapter, swirl gently until the liquid is clear and free of undissolved particles or powder. If the powder adheres to the vial above the surface of the liquid, the vial can be tilted slightly. Avoid it. shaking to prevent foaming. Forming a ring of small air bubbles on the liquid surface is acceptable. The reconstitution procedure usually takes a few minutes but, in some cases, it can take up to 15 minutes.
- Turn the vial upside down and draw up to the injection syringe marking line. Always make sure to aspirate the exact volume and adjust for any bubbles.
- Detach the syringe from the adapter and insert the deep subcutaneous injection needle into the syringe.
- Give a deep subcutaneous injection. To do this: grasp the skin of the abdomen, lift the subcutaneous tissue and insert the needle deeply at an angle of no less than 45 degrees. Slowly inject 4 ml of FIRMAGON 80 mg immediately after reconstitution. *
- Injections should not be given in areas where the patient may be exposed to pressure, for example in the belt area, where there are bands or near the ribs. Do not inject directly into a vein. Gently pull back the syringe plunger to check if blood has been aspirated. If there is blood in the syringe, the medicine must no longer be used, stop the procedure and discard the syringe and needle (reconstitute a new dose for the patient).
* Chemical-physical stability has been demonstrated during use for 2 hours at 25 ° C. From a microbiological point of view, unless the method of reconstitution excludes the risk of bacterial contamination, the product should be used immediately. If not used immediately, the times and conditions of use are the responsibility of the user.
Side Effects What are the side effects of Firmagon
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Severe allergic reactions to this drug are rare. Contact your doctor urgently if you develop a severe rash, itching, or shortness of breath or difficulty. These can be symptoms of a severe allergic reaction.
Very common (may affect more than 1 in 10 users)
Flushing, pain and redness at the injection site. Side effects at the injection site are more common with the starting dose and less common with the maintenance dose.
Common (may affect up to 1 in 10 users)
- swelling, nodules and induration at the injection site
- chills, fever or flu-like syndrome after injection
- sleep disturbances, fatigue, dizziness, headache
- weight gain, nausea, diarrhea, high levels of some liver enzymes
- excessive sweating (including night sweats), rash
- anemia
- pain and musculoskeletal disorders
- reduction of testicular volume, breast swelling, impotence.
Uncommon (may affect up to 1 in 100 users)
- loss of sex drive, testicular pain, pelvic pain, ejaculatory failure, genital irritation, breast pain
- depression, psychic alterations
- skin redness, hair loss, skin nodules, numbness
- allergic reactions, hives, itching
- decreased appetite, constipation, vomiting, dry mouth, abdominal pain and discomfort, increased blood sugar / diabetes mellitus, increased cholesterol, changes in blood calcium, decreased weight
- increased blood pressure, changes in heart rhythm, changes in ECG (prolongation of the QT interval), sensation of abnormal heartbeat, dyspnoea, peripheral edema
- muscle weakness, muscle spasms, joint swelling / stiffness, osteoporosis / osteopenia, joint pain
- frequent urge to pass urine, urge to pass urine, difficulty or pain in passing urine, urination at night, kidney impairment, incontinence
- blurred vision
- discomfort at the injection site including decreased blood pressure and heart rate (vasovagal reaction)
- malaise
Rare (may affect up to 1 in 1000 users)
- Febrile neutropenia (very low white blood cell count in combination with fever) heart attack, heart failure.
Very rare (may affect up to 1 in 10,000 users)
- Infection, abscess and necrosis at the injection site
Reporting of side effects
If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system.
By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the vials, syringes and carton. The expiry date refers to the last day of that month.
This medicinal product does not require any special storage precautions.
After reconstitution
This medicine is stable for 2 hours at 25 ° C.
Due to the risk of microbial contamination, this medicine should be used immediately. If not used immediately, the use of this medicine is the responsibility of the user.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Other Information
What FIRMAGON contains
- The active substance is degarelix. Each vial contains 80 mg of degarelix (as acetate). After reconstitution 1 ml of the reconstituted solution contains 20 mg of degarelix
- The other ingredient in the powder is mannitol (E421).
- The solvent is water for injections.
What the FIRMAGON box looks like and what it contains
FIRMAGON is powder and solvent for solution for injection. The powder has a white to off-white appearance. The solvent is a clear, colorless solution.
FIRMAGON is available in two packs.
Pack of 1 tray containing: 1 vial of powder containing 80 mg of degarelix and 1 pre-filled syringe containing 4.2 ml of solvent, 1 plunger, 1 vial adapter and 1 injection needle.
Pack of 3 trays containing: 3 vials of powder containing 80 mg of degarelix and 3 pre-filled syringes containing 4.2 ml of solvent, 3 plungers, 3 vial adapters and 3 injection needles.
Not all packs may be for sale.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
FIRMAGON 80 MG POWDER AND SOLVENT FOR INJECTABLE SOLUTION
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each vial contains 80 mg of degarelix (in acetate form).
After reconstitution, each ml of solution contains 20 mg of degarelix.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Powder and solvent for solution for injection.
Powder: White to off-white powder.
Solvent: Clear, colorless solution.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
FIRMAGON is a gonadotropin releasing hormone (GnRH) antagonist indicated for the treatment of adult male patients with advanced hormone-dependent prostate cancer.
04.2 Posology and method of administration
Dosage
The first maintenance dose should be administered one month after the initial dose.
The therapeutic effect of degarelix should be monitored by means of clinical parameters and serum prostate specific antigen (PSA) levels. Clinical studies have shown that suppression of testosterone (T) levels occurs immediately after administration of the initial dose, with serum testosterone levels corresponding to those of a medical castration (Ttestosterone (T
In the case of patients with suboptimal response, it must be confirmed that serum testosterone levels remain sufficiently suppressed.
Since degarelix does not induce testosterone increases, it is not necessary to combine an antiandrogen as protection against the increase at the start of therapy.
Special populations
Elderly, patients with hepatic or renal impairment:
No dose adjustment is necessary in the elderly or in patients with mild to moderate hepatic or renal impairment (see section 5.2). No studies have been conducted in patients with severe hepatic or renal impairment and therefore caution is recommended in their treatment (see section 4.4).
Pediatric population
There is no specific use of FIRMAGON in children and adolescents in the treatment of male adults with hormone-dependent prostate cancer.
Method of administration
FIRMAGON must be reconstituted prior to administration. See section 6.6 for reconstitution and administration instructions.
FIRMAGON is for subcutaneous use ONLY, do not administer intravenously.
Intramuscular administration is not recommended as it has not been studied.
FIRMAGON is administered by subcutaneous injection in the abdominal area. The injection site should be changed periodically. Injections should be given in non-pressure areas, for example away from belts or elastic bands and not near the ribs.
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients, listed in section 6.
04.4 Special warnings and appropriate precautions for use
Effects on the QT / QTc interval
Long-term androgen deprivation therapy may prolong the QT interval. Periodic (monthly) follow-up electrocardiograms (ECGs) were performed in the confirmatory study comparing FIRMAGON with leuprorelin; an interval was observed with both therapies. QT / QTc greater than 450 msec in approximately 20% of patients and greater than 500 msec in 1% and 2% of patients in the degarelix and leuprorelin groups, respectively (see section 5.1).
FIRMAGON has not been studied in patients with a history of corrected QT interval above 450 msec, in patients with a history or risk factors for torsades de pointes, and in patients on concomitant therapy with drugs that can prolong the QT interval. Therefore. , the benefit / risk ratio of FIRMAGON treatment should be carefully considered in such patients (see sections 4.5 and 4.8).
A thorough QT study showed that there was no intrinsic effect of degarelix on the QT / QTc interval (see section 4.8).
Hepatic impairment
Patients with known or suspected liver problems were not included in long-term clinical studies with degarelix. Moderate, transient elevations in ALT and AST were observed, not accompanied by elevations in bilirubin or clinical symptoms. Monitoring of liver function is recommended in patients with known or suspected liver disorders during treatment. The pharmacokinetics of degarelix were studied following single intravenous administration in subjects with mild to moderate hepatic impairment (see section 5.2).
Renal impairment
Degarelix has not been studied in patients with severe renal impairment, therefore caution is recommended in such patients.
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
Cases of decreased bone density have been reported in the medical literature in men undergoing orchiectomy or treated with GnRH agonists. It can be assumed that long periods of suppression of testosterone levels in humans may have effects on bone density. Bone density has not been measured during treatment with degarelix.
Glucose tolerance
A reduction in glucose tolerance was observed in men undergoing orchiectomy or treated with GnRH agonists. The development or worsening of diabetes may be observed, therefore diabetic patients should be subjected to more frequent monitoring of blood glucose levels when undergoing androgen deprivation therapy. The effect of degarelix on insulin and glucose levels has not been studied.
Cardiovascular diseases
In patients undergoing androgen deprivation treatment, cardiovascular diseases such as stroke and myocardial infarction have been reported in the literature. Therefore, all cardiovascular risk factors must be considered.
04.5 Interactions with other medicinal products and other forms of interaction
No formal drug interaction studies have been conducted.
Since androgen deprivation treatment can prolong the QTc interval, concomitant use of degarelix with drugs known to prolong the QTc interval or drugs capable of inducing torsade de pointes, such as class IA antiarrhythmic drugs, should be carefully considered. e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol, dofetilide, ibutilide), methadone, moxifloxacin, antipsychotics, etc. (see section 4.4).
Degarelix is not a substrate of the human CYP450 system and has not shown any induction or inhibition in vitro of CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4 / 5. Therefore clinically significant pharmacokinetic interactions between drugs linked to the aforementioned isoenzymes are unlikely.
04.6 Pregnancy and breastfeeding
Pregnancy and breastfeeding
There are no indications for the use of FIRMAGON in women.
Fertility
FIRMAGON can inhibit male fertility as long as testosterone is suppressed.
04.7 Effects on ability to drive and use machines
FIRMAGON has no or negligible influence on the ability to drive and use machines. Fatigue and wobbling are common side effects that can affect the ability to drive or use machines.
04.8 Undesirable effects
Summary of the safety profile
The most commonly observed undesirable effects during degarelix treatment in confirmatory phase III studies (N = 409) are due to the expected physiological effects of testosterone suppression, and include flushing and weight gain (observed in 25% and 7% , respectively, of patients treated for one year), or adverse reactions at the injection site. Transient onset of chills, fever or flu-like symptoms have been reported (in 3%, 2% and 1% of patients, respectively) within hours after administration.
Injection site adverse reactions reported were mainly pain and erythema, reported in 28% and 17% of patients, respectively, swelling (6%), induration (4%) and lump formation (3) were reported less frequently. %). These events occurred mainly with the starting dose while during maintenance therapy at the 80 mg dose the incidence of these events per 100 injections was: 3 for pain and abscess at the injection site or necrosis at the injection site which may require surgical treatment / drainage.
Table of adverse reactions
The frequency of the undesirable effects listed below is defined according to the following conventions:
Very common (≥ 1/10); common (≥ 1/100 e
Table 1: Frequency of adverse reactions reported in 1259 patients treated for a total of 1781 patients over one year (phase II and III studies) and from post-marketing reports
* Known physiological consequence of testosterone suppression
Description of selected adverse reactions
Variations in laboratory parameters
Changes in laboratory parameters observed during one year of treatment in the confirmatory phase III study (N = 409) were in the same range in both the degarelix and the GnRH agonist (leuprorelin) comparator group. . Markedly abnormal values (> 3 * ULN) of hepatic transaminases (ALT, AST and GGT) were observed in 2-6% of patients with normal values at the start of treatment after therapy with both drugs. In patients with normal values before treatment, marked decreases in haematological values, hematocrit (≤0.37) and hemoglobin (≤115 g / l) were observed in 40% and 13-15%, respectively, after treatment with both drugs. It is not known in which measures this decrease in haematological values is attributable to the underlying pathology or is a consequence of androgen deprivation therapy. Markedly abnormal values of potassium
(≥5.8 mmol / L), creatinine (≥177 μmol / L) and BUN (≥10.7 mmol / L) in patients with normal values before treatment, were observed in 6%, 2% and 15%, respectively. % of patients treated with degarelix and in
3%, 2% and 14% of patients treated with leuprorelin.
Changes in ECG values
Changes in ECG measurements observed during one year of treatment in the confirmatory phase III study (N = 409) were in the same range in both the degarelix and the
treated with a GnRH agonist (leuprorelin) as the comparator. Three patients (500 msec. From baseline to end of study, mean QTcF changes were 12.0 msec in the degarelix group and 16.7 msec in the leuprorelin group.
The lack of inherent effect of degarelix on cardiac repolarization (QTcF), heart rate, AV conduction, cardiac depolarization, or T or U wave morphology was confirmed by a thorough QT study in healthy subjects (N = 80) which received an "IV infusion of degarelix over 60 min, reaching a mean Cmax of 222 ng / ml, approximately 3-4 times the Cmax obtained during the treatment of prostate cancer.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions after authorization of the medicinal product is important, as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "Annex V.
04.9 Overdose
There is no clinical experience on the effects of acute degarelix overdose. In the event of an overdose, the patient should be closely monitored and, if considered necessary, supportive therapy should be given.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: endocrine therapy, other hormone antagonists and related substances.
ATC code: L02BX02.
Mechanism of action
Degarelix is a selective gonadotropin releasing hormone (GnRH) antagonist that competitively and reversibly binds to pituitary GnRH receptors, thereby rapidly reducing the release of gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH), resulting in reduced secretion of testosterone (T) by the testes. It is known that prostate cancer is sensitive and responds to treatments that remove the source of androgens. Unlike GnRH agonists, GnRH antagonists do not induce an increase in LH resulting in spike in testosterone / tumor stimulation and potential symptomatic flare-up after initiation of treatment.
A single 240 mg dose of degarelix, followed by a monthly maintenance dose of 80 mg, causes a rapid decrease in LH and FSH concentrations and, consequently, testosterone. Serum concentrations of dihydrotestosterone (DHT) decrease in the same way as those of testosterone. Degarelix is effective in achieving and maintaining testosterone suppression well below medical castration levels of 0.5 ng / mL. The monthly maintenance dose of 80 mg allows to sustain testosterone suppression in 97% of patients for at least one year. No testosterone peaks were observed after injections after the first one during treatment with degarelix. Median testosterone levels after one year of treatment were 0.087 ng / mL (interquartile range 0.06-0.15) N = 167.
Results of the confirmatory phase III study
The efficacy and safety of degarelix were evaluated in an open, multicentre, randomized, active control, parallel group study. The study evaluated the efficacy and safety of two monthly degarelix dosing regimens with one starting dose of 240 mg (40 mg / ml) followed by a monthly subcutaneous dose of 160 mg (40 mg / ml) or 80 mg (20 mg / ml), compared to a monthly intramuscular administration of 7.5 mg of leuprorelin in patients with prostate cancer requiring androgen deprivation therapy. A total of 620 patients were randomized into the three treatment groups, of which 504 (81%) patients completed the study. In the degarelix 240/80 mg group, 41 (20%) patients discontinued the study, versus 32 (16%) patients in the leuprorelin group.
Of the 610 patients treated:
• 31% had localized prostate cancer
• 29% had locally advanced prostate cancer
• 20% had metastatic prostate cancer
• 7% had unknown metastatic status
• 13% had previously been treated with surgery or radiation or had increased PSA.
The basic demographics are similar for 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 the 12 months of Treatment: The lowest effective maintenance dose of 80 mg degarelix was chosen.
Achievement of serum testosterone (T) levels ≤0.5 ng / ml
FIRMAGON is effective in achieving rapid testosterone suppression, see Table 2.
Table 2: Percentage of patients who achieved T≤0.5 ng / mL after initiation of treatment.
Avoid sudden increases in testosterone
A sudden rise is defined as exceeding the baseline testosterone level of ≥15% in the first two weeks.
A sudden rise in testosterone was not observed in any of the degarelix-treated patients; there was an average 94% decrease in testosterone on day 3. Most patients treated with leuprorelin experienced elevations of testosterone, with an average increase in testosterone levels of 65% on day 3. These differences were statistically significant (p
The primary end point of the study was the rate of testosterone suppression after one year of treatment with degarelix or leuprorelin. The clinical benefit of degarelix compared with antiandrogen-associated leuprorelin in early treatment was not demonstrated.
Restoration of testosterone levels
In a study involving patients with PSA elevation after localized therapy (mainly radical prostatectomy and radiotherapy), FIRMAGON was administered for a seven-month period followed by a seven-month monitoring period. The median time to recovery of testosterone levels (> 0.5 ng / mL, beyond castration levels) after discontinuation of treatment was 112 days (calculated from the start of the monitoring period, i.e. 28 days after the last injection. ). The median time to reach testosterone levels> 1.5 ng / mL (above the lower limit of the normal range) was 168 days.
Long-term efficacy
Therapeutic success was defined in the study as achieving medical castration levels on day 28 and maintaining testosterone concentrations not exceeding 0.5 ng / ml on any of the 364 days of treatment.
Table 3: Cumulative Probability of Testosterone ≤0.5 ng / mL from Day 28 to Day 364.
* Kaplan Meier estimates for groups
Achievement of reduction of prostate specific antigen (PSA)
Tumor size was not measured directly during the clinical study but there was an indirect positive tumor response demonstrable as 95% median PSA reduction with degarelix after 12 months.
The median PSA values in the study at baseline were:
• 19.8 ng / mL (interquartile range: P25 9.4 ng / mL, P75 46.4 ng / mL) in the degarelix 240/80 mg group
• 17.4 ng / mL (interquartile range: P25 8.4 ng / mL, P75 56.5 ng / mL) in the 7.5 mg leuprorelin group.
The differences are statistically significant (p
Prostate specific antigen (PSA) levels were reduced by 64% after two weeks of degarelix administration, by 85% after one month and by 95% after three months, remaining suppressed (approximately 97%) for one treatment period. one year.
From day 56 to day 364, there were no significant differences in the rates of change from baseline between degarelix and the comparator.
Effects on prostate volume
Three months of degarelix therapy (240/80 mg dose regimen) resulted in a 37% reduction in prostate volume measured by trans-rectal ultrasound in patients requiring hormone therapy prior to radiotherapy and in patients who were candidates for medical castration. The reduction in prostate volume was similar to that achieved with goserelin plus anti-androgen protection.
Effects on QT / QTc intervals
Control electrocardiograms were performed periodically in the confirmatory study comparing FIRMAGON with leuprorelin. With both therapies, a QT / QTc interval greater than 450 msec was observed in approximately 20% of patients. From baseline to end of study, median changes measured with FIRMAGON were 12.0 msec and with leuprorelin was 16.7 msec.
Anti-degarelix antibodies
The development of anti-degarelix antibodies was observed in 10% of patients after one year of treatment with FIRMAGON and in 29% of patients after treatment with FIRMAGON for up to 5.5 years. There are no indications that the formation of these antibodies affects the efficacy and safety of FIRMAGON up to 5.5 years of treatment.
Pediatric population
The European Medicines Agency has released FIRMAGON from its obligation to submit the results of studies in all subsets of the pediatric population (see section 4.2 for information on pediatric use).
05.2 Pharmacokinetic properties
Absorption
Following subcutaneous administration of 240 mg degarelix at a concentration of 40 mg / ml to patients with prostate cancer in the pivotal study CS21, the AUC0-28 days was 635 (602-668) day * ng / ml, Cmax was 66.0 (61.0-71.0) ng / mL and was reached at Tmax 40 (37-42) hours. Mean values were approximately 11-12 ng / mL after starting dose and 11-16 ng / ml after the maintenance dose of 80 mg at concentrations of 20 mg / ml. After Cmax, the plasma concentration of degarelix decreases in a biphasic manner with a mean final half-life (t½) of 29 days with the maintenance dose. for subcutaneous administration is a consequence of a very slow release of degarelix from the deposit that forms at the injection site. The pharmacokinetic behavior of the drug is influenced by its concentration in the solution for injection. Therefore, Cmax and bioavailability tend to decrease with increasing of the dose concentration while the half-life tends to d increase. Therefore, no dose strengths other than those recommended should be used.
Distribution
The volume of distribution in healthy elderly men is approximately 1 L / kg. Plasma protein binding is estimated to be approximately 90%.
Biotransformation
Degarelix undergoes common peptide degradation during passage through the hepato-biliary system and is mainly excreted as peptide fragments in the faeces. No significant metabolites were detected in plasma samples after subcutaneous administration. Education in vitro demonstrated that degarelix is not a substrate of the human CYP450 system.
Elimination
In healthy men, approximately 20-30% of a single intravenous dose is excreted in the urine, suggesting that 70-80% is excreted via the hepato-biliary system. The clearance of degarelix given as a single intravenous dose (0.864-49.4 mcg / kg) in healthy elderly men was 35-50 ml / h / kg.
Special populations:
Patients with renal impairment
Pharmacokinetic studies have not been conducted in patients with renal dysfunction. Only about 20-30% of the administered dose of degarelix is excreted unchanged by the kidneys. A population pharmacokinetic analysis of the phase III confirmatory study demonstrated that the clearance of degarelix in patients with mild or moderate renal impairment is reduced by approximately 23%; therefore no dose adjustment is recommended in such patients. Data on patients with severe renal impairment are scarce and therefore caution is recommended in these patients.
Patients with hepatic impairment
Degarelix was evaluated in a pharmacokinetic study in patients with mild to moderate hepatic impairment. No signs of overexposure were observed in patients with hepatic dysfunction compared to healthy subjects. No dosage adjustments are required in patients with mild to moderate hepatic dysfunction. Patients with severe hepatic dysfunction have not been studied, therefore caution is recommended in this group.
05.3 Preclinical safety data
Animal reproduction studies have shown that degarelix causes infertility in male animals. This is due to the pharmacological effect which is reversible.
In reproductive toxicity studies in females, degarelix gave expected results due to its pharmacological characteristics. It causes a dose-dependent prolongation of the time of mating and pregnancy, a small number of corpora lutea, and an increase in pre- and post-implantation losses, abortions, early embryo / fetal deaths, premature births and duration of delivery.
Preclinical pharmacological safety studies, studies of repeated toxicity, genotoxicity and carcinogenic potential did not show particular risks for humans. In particular, both studies in vitro that in vivo showed no QT prolongation.
No organ specific toxicity was observed in acute, subacute or chronic studies in rats and monkeys following subcutaneous administration of degarelix. Drug-related local irritation was noted when degarelix was administered subcutaneously at high doses to animals.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Dust
Mannitol (E421)
Solvent
Water for injections
06.2 Incompatibility
In the absence of compatibility studies, do not mix this product with other drugs.
06.3 Period of validity
3 years.
After reconstitution
Chemical-physical stability has been demonstrated during use for 2 hours at 25 ° C. From a microbiological point of view, unless the method of reconstitution excludes the risk of bacterial contamination, the product should be used immediately. If not used. immediately, the times and conditions of use are the responsibility of the user.
06.4 Special precautions for storage
No special precautions.
For storage conditions of the reconstituted product see section 6.3.
06.5 Nature of the immediate packaging and contents of the package
Glass vial (type I) with bromobutyl rubber stopper and aluminum flip-off seal containing 80 mg powder for solution for injection
Pre-filled glass syringe (type I) with elastomer plunger, cap and 4 ml marking line containing 4.2 ml of solvent
Piston
Vial adapter
Injection needle (25G 0.5 x 25mm)
Packaging FIRMAGON is available in two packages:
Pack of 1 tray containing: 1 vial of powder, 1 pre-filled syringe of solvent, 1 plunger, 1 vial adapter and 1 needle.
Pack of 3 trays containing: 3 vials of powder, 3 pre-filled syringes of solvent, 3 plungers, 3 vial adapters and 3 needles.
Not all pack sizes may be on the market.
06.6 Instructions for use and handling
Follow the instructions for reconstitution carefully.
Administration of different concentrations is not recommended as gel deposit formation is affected by the concentration. The reconstituted solution should be a clear liquid, free from undissolved particles.
NOTE:
• DO NOT SHAKE THE VIALS
The pack contains a vial of powder and a pre-filled syringe of solvent which are to be prepared for subcutaneous injection.
1. Remove the cover from the vial adapter package. Attach the adapter to the powder vial by pressing down until the tip passes through the rubber stopper and the adapter clicks into place.
2. Prepare the pre-filled syringe by inserting the plunger
3. Remove the pre-filled syringe cap. Attach the syringe to the powder vial by screwing it onto the adapter. Transfer all the solvent to the powder vial.
4. Keeping the syringe inserted into the adapter, swirl gently until the liquid is clear and free of undissolved particles or powder. If the powder adheres to the vial above the surface of the liquid, the vial can be tilted slightly. Avoid shaking to prevent foaming.
The formation of a ring of small air bubbles on the surface of the liquid is acceptable. The reconstitution procedure usually takes a few minutes but in some cases it can take up to 15 minutes.
5. Turn the vial upside down and draw up to the injection syringe marking line.
Always make sure to aspirate the exact volume and adjust for any air bubbles.
6. Detach the syringe from the adapter and insert the needle for deep subcutaneous injection into the syringe.
7. Give a deep subcutaneous injection. To do this: grasp the skin of the abdomen, lift the subcutaneous tissue and insert the needle deeply at an angle of no less than 45 degrees.
Slowly inject 4 ml of FIRMAGON 80 mg immediately after reconstitution.
Injections should not be given in areas where the patient may be subjected to pressure, for example in the belt area, where there are bands or near the ribs.
Do not inject directly into a vein. Gently pull back the syringe plunger to check if blood has been aspirated. If there is blood in the syringe, the medicine must no longer be used, stop the procedure and discard the syringe and needle (reconstitute a new dose for the patient).
No special provisions are required for elimination.
07.0 MARKETING AUTHORIZATION HOLDER
Ferring Pharmaceuticals A / S
Kay Fiskers Plads 11
DK-2300 Copenhagen S
Denmark
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/08/504/001
039232018
EU / 1/08/504/003
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 17/02/2009
Date of the last renewal: 19/09/2013
10.0 DATE OF REVISION OF THE TEXT
D.CCE November 2014
