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Firmagon 地加瑞克粉针剂

通用名称地加瑞克粉针剂 DEGARELIX
品牌名称Firmagon
产地|公司美国(USA) | FERRING(FERRING)
技术状态原研产品
成分|含量80mg
包装|存储1瓶/盒 室温
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通用中文 地加瑞克粉针剂 通用外文 DEGARELIX
品牌中文 品牌外文 Firmagon
其他名称
公司 FERRING(FERRING) 产地 美国(USA)
含量 80mg 包装 1瓶/盒
剂型给药 储存 室温
适用范围 前列腺癌
通用中文 地加瑞克粉针剂
通用外文 DEGARELIX
品牌中文
品牌外文 Firmagon
其他名称
公司 FERRING(FERRING)
产地 美国(USA)
含量 80mg
包装 1瓶/盒
剂型给药
储存 室温
适用范围 前列腺癌

使用说明书

（免责声明：本说明书仅供参考，不作为治疗的依据，不可取代任何医生、药剂师等专业性的指导。本站不提供治疗建议，药物是否适合您，请专业医生（或药剂师）决定。）

简介：

 

欧洲批准Firmagon(degarelix)用于前列腺癌
Ferring公司近日表示欧洲药品审评中心（EMEA）近日推荐批准Firmagon (degarelix)用于晚期激素依赖型前列腺癌，其为一种促性腺激素释放激素(GnRH)受体抑制剂。在3期试验中显示使用Firmagon三天96%受试者的睾丸激素水平显著下降，睾丸激素在前列腺癌细胞的生长与扩散方面有重要作用。
数据显示Firmagon可对睾丸激素水平产生超快速的作用，与进行睾丸切除术的快速作用相似。这项试验比较了每月一次使用Firmagon与每月使用一次缓释亮丙瑞林的作用，显示Firmagon抑制睾丸激素与前列腺特异抗原(PSA)的效果更快，此外在12个月的试验中 Firmagon始终能产生持续作用。
FIRMAGON是注射 含degarelix无菌冻干粉（如醋酸）和甘露醇。Degarelix是合成 线性肽酰胺含七自然氨基酸，其中五 是damino酸。已经经过乙酸盐是一种白色无定形粉末 低密度后得到的冻干。
用法与用量
定量信息
FIRMAGON管理作为 腹部皮下注射。
第一维持剂量应 起始剂量后28天。
适应症
FIRMAGON是促性腺激素释放激素受体拮抗剂用于晚期患者治疗 前列腺癌。
与皮下 注射其他药物，注射部位应周期性变化。注射应 在腹部，将不会受到压力，地区如不 接近腰带或皮带或紧贴肋骨。
警告及注意事项
（1）在怀孕期间使用
怀孕或可能怀孕的妇女不应该 FIRMAGON
（2）过敏反应
过敏反应，包括过敏反应，荨麻疹和血管性水肿上市后，已报告有FIRMAGON。在严重的过敏反应 情况，立即停止 FIRMAGON 如果注入尚未完成，和管理的临床指征。 患者已知的严重过敏反应史 FIRMAGON 不应再挑战。
（3）QT / QTc间期的影响
雄激素剥夺治疗可能延长QT间期。 提供者应利益考虑是否 雄激素剥夺治疗的潜在风险 大于在先天性 长QT综合征，充血性心力衰竭，频繁的电解质异常，在患者 服用QT间期延长。电解质异常应 被纠正。考虑 定期监测心电图和电解质。
在随机对照研究中，主动 FIRMAGON对醋酸亮丙瑞林，定期进行心电图。七 患者，三（＜1%）在汇总degarelix组和四（2%）患者 在醋酸亮丙瑞林7.5毫克组，有一个≥QTcF间500毫秒。从基线到 研究 端，为FIRMAGON中位数的变化为12.3毫秒，16.7毫秒 醋酸亮丙瑞林。
FIRMAGON的初始剂量为240毫克，给予皮下注射120毫克每两。维持剂量是一个单一的注射80毫克每28天。其他药物相互作用与FIRMAGON。告诉你的医生你的所有药物的使用。FIRMAGON不是用于女性，所以，怀孕的妇女，谁可能怀孕或正在哺乳不应该FIRMAGON。
副作用
因为临床试验广泛 变化的条件下进行的，不良反应发生率观察到一 药物的临床试验不能直接相比，在另一 药物和临床试验的利率可能不会反映在实践中发现率。
共1325例前列腺癌收到 FIRMAGON是每月处理（60-160毫克）或作为一个单一的剂量（高达 320毫克）。共有1032例患者（78%）有至少6个月， 治疗的853例患者（64%）有一年以上的治疗。最常见的 FIRMAGON治疗期间观察不良反应包括注射部位反应（例如，疼痛 ，红斑，肿胀或硬结），潮热 ，增加体重，疲劳，和血清转氨酶和 γ-谷氨酰转移酶（GGT）水平增加。的不良反应多数是 1年级或2、3级4 / 1%或更少的不良反应发生率。
在主动控制试验研究（n = FIRMAGON 610）在前列腺癌患者随机接受FIRMAGON （皮下）或肌肉）每月为12个月。不良反应报告 5%或更多的患者如表1所示。
最常见的不良反应是 注射部位疼痛（28%）、红斑（17%）、肿胀（6%）、硬结（4%） 结节（3%）。这些不良反应大多都是短暂的，轻度到中等强度的 ，主要发生的起始剂量，导致几 中断（＜1%）。3年级的注射部位反应发生在2%或更少的患者 degarelix。
Firmagon 120mg Injection
1. Name of the medicinal product
FIRMAGON 120 mg powder and solvent for solution for injection
2. Qualitative and quantitative composition
Each vial contains 120 mg degarelix (as acetate). After reconstitution, each ml of solution contains 40 mg of degarelix.
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
Powder and solvent for solution for injection.
Powder: White to off-white powder
Solvent: Clear, colourless solution
4. Clinical particulars
4.1 Therapeutic indications
FIRMAGON is a gonadotrophin releasing hormone (GnRH) antagonist indicated for treatment of adult male patients with advanced hormone-dependent prostate cancer.
4.2 Posology and method of administration
Posology
The first maintenance dose should be given one month after the starting dose.
The therapeutic effect of degarelix should be monitored by clinical parameters and prostate specific antigen (PSA) serum levels. Clinical studies have shown that testosterone (T) suppression occurs immediately after administration of the starting dose with 96% of the patients having serum testosterone levels corresponding to medical castration (T≤0.5 ng/ml) after three days and 100% after one 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 anti-androgen as surge protection at initiation of therapy.
Special populations
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 section 5.2). Patients with severe liver or kidney impairment have not been studied and caution is therefore warranted (see section 4.4).
Paediatric population
There is no relevant use of FIRMAGON in children and adolescents in the treatment of adult male patients with advanced hormone-dependent prostate cancer.
Method of administration
FIRMAGON must be reconstituted prior to administration. For instructions on reconstitution and administration, please see section 6.6.
FIRMAGON is for subcutaneous use ONLY, not to be administered intravenously. Intramuscular administration is not recommended as it has not been studied.
FIRMAGON is administered as a subcutaneous injection in the abdominal region. The injection site should vary periodically. Injections should be given in areas where the patient will not be exposed to pressure e.g. not close to waistband or belt and not close to the ribs.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.
4.4 Special warnings and precautions for use
Effect on QT/QTc interval
Long-term androgen deprivation therapy may prolong the QT interval. In the confirmatory study comparing FIRMAGON to leuprorelin periodic (monthly) electrocardiograms (ECGs) were performed; 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 section 5.1).
FIRMAGON has not been studied in patients with a history of a corrected QT interval over 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 sections 4.5 and 4.8).
A thorough QT study showed that there was no intrinsic effect of degarelix on QT/QTc interval (see section 4.8).
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 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 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.
Cardiovascular disease
Cardiovascular disease such as stroke and myocardial infarction has been reported in the medical literature in patients with androgen deprivation therapy. Therefore, all cardiovascular risk factors should be taken into account.
4.5 Interaction with other medicinal products and other forms of interaction
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 such as class IA (e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicinal products, methadone, moxifloxacin, antipsychotics, etc. should be carefully eva luated (see section 4.4).
Degarelix is not a substrate for the human CYP450 system and has not been shown to induce or inhibit CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4/5 to any great extent in vitro. Therefore, clinically significant pharmacokinetic drug-drug interactions in metabolism related to these isoenzymes are unlikely.
4.6 Fertility, pregnancy and lactation
Pregnancy and breast-feeding
There is no relevant indication for use of FIRMAGON in women.
Fertility
FIRMAGON may inhibit male fertility as long as the testosterone is suppressed.
4.7 Effects on ability to drive and use machines
FIRMAGON has no or negligible influence on the ability to drive and use machines. Fatigue and dizziness are common adverse reactions that might influence the ability to drive and use machines.
4.8 Undesirable effects
Summary of the safety profile
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 weight increase (reported in 25% and 7%, respectively, of patients receiving treatment for one year), or injection site adverse reactions. 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 reactions 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 pr 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%).
Tabulated list of adverse reactions
The frequency of undesirable effects listed below is defined using the following convention: Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to <1/1,000) and very rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Table 1: Frequency of adverse drug reactions reported in 1,259 patients treated for a total of 1781 patient years (phase II and III studies) and from post-marketing reports
*Known physiological consequence of testosterone suppression
Changes in laboratory parameters
Changes in laboratory values seen during one year of treatment in the confirmatory phase III study (N=409) were in the same range for degarelix and a GnRH-agonist (leuprorelin) used as comparator. Markedly abnormal (>3*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 μmol/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 one year of treatment in the confirmatory phase III study (N=409) were in the same range for degarelix and a GnRH-agonist (leuprorelin) used as comparator. Three (<1%) out of 409 patients in the degarelix group and four (2%) out of 201 patients in the leuprorelin 7.5 mg group, had a QTcF ≥ 500 msec. From baseline to end of study the median change in QTcF for degarelix was 12.0 msec and for leuprorelin was 16.7 msec.
The lack of intrinsic effect of degarelix on cardiac repolarisation (QTcF), heart rate, AV conduction, cardiac depolarisation, or T or U wave morphology was confirmed in a thorough QT study in healthy subjects (N=80) receiving an i.v. infusion of degarelix over 60 min, reaching a mean Cmax of 222 ng/mL, approx. 3-4-fold the Cmax obtained during prostate cancer treatment.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued 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
4.9 Overdose
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.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Endocrine therapy, Other hormone antagonists and related agents, ATC code: L02BX02
Mechanism of action
Degarelix is a selective gonadotrophin releasing-hormone (GnRH) antagonist 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 (T) 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 antagonists do not induce a LH surge with subsequent testosterone surge/tumour stimulation and potential symptomatic flare after the initiation of treatment.
A single dose of 240 mg degarelix, followed by a monthly maintenance dose of 80 mg, rapidly causes a decrease in the concentrations of LH, FSH and subsequently testosterone. The serum 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 one year. No testosterone microsurges were observed after re-injection during degarelix treatment. 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 was eva luated in an open-label, multi-centre, randomised, active comparator controlled, parallel-group study. The study investigated the efficacy and safety of two different degarelix monthly dosing regimens with a starting dose of 240 mg (40 mg/ml) followed by monthly doses subcutaneous administration of 160 mg (40 mg/ml) or 80 mg (20 mg/ml), in comparison to monthly intramuscular administration of 7.5 mg leuprorelin in patients with prostate cancer requiring androgen deprivation therapy. In total 620 patients were randomised to one of the three treatment groups, of which 504 (81%) patients completed the study. In the degarelix 240/80 mg treatment group 41 (20%) 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 PSA
Baseline demographics were similar between the arms. The median age was 74 years (range 47 to 98 years). The primary objective was to demonstrate that degarelix is effective with respect to achieving and maintaining testosterone suppression to below 0.5 ng/ml, during 12 months of treatment.
The lowest effective maintenance dose of 80 mg degarelix was chosen.
Attainment of serum testosterone (T) ≤0.5 ng/ml
FIRMAGON is effective in achieving fast testosterone suppression, see Table 2.
Table 2: Percentage of patients attaining T≤0.5 ng/ml after start of treatment
Avoidance of testosterone surge
Surge was defined as testosterone exceeding baseline by ≥15% within the first 2 weeks.
None of the degarelix-treated patients experienced a testosterone surge; there was an average decrease 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).
Figure 1: Percentage change in testosterone from baseline by treatment group until day 28 (median with interquartile ranges).
The primary end-point in the study was testosterone suppression rates after one year of treatment with degarelix or leuprorelin. The clinical benefit for degarelix compared to leuprorelin plus anti-androgen in the initial phase of treatment has not been demonstrated.
Testosterone Reversibility
In a study involving patients with rising PSA after localised therapy (mainly radical prostatectomy and radiation) were administered FIRMAGON for seven months followed by a seven months monitoring period. The median time to testosterone recovery (>0.5 ng/mL, above castrate level) after discontinuation of treatment was 112 days (counted from start of monitoring period, i.e 28 days after last injection). The median time to testosterone >1.5 ng/mL (above lower limit of normal range) was 168 days.
Long-term effect
Successful response in the study was defined as attainment of medical castration at day 28 and maintenance through day 364 where no single testosterone concentration was greater than 0.5 ng/ml.
Table 3: Cumulative probability of testosterone ≤0.5 ng/ml from Day 28 to Day 364.
* Kaplan Meier estimates within group
Attainment of prostate specific antigen (PSA) reduction
Tumour size was not measured directly during the clinical trial programme, but there was an 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 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 by treatment group until day 56 (median with interquartile ranges).
This difference was statistically significant (p<0.001) for the pre-specified analysis at day 14 and day 28.
Prostate specific antigen (PSA) levels are lowered by 64% two weeks after administration of degarelix, 85% after one month, 95% after three months, and remained suppressed (approximately 97%) throughout the one year of treatment.
From day 56 to day 364 there were no significant differences between degarelix and the comparator in the percentage change from baseline.
Effect on prostate volume
Three months therapy with degarelix (240/80 mg dose regimen) resulted in a 37% reduction in prostate volume as measured by trans-rectal ultrasound scan (TRUS) in patients requiring hormonal therapy prior to radiotherapy and in patients who were candidates for medical castration. The prostate volume reduction was similar to that attained with goserelin plus anti-androgen protection.
Effect on QT/QTc intervals
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 12.0 msec and for leuprorelin it was 16.7 msec.
Anti-degarelix antibody
Anti-degarelix antibody development has been observed in 10% of patients after treatment with FIRMAGON for one year and 29% of patients after treatment with FIRMAGON for up to 5.5 years. There is no indication that the efficacy or safety of FIRMAGON treatment is affected by antibody formation after up to 5.5 years of treatment.
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with FIRMAGON in all subsets of the paediatric population (see section 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties
Absorption
Following subcutaneous administration of 240 mg degarelix 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 66.0 (61.0-71.0) ng/ml and occurred at tmax at 40 (37-42) hours. 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. Cmax degarelix plasma concentration decreases in a biphasic fashion, with a mean terminal half-life (t½) of 29 days for the maintenance dose. The long half-life after subcutaneous administration is a consequence of a very slow release of degarelix from the depot formed at the injection site(s). The pharmacokinetic behaviour of the medicinal product is influenced by its concentration in the solution for injection. Thus, Cmax and bioavailability tend to decrease with increasing dose concentration while the half-life 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%.
Biotransformation
Degarelix is subject to common peptidic degradation during the passage of 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. In vitro studies have shown that degarelix is not a substrate for the human CYP450 system.
Elimination
In healthy men, approximately 20-30% of a single intravenously administered dose is excreted in the urine, suggesting that 70-80% is excreted via the hepato-biliary system. The clearance of degarelix when administered as single intravenous doses (0.864-49.4 µg/kg) in healthy elderly men was found to be 35-50 ml/h/kg.
Special populations
Patients with 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.
Patients with 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.
5.3 Preclinical safety data
Animal reproduction studies showed that degarelix caused infertility in male animals. This is due to the pharmacological effect; and the effect was reversible.
In female reproduction toxicity studies degarelix revealed findings expected from the pharmacological properties. It caused a dosage dependent prolongation of the time to mating and to pregnancy, a reduced number of corpora lutea, and an increase in the number of pre- and post-implantation losses, abortions, early embryo/foetal deaths, premature deliveries and in the duration of parturition.
Preclinical studies on safety pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential revealed no special hazard for humans. Both in vitro and in vivo studies showed no signs of QT prolongation.
No target organ toxicity was observed from acute, subacute and chronic toxicity studies in rats and monkeys following subcutaneous administration of degarelix. Drug-related local irritation was noted in animals when degarelix was administered subcutaneously in high doses.
6. Pharmaceutical particulars
6.1 List of excipients
Powder
Mannitol (E421)
Solvent
Water for injections
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
6.3 Shelf life
3 years.
After reconstitution
Chemical and physical in-use stability has been demonstrated for 2 hours at 25°C. From a microbiological point of view, unless the method of reconstitution precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
For storage conditions of the reconstituted medicinal product, see section 6.3.
6.5 Nature and contents of container
Glass (type I) vial with bromobutyl rubber stopper and aluminium flip-off seal containing 120 mg powder for solution for injection
Pre-filled glass (type I) syringe with elastomer plunger stopper, tip cap and line-marking at 3 ml containing 3 ml solvent
Plunger rod
Vial adapter
Injection needle (25G 0.5 x 25 mm)
Pack size
Pack-size of 2 trays containing 2 powder vials, 2 solvent pre-filled syringes, 2 plunger rods, 2 vial adapters and 2 needles
6.6 Special precautions for disposal and other handling
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.
NOTE:
• THE VIALS SHOULD NOT BE SHAKEN
The pack contains two vials of powder and two pre-filled syringes with solvent that must be prepared for subcutaneous injection. Hence, the procedure described below need to be repeated a second time.
1 . Remove the cover from the vial adapter pack. Attach the adapters to the powder vial by pressing the adapter down until the spike pushes through the rubber stopper and the adapter snaps in place.
2 . Prepare the pre-filled syringe by attaching the plunger rod.
3 . Remove the cap of the pre-filled syringe. Attach the syringe to the powder vial by screwing it on to the adapter. Transfer all solvent to the powder vial
4. With the syringe still attached to the adapter, swirl gently until the liquid looks clear and without undissolved powder or particles. If the powder adheres to the side of the vial above 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 usually takes a few minutes, but may take up to 15 minutes in some cases.
5. Turn the vial upside down and draw up to the line mark on the syringe for injection.
Always make sure to withdraw the precise volume and adjust for any air bubbles.
6. Detach the syringe from the vial adapter and attach the needle for deep subcutaneous injection to the syringe.
7. Perform a deep subcutaneous injection. To do so: grasp the skin of the abdomen, elevate the subcutaneous tissue and insert the needle deeply at an angle of not less than 45 degrees.
Inject 3 ml of FIRMAGON 120 mg slowly, immediately after reconstitution.
8. No injections should be given in areas where the patient will be exposed to pressure, e.g. around the belt or waistband or close to the ribs.
Do not inject directly into a vein. Gently pull back the plunger to check if blood is aspirated. If blood appears in the syringe, the medicinal product can no longer be used. Discontinue the procedure and discard the syringe and the needle (reconstitute a new dose for the patient).
9. Repeat the reconstitution procedure for the second dose. Choose a different injection site and inject 3 ml.
No special requirements for disposal.
7. Marketing authorisation holder
Ferring Pharmaceuticals A/S
Kay Fiskers Plads 11
DK-2300 Copenhagen S
Denmark
Tel: +45 88 33 88 34
8. Marketing authorisation number(s)
EU/1/08/504/002
9. Date of first authorisation/renewal of the authorisation
17/02/2009
10. Date of revision of the text
28 November 2013
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu/
----------------------------------------------------
附件:
201071400533514.pdf

中文说明

（免责声明：本说明书仅供参考，不作为治疗的依据，不可取代任何医生、药剂师等专业性的指导。本站不提供治疗建议，药物是否适合您，请专业医生（或药剂师）决定。）

简介：

 

欧洲批准Firmagon(degarelix)用于前列腺癌
Ferring公司近日表示欧洲药品审评中心（EMEA）近日推荐批准Firmagon (degarelix)用于晚期激素依赖型前列腺癌，其为一种促性腺激素释放激素(GnRH)受体抑制剂。在3期试验中显示使用Firmagon三天96%受试者的睾丸激素水平显著下降，睾丸激素在前列腺癌细胞的生长与扩散方面有重要作用。
数据显示Firmagon可对睾丸激素水平产生超快速的作用，与进行睾丸切除术的快速作用相似。这项试验比较了每月一次使用Firmagon与每月使用一次缓释亮丙瑞林的作用，显示Firmagon抑制睾丸激素与前列腺特异抗原(PSA)的效果更快，此外在12个月的试验中 Firmagon始终能产生持续作用。
FIRMAGON是注射 含degarelix无菌冻干粉（如醋酸）和甘露醇。Degarelix是合成 线性肽酰胺含七自然氨基酸，其中五 是damino酸。已经经过乙酸盐是一种白色无定形粉末 低密度后得到的冻干。
用法与用量
定量信息
FIRMAGON管理作为 腹部皮下注射。
第一维持剂量应 起始剂量后28天。
适应症
FIRMAGON是促性腺激素释放激素受体拮抗剂用于晚期患者治疗 前列腺癌。
与皮下 注射其他药物，注射部位应周期性变化。注射应 在腹部，将不会受到压力，地区如不 接近腰带或皮带或紧贴肋骨。
警告及注意事项
（1）在怀孕期间使用
怀孕或可能怀孕的妇女不应该 FIRMAGON
（2）过敏反应
过敏反应，包括过敏反应，荨麻疹和血管性水肿上市后，已报告有FIRMAGON。在严重的过敏反应 情况，立即停止 FIRMAGON 如果注入尚未完成，和管理的临床指征。 患者已知的严重过敏反应史 FIRMAGON 不应再挑战。
（3）QT / QTc间期的影响
雄激素剥夺治疗可能延长QT间期。 提供者应利益考虑是否 雄激素剥夺治疗的潜在风险 大于在先天性 长QT综合征，充血性心力衰竭，频繁的电解质异常，在患者 服用QT间期延长。电解质异常应 被纠正。考虑 定期监测心电图和电解质。
在随机对照研究中，主动 FIRMAGON对醋酸亮丙瑞林，定期进行心电图。七 患者，三（＜1%）在汇总degarelix组和四（2%）患者 在醋酸亮丙瑞林7.5毫克组，有一个≥QTcF间500毫秒。从基线到 研究 端，为FIRMAGON中位数的变化为12.3毫秒，16.7毫秒 醋酸亮丙瑞林。
FIRMAGON的初始剂量为240毫克，给予皮下注射120毫克每两。维持剂量是一个单一的注射80毫克每28天。其他药物相互作用与FIRMAGON。告诉你的医生你的所有药物的使用。FIRMAGON不是用于女性，所以，怀孕的妇女，谁可能怀孕或正在哺乳不应该FIRMAGON。
副作用
因为临床试验广泛 变化的条件下进行的，不良反应发生率观察到一 药物的临床试验不能直接相比，在另一 药物和临床试验的利率可能不会反映在实践中发现率。
共1325例前列腺癌收到 FIRMAGON是每月处理（60-160毫克）或作为一个单一的剂量（高达 320毫克）。共有1032例患者（78%）有至少6个月， 治疗的853例患者（64%）有一年以上的治疗。最常见的 FIRMAGON治疗期间观察不良反应包括注射部位反应（例如，疼痛 ，红斑，肿胀或硬结），潮热 ，增加体重，疲劳，和血清转氨酶和 γ-谷氨酰转移酶（GGT）水平增加。的不良反应多数是 1年级或2、3级4 / 1%或更少的不良反应发生率。
在主动控制试验研究（n = FIRMAGON 610）在前列腺癌患者随机接受FIRMAGON （皮下）或肌肉）每月为12个月。不良反应报告 5%或更多的患者如表1所示。
最常见的不良反应是 注射部位疼痛（28%）、红斑（17%）、肿胀（6%）、硬结（4%） 结节（3%）。这些不良反应大多都是短暂的，轻度到中等强度的 ，主要发生的起始剂量，导致几 中断（＜1%）。3年级的注射部位反应发生在2%或更少的患者 degarelix。
Firmagon 120mg Injection
1. Name of the medicinal product
FIRMAGON 120 mg powder and solvent for solution for injection
2. Qualitative and quantitative composition
Each vial contains 120 mg degarelix (as acetate). After reconstitution, each ml of solution contains 40 mg of degarelix.
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
Powder and solvent for solution for injection.
Powder: White to off-white powder
Solvent: Clear, colourless solution
4. Clinical particulars
4.1 Therapeutic indications
FIRMAGON is a gonadotrophin releasing hormone (GnRH) antagonist indicated for treatment of adult male patients with advanced hormone-dependent prostate cancer.
4.2 Posology and method of administration
Posology
The first maintenance dose should be given one month after the starting dose.
The therapeutic effect of degarelix should be monitored by clinical parameters and prostate specific antigen (PSA) serum levels. Clinical studies have shown that testosterone (T) suppression occurs immediately after administration of the starting dose with 96% of the patients having serum testosterone levels corresponding to medical castration (T≤0.5 ng/ml) after three days and 100% after one 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 anti-androgen as surge protection at initiation of therapy.
Special populations
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 section 5.2). Patients with severe liver or kidney impairment have not been studied and caution is therefore warranted (see section 4.4).
Paediatric population
There is no relevant use of FIRMAGON in children and adolescents in the treatment of adult male patients with advanced hormone-dependent prostate cancer.
Method of administration
FIRMAGON must be reconstituted prior to administration. For instructions on reconstitution and administration, please see section 6.6.
FIRMAGON is for subcutaneous use ONLY, not to be administered intravenously. Intramuscular administration is not recommended as it has not been studied.
FIRMAGON is administered as a subcutaneous injection in the abdominal region. The injection site should vary periodically. Injections should be given in areas where the patient will not be exposed to pressure e.g. not close to waistband or belt and not close to the ribs.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.
4.4 Special warnings and precautions for use
Effect on QT/QTc interval
Long-term androgen deprivation therapy may prolong the QT interval. In the confirmatory study comparing FIRMAGON to leuprorelin periodic (monthly) electrocardiograms (ECGs) were performed; 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 section 5.1).
FIRMAGON has not been studied in patients with a history of a corrected QT interval over 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 sections 4.5 and 4.8).
A thorough QT study showed that there was no intrinsic effect of degarelix on QT/QTc interval (see section 4.8).
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 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 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.
Cardiovascular disease
Cardiovascular disease such as stroke and myocardial infarction has been reported in the medical literature in patients with androgen deprivation therapy. Therefore, all cardiovascular risk factors should be taken into account.
4.5 Interaction with other medicinal products and other forms of interaction
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 such as class IA (e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicinal products, methadone, moxifloxacin, antipsychotics, etc. should be carefully eva luated (see section 4.4).
Degarelix is not a substrate for the human CYP450 system and has not been shown to induce or inhibit CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4/5 to any great extent in vitro. Therefore, clinically significant pharmacokinetic drug-drug interactions in metabolism related to these isoenzymes are unlikely.
4.6 Fertility, pregnancy and lactation
Pregnancy and breast-feeding
There is no relevant indication for use of FIRMAGON in women.
Fertility
FIRMAGON may inhibit male fertility as long as the testosterone is suppressed.
4.7 Effects on ability to drive and use machines
FIRMAGON has no or negligible influence on the ability to drive and use machines. Fatigue and dizziness are common adverse reactions that might influence the ability to drive and use machines.
4.8 Undesirable effects
Summary of the safety profile
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 weight increase (reported in 25% and 7%, respectively, of patients receiving treatment for one year), or injection site adverse reactions. 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 reactions 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 pr 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%).
Tabulated list of adverse reactions
The frequency of undesirable effects listed below is defined using the following convention: Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to <1/1,000) and very rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Table 1: Frequency of adverse drug reactions reported in 1,259 patients treated for a total of 1781 patient years (phase II and III studies) and from post-marketing reports
*Known physiological consequence of testosterone suppression
Changes in laboratory parameters
Changes in laboratory values seen during one year of treatment in the confirmatory phase III study (N=409) were in the same range for degarelix and a GnRH-agonist (leuprorelin) used as comparator. Markedly abnormal (>3*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 μmol/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 one year of treatment in the confirmatory phase III study (N=409) were in the same range for degarelix and a GnRH-agonist (leuprorelin) used as comparator. Three (<1%) out of 409 patients in the degarelix group and four (2%) out of 201 patients in the leuprorelin 7.5 mg group, had a QTcF ≥ 500 msec. From baseline to end of study the median change in QTcF for degarelix was 12.0 msec and for leuprorelin was 16.7 msec.
The lack of intrinsic effect of degarelix on cardiac repolarisation (QTcF), heart rate, AV conduction, cardiac depolarisation, or T or U wave morphology was confirmed in a thorough QT study in healthy subjects (N=80) receiving an i.v. infusion of degarelix over 60 min, reaching a mean Cmax of 222 ng/mL, approx. 3-4-fold the Cmax obtained during prostate cancer treatment.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued 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
4.9 Overdose
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.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Endocrine therapy, Other hormone antagonists and related agents, ATC code: L02BX02
Mechanism of action
Degarelix is a selective gonadotrophin releasing-hormone (GnRH) antagonist 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 (T) 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 antagonists do not induce a LH surge with subsequent testosterone surge/tumour stimulation and potential symptomatic flare after the initiation of treatment.
A single dose of 240 mg degarelix, followed by a monthly maintenance dose of 80 mg, rapidly causes a decrease in the concentrations of LH, FSH and subsequently testosterone. The serum 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 one year. No testosterone microsurges were observed after re-injection during degarelix treatment. 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 was eva luated in an open-label, multi-centre, randomised, active comparator controlled, parallel-group study. The study investigated the efficacy and safety of two different degarelix monthly dosing regimens with a starting dose of 240 mg (40 mg/ml) followed by monthly doses subcutaneous administration of 160 mg (40 mg/ml) or 80 mg (20 mg/ml), in comparison to monthly intramuscular administration of 7.5 mg leuprorelin in patients with prostate cancer requiring androgen deprivation therapy. In total 620 patients were randomised to one of the three treatment groups, of which 504 (81%) patients completed the study. In the degarelix 240/80 mg treatment group 41 (20%) 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 PSA
Baseline demographics were similar between the arms. The median age was 74 years (range 47 to 98 years). The primary objective was to demonstrate that degarelix is effective with respect to achieving and maintaining testosterone suppression to below 0.5 ng/ml, during 12 months of treatment.
The lowest effective maintenance dose of 80 mg degarelix was chosen.
Attainment of serum testosterone (T) ≤0.5 ng/ml
FIRMAGON is effective in achieving fast testosterone suppression, see Table 2.
Table 2: Percentage of patients attaining T≤0.5 ng/ml after start of treatment
Avoidance of testosterone surge
Surge was defined as testosterone exceeding baseline by ≥15% within the first 2 weeks.
None of the degarelix-treated patients experienced a testosterone surge; there was an average decrease 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).
Figure 1: Percentage change in testosterone from baseline by treatment group until day 28 (median with interquartile ranges).
The primary end-point in the study was testosterone suppression rates after one year of treatment with degarelix or leuprorelin. The clinical benefit for degarelix compared to leuprorelin plus anti-androgen in the initial phase of treatment has not been demonstrated.
Testosterone Reversibility
In a study involving patients with rising PSA after localised therapy (mainly radical prostatectomy and radiation) were administered FIRMAGON for seven months followed by a seven months monitoring period. The median time to testosterone recovery (>0.5 ng/mL, above castrate level) after discontinuation of treatment was 112 days (counted from start of monitoring period, i.e 28 days after last injection). The median time to testosterone >1.5 ng/mL (above lower limit of normal range) was 168 days.
Long-term effect
Successful response in the study was defined as attainment of medical castration at day 28 and maintenance through day 364 where no single testosterone concentration was greater than 0.5 ng/ml.
Table 3: Cumulative probability of testosterone ≤0.5 ng/ml from Day 28 to Day 364.
* Kaplan Meier estimates within group
Attainment of prostate specific antigen (PSA) reduction
Tumour size was not measured directly during the clinical trial programme, but there was an 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 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 by treatment group until day 56 (median with interquartile ranges).
This difference was statistically significant (p<0.001) for the pre-specified analysis at day 14 and day 28.
Prostate specific antigen (PSA) levels are lowered by 64% two weeks after administration of degarelix, 85% after one month, 95% after three months, and remained suppressed (approximately 97%) throughout the one year of treatment.
From day 56 to day 364 there were no significant differences between degarelix and the comparator in the percentage change from baseline.
Effect on prostate volume
Three months therapy with degarelix (240/80 mg dose regimen) resulted in a 37% reduction in prostate volume as measured by trans-rectal ultrasound scan (TRUS) in patients requiring hormonal therapy prior to radiotherapy and in patients who were candidates for medical castration. The prostate volume reduction was similar to that attained with goserelin plus anti-androgen protection.
Effect on QT/QTc intervals
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 12.0 msec and for leuprorelin it was 16.7 msec.
Anti-degarelix antibody
Anti-degarelix antibody development has been observed in 10% of patients after treatment with FIRMAGON for one year and 29% of patients after treatment with FIRMAGON for up to 5.5 years. There is no indication that the efficacy or safety of FIRMAGON treatment is affected by antibody formation after up to 5.5 years of treatment.
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with FIRMAGON in all subsets of the paediatric population (see section 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties
Absorption
Following subcutaneous administration of 240 mg degarelix 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 66.0 (61.0-71.0) ng/ml and occurred at tmax at 40 (37-42) hours. 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. Cmax degarelix plasma concentration decreases in a biphasic fashion, with a mean terminal half-life (t½) of 29 days for the maintenance dose. The long half-life after subcutaneous administration is a consequence of a very slow release of degarelix from the depot formed at the injection site(s). The pharmacokinetic behaviour of the medicinal product is influenced by its concentration in the solution for injection. Thus, Cmax and bioavailability tend to decrease with increasing dose concentration while the half-life 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%.
Biotransformation
Degarelix is subject to common peptidic degradation during the passage of 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. In vitro studies have shown that degarelix is not a substrate for the human CYP450 system.
Elimination
In healthy men, approximately 20-30% of a single intravenously administered dose is excreted in the urine, suggesting that 70-80% is excreted via the hepato-biliary system. The clearance of degarelix when administered as single intravenous doses (0.864-49.4 µg/kg) in healthy elderly men was found to be 35-50 ml/h/kg.
Special populations
Patients with 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.
Patients with 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.
5.3 Preclinical safety data
Animal reproduction studies showed that degarelix caused infertility in male animals. This is due to the pharmacological effect; and the effect was reversible.
In female reproduction toxicity studies degarelix revealed findings expected from the pharmacological properties. It caused a dosage dependent prolongation of the time to mating and to pregnancy, a reduced number of corpora lutea, and an increase in the number of pre- and post-implantation losses, abortions, early embryo/foetal deaths, premature deliveries and in the duration of parturition.
Preclinical studies on safety pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential revealed no special hazard for humans. Both in vitro and in vivo studies showed no signs of QT prolongation.
No target organ toxicity was observed from acute, subacute and chronic toxicity studies in rats and monkeys following subcutaneous administration of degarelix. Drug-related local irritation was noted in animals when degarelix was administered subcutaneously in high doses.
6. Pharmaceutical particulars
6.1 List of excipients
Powder
Mannitol (E421)
Solvent
Water for injections
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
6.3 Shelf life
3 years.
After reconstitution
Chemical and physical in-use stability has been demonstrated for 2 hours at 25°C. From a microbiological point of view, unless the method of reconstitution precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
For storage conditions of the reconstituted medicinal product, see section 6.3.
6.5 Nature and contents of container
Glass (type I) vial with bromobutyl rubber stopper and aluminium flip-off seal containing 120 mg powder for solution for injection
Pre-filled glass (type I) syringe with elastomer plunger stopper, tip cap and line-marking at 3 ml containing 3 ml solvent
Plunger rod
Vial adapter
Injection needle (25G 0.5 x 25 mm)
Pack size
Pack-size of 2 trays containing 2 powder vials, 2 solvent pre-filled syringes, 2 plunger rods, 2 vial adapters and 2 needles
6.6 Special precautions for disposal and other handling
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.
NOTE:
• THE VIALS SHOULD NOT BE SHAKEN
The pack contains two vials of powder and two pre-filled syringes with solvent that must be prepared for subcutaneous injection. Hence, the procedure described below need to be repeated a second time.
1 . Remove the cover from the vial adapter pack. Attach the adapters to the powder vial by pressing the adapter down until the spike pushes through the rubber stopper and the adapter snaps in place.
2 . Prepare the pre-filled syringe by attaching the plunger rod.
3 . Remove the cap of the pre-filled syringe. Attach the syringe to the powder vial by screwing it on to the adapter. Transfer all solvent to the powder vial
4. With the syringe still attached to the adapter, swirl gently until the liquid looks clear and without undissolved powder or particles. If the powder adheres to the side of the vial above 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 usually takes a few minutes, but may take up to 15 minutes in some cases.
5. Turn the vial upside down and draw up to the line mark on the syringe for injection.
Always make sure to withdraw the precise volume and adjust for any air bubbles.
6. Detach the syringe from the vial adapter and attach the needle for deep subcutaneous injection to the syringe.
7. Perform a deep subcutaneous injection. To do so: grasp the skin of the abdomen, elevate the subcutaneous tissue and insert the needle deeply at an angle of not less than 45 degrees.
Inject 3 ml of FIRMAGON 120 mg slowly, immediately after reconstitution.
8. No injections should be given in areas where the patient will be exposed to pressure, e.g. around the belt or waistband or close to the ribs.
Do not inject directly into a vein. Gently pull back the plunger to check if blood is aspirated. If blood appears in the syringe, the medicinal product can no longer be used. Discontinue the procedure and discard the syringe and the needle (reconstitute a new dose for the patient).
9. Repeat the reconstitution procedure for the second dose. Choose a different injection site and inject 3 ml.
No special requirements for disposal.
7. Marketing authorisation holder
Ferring Pharmaceuticals A/S
Kay Fiskers Plads 11
DK-2300 Copenhagen S
Denmark
Tel: +45 88 33 88 34
8. Marketing authorisation number(s)
EU/1/08/504/002
9. Date of first authorisation/renewal of the authorisation
17/02/2009
10. Date of revision of the text
28 November 2013
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu/
----------------------------------------------------
附件:
201071400533514.pdf

外文说明

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Indications and Usage for Firmagon

Firmagon is a GnRH receptor antagonist indicated for treatment of patients with advanced prostate cancer.




Firmagon Dosage and AdministrationDosing information

Firmagon is administered as a subcutaneous injection in the abdominal region only.

Starting dose

Maintenance dose – Administration every 28 days

240 mg given as two subcutaneous injections of 120 mg at a concentration of 40 mg/mL

80 mg given as one subcutaneous injection at a concentration of 20 mg/mL

The first maintenance dose should be given 28 days after the starting dose.

Reconstitution and Administration Instructions

Firmagon® is to be administered by a healthcare professional only. Before administering Firmagon read the Instructions for reconstitution and administration carefully.

As with other drugs administered by subcutaneous injection, the injection site should vary periodically. Injections should be given in areas of the abdomen that will not be exposed to pressure, e.g., not close to waistband or belt nor close to the ribs.

Firmagon is supplied as a powder to be reconstituted with Sterile Water for Injection, USP (WFI). The instruction for reconstitution needs to be carefully followed. Administration of other concentrations is not recommended. Read the complete instructions before performing the injection.

NOTE: Firmagon is for subcutaneous administration to the abdominal region only.

·         Reconstituted drug must be administered within one hour after addition of Sterile Water for Injection, USP.

·         Do not shake the vials.

Follow aseptic technique.

Firmagon 240 mg Starting Dose Kit contains:

·         2 vials containing the 120 mg Firmagon® powder (a)

·         2 syringes containing Sterile Water for Injection, USP (b)

·         2 vial adapters (c)

·         2 injection needles (d)

·         2 plunger rods (e)

Firmagon 80 mg Maintenance Dose Kit contains:

·         1 vial containing the 80 mg Firmagon® powder (f)

·         1 syringe containing Sterile Water for Injection, USP (g)

·         1 vial adapter (h)

·         1 injection needle (i)

·         1 plunger rod (j)

In addition the healthcare professional will need:

·         gloves (k)

·         alcohol pads (l)

·         a clean, flat surface (m) to work on, like a table

·         a sharps disposal container (n) for throwing away your used needles and syringes. See "Disposing used needles and syringes" at the end of these instructions.

The drug product must be prepared using the following instructions:

NOTE: The mixing process must be repeated for the two injections of the Starting Dose prior to injecting the product into the patient's abdomen.

Step 1: Attaching the vial adaptor to the vial

·         Thoroughly wash your hands using soap and water and put on a pair of clean gloves.

·         Place all the supplies required on a clean surface.

·         Check that there is powder in the Firmagon® vial and that the Sterile Water, USP is clear and free from particles.

IMPORTANT: DO NOT USE if there is no powder in the vial or the Sterile Water, USP is discolored.

·         Uncap the vial containing the Firmagon® powder (o).

·         Wipe the vial rubber stopper with an alcohol pad.

IMPORTANT: Do not touch the top of the vial after wiping.

·         Peel off the seal from the vial adaptor cover.

IMPORTANT: Do not touch the vial adapter.

·         Firmly press the vial adaptor (p) onto the vial containing the Firmagon® powder until the adaptor snaps into place.

·         Pull the vial adaptor cover off the vial.

Step 2: Assembling the syringe

·         Insert the plunger rod (q) into the prefilled syringe containing Sterile Water, USP (r) and screw the plunger rod clockwise to tighten.

IMPORTANT: Do not pull the back stopper (flange) (s) off the syringe.

NOTE: You will only feel light resistance screwing the plunger rod in position.

Step 3: Transferring sterile water, USP from the syringe to the vial

·         Unscrew the gray syringe plug (t) attached to the Luer lock adaptor on the syringe.

IMPORTANT: Do not pull off the Luer lock adaptor (u).

·         Carefully twist the prefilled syringe containing sterile water, USP onto the vial adapter on the Firmagon® powder vial, until it is tight.

IMPORTANT: Be careful not to over twist the syringe.

·         Press the plunger slowly to transfer all the sterile water, USP from the syringe to the Firmagon® powder vial.

Step 4: Preparing the reconstituted injection

·         With the syringe still attached to the vial adaptor, swirl gently until the liquid is clear with no powder or visible particles.

IMPORTANT:

·         Do not shake the vial as this will cause bubbles.

·         Reconstitute just prior to administration.

NOTE: If the powder adheres to the side of the vial, tilt the vial slightly. A ring of small air bubbles on the surface of the liquid is acceptable.
Reconstitution time can take up to 15 min but usually takes a few minutes.

Step 5: Transferring the liquid to the syringe

·         Turn the vial completely upside down and pull down the plunger to withdraw all of the reconstituted liquid from the vial to the syringe.

·         Tap the syringe gently with your fingers to raise air bubbles in the syringe tip.

·         Press the plunger to the line marked on the syringe to expel all air bubbles.

Step 6: Preparing the syringe for injection

·         Holding the vial adaptor detach the syringe from the vial by unscrewing the syringe from the vial adaptor.

NOTE: Reconstitute just prior to administration.

·         While holding the syringe with the tip pointing up, screw the injection needle (v) clockwise (right) onto the syringe.

Step 7: Preparing the patient

·         Select one of the four available injection sites on the abdomen.

IMPORTANT:

o    Do not inject in areas where the patient will be exposed to pressure, such as area around the belt of the waistband or close to the ribs.

o    Vary the injection site periodically during treatment to minimize discomfort to the patient.

·         Clean the injection site with an alcohol pad.

Step 8: Performing the injection

·         Move the needle shield (w) away from the needle and carefully remove the needle cover (x).

·         Pinch and elevate the skin of the abdomen.

·         Insert the needle into the skin at a 45 degree angle all the way to the hub.

·         Do not inject into a vein or muscle. Gently pull back the plunger to check if blood is aspirated.

IMPORTANT: If blood appears in the syringe, the product should not be injected. Discontinue the injection and discard the syringe and the needle (reconstitute a new dose for the patient).

·         Perform a slow, deep subcutaneous injection over 30 seconds.

·         Remove the needle and then release the skin.

IMPORTANT: Do not rub the injection site after retracting the needle.

Step 9: Locking the needle into the shield

·         Position the needle shield approximately 45 degrees to a flat surface.

·         Press down with a firm, quick motion until a distinct, audible "click" is heard.

·         Visually confirm that the needle is fully engaged under the lock (y).

IMPORTANT: Syringe is for single use only. Do not reuse the syringe and needle.

Step 10: Advising the patient

·         Instruct the patient not to rub or scratch the injection site.

·         Inform that some patients may feel a lump at the injection site and experience redness, soreness and discomfort for a few days after the injection.

Disposing used needles and syringes

·         Put used alcohol swabs, needles and syringes in an FDA-cleared sharps disposal container right away after use. Do not throw away loose needles and syringes in the trash.

·         For more information about safe sharps disposal, go to the FDA's website at: http://www.fda.gov/safesharpsdisposal.

Dosage Forms and Strengths

Starting dose

One starting dose comprises 240 mg given as two 3 mL injections of 120 mg each.

Powder for injection 120 mg:

One vial of Firmagon 120 mg contains 120 mg degarelix. Each vial is to be reconstituted with a prefilled syringe containing 3 mL of Sterile Water for Injection. 3 mL is withdrawn to deliver 120 mg degarelix at a concentration of 40 mg/mL.

Maintenance dose

One maintenance dose comprises 80 mg given as one 4 mL injection.

Powder for injection 80 mg:

One vial of Firmagon 80 mg contains 80 mg degarelix. Each vial is to be reconstituted with a prefilled syringe containing 4.2 mL of Sterile Water for Injection. 4 mL is withdrawn to deliver 80 mg degarelix at a concentration of 20 mg/mL.

Contraindications

Firmagon is contraindicated in patients with known hypersensitivity to degarelix or to any of the product components. [see Warnings and Precautions (5.2)].

Degarelix is contraindicated in women who are or may become pregnant. Degarelix can cause fetal harm when administered to a pregnant woman. Degarelix given to rabbits during organogenesis at doses that were 0.02% of the clinical loading dose (240 mg) on a mg/m2 basis caused embryo/fetal lethality and abortion. When degarelix was given to female rats during organogenesis, at doses that were just 0.036% of the clinical loading dose on an mg/m2 basis, there was an increase post implantation loss and a decrease in the number of live fetuses. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Warnings and PrecautionsUse in Pregnancy

Pregnancy Category X

Women who are or may become pregnant should not take Firmagon [see Contraindications (4) and Use in Specific Populations (8.1)].

Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylaxis, urticaria and angioedema, have been reported post-marketing with Firmagon. In case of a serious hypersensitivity reaction, discontinue Firmagon immediately if the injection has not been completed, and manage as clinically indicated. Patients with a known history of serious hypersensitivity reactions to Firmagon should not be re-challenged with Firmagon.

Effect on QT/QTc Interval

Androgen deprivation therapy may prolong the QT interval. Providers should consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients with congenital long QT syndrome, congestive heart failure, frequent electrolyte abnormalities, and in patients taking drugs known to prolong the QT interval. Electrolyte abnormalities should be corrected. Consider periodic monitoring of electrocardiograms and electrolytes.

In the randomized, active-controlled trial comparing Firmagon to leuprolide, periodic electro-cardiograms were performed. Seven patients, three (<1%) in the pooled degarelix group and four (2%) patients in the leuprolide 7.5 mg group, had a QTcF ≥ 500 msec. From baseline to end of study, the median change for Firmagon was 12.3 msec and for leuprolide was 16.7 msec.

Laboratory Testing

Therapy with Firmagon results in suppression of the pituitary gonadal system. Results of diagnostic tests of the pituitary gonadotropic and gonadal functions conducted during and after Firmagon may be affected. The therapeutic effect of Firmagon should be monitored by measuring serum concentrations of prostate-specific antigen (PSA) periodically. If PSA increases, serum concentrations of testosterone should be measured.

Adverse Reactions

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

A total of 1325 patients with prostate cancer received Firmagon either as a monthly treatment (60-160 mg) or as a single dose (up to 320 mg). A total of 1032 patients (78%) were treated for at least 6 months and 853 patients (64%) were treated for one year or more. The most commonly observed adverse reactions during Firmagon therapy included injection site reactions (e.g., pain, erythema, swelling or induration), hot flashes, increased weight, fatigue, and increases in serum levels of transaminases and gamma-glutamyltransferase (GGT). The majority of the adverse reactions were Grade 1 or 2, with Grade 3/4 adverse reaction incidences of 1% or less.

Firmagon was studied in an active-controlled trial (N = 610) in which patients with prostate cancer were randomized to receive Firmagon (subcutaneous) or leuprolide (intramuscular) monthly for 12 months. Adverse reactions reported in 5% of patients or more are shown in Table 1.

Table 1. Adverse Reactions Reported in ≥ 5% of Patients in an Active Controlled Study

Firmagon
240/160 mg
(subcutaneous)
N = 202

Firmagon
240/80 mg
(subcutaneous)
N = 207

Leuprolide
7.5 mg
(intramuscular)
N = 201

Percentage of subjects with adverse events

83%

79%

78%

Body as a whole

Injection site adverse events

44%

35%

<1%

Weight increase

11%

9%

12%

Fatigue

6%

3%

6%

Chills

4%

5%

0%

Cardiovascular system

Hot flash

26%

26%

21%

Hypertension

7%

6%

4%

Musculoskeletal system

Back pain

6%

6%

8%

Arthralgia

4%

5%

9%

Urogenital system

Urinary tract infection

2%

5%

9%

Digestive system

Increases in Transaminases and GGT

10%

10%

5%

Constipation

3%

5%

5%

The most frequently reported adverse reactions at the injection sites were pain (28%), erythema (17%), swelling (6%), induration (4%) and nodule (3%). These adverse reactions were mostly transient, of mild to moderate intensity, occurred primarily with the starting dose and led to few discontinuations (<1%). Grade 3 injection site reactions occurred in 2% or less of patients receiving degarelix.

Hepatic laboratory abnormalities were primarily Grade 1 or 2 and were generally reversible. Grade 3 hepatic laboratory abnormalities occurred in less than 1% of patients.

In 1-5% of patients the following adverse reactions, not already listed, were considered related to Firmagon by the investigator:

Body as a whole: Asthenia, fever, night sweats; Digestive system: Nausea; Nervous system: Dizziness, headache, insomnia.

The following adverse reactions, not already listed, were reported to be drug-related by the investigator in ≥1% of patients: erectile dysfunction, gynecomastia, hyperhidrosis, testicular atrophy, and diarrhea.

The safety of Firmagon administered monthly was evaluated further in an extension study in 385 patients who completed the above active-controlled trial. Of the 385 patients, 251 patients continued treatment with Firmagon and 135 patients crossed over treatment from leuprolide to Firmagon. The median treatment duration on the extension study was approximately 43 months (range 1 to 58 months). The most common adverse reactions reported in ≥10% of the patients were injection site reactions (e.g., pain, erythema, swelling, induration or inflammation), pyrexia, hot flush, weight loss or gain, fatigue, increases in serum levels of hepatic transaminases and GGT. One percent of patients had injection site infections including abscess. Hepatic laboratory abnormalities in the extension study included the following: Grade 1/2 elevations in hepatic transaminases occurred in 47% of patients and Grade 3 elevations occurred in 1% of patients.

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 medical castration in men will result in decreased bone density.

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.

Drug Interactions

No drug-drug interaction studies were conducted.

Degarelix is not a substrate for the human CYP450 system. Degarelix is not an inducer or inhibitor of the CYP450 system in vitro. Therefore, clinically significant CYP450 pharmacokinetic drug-drug interactions are unlikely.

USE IN SPECIFIC POPULATIONSPregnancy

Category X [see Contraindications (4) and Warnings and Precautions (5.1)]

Women who are or may become pregnant should not take Firmagon.

When degarelix was given to rabbits during early organogenesis at doses of 0.002 mg/kg/day (about 0.02% of the clinical loading dose on a mg/m2 basis), there was an increase in early post-implantation loss. Degarelix given to rabbits during mid and late organogenesis at doses of 0.006 mg/kg/day (about 0.05% of the clinical loading dose on a mg/m2 basis) caused embryo/fetal lethality and abortion. When degarelix was given to female rats during early organogenesis, at doses of 0.0045 mg/kg/day (about 0.036% of the clinical loading dose on a mg/m2 basis), there was an increase in early post-implantation loss. When degarelix was given to female rats during mid and late organogenesis, at doses of 0.045 mg/kg/day (about 0.36% of the clinical loading dose on a mg/m2 basis), there was an increase in the number of minor skeletal abnormalities and variants.

Nursing Mothers

Firmagon is not indicated for use in women and is contraindicated in women who are or who may become pregnant. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from degarelix, a decision should be made whether to discontinue nursing or discontinue the drug taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Of the total number of subjects in clinical studies of Firmagon, 82% were age 65 and over, while 42% were age 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.

Renal Impairment

No pharmacokinetic studies in renally impaired patients have been conducted. At least 20-30% of a given dose of degarelix is excreted unchanged in the urine.

A population pharmacokinetic analysis of data from the randomized study demonstrated that there is no significant effect of mild renal impairment [creatinine clearance (CrCL) 50-80 mL/min] on either the degarelix concentration or testosterone concentration. Data on patients with moderate or severe renal impairment is limited and therefore degarelix should be used with caution in patients with CrCL < 50 mL/min.

Hepatic Impairment

Patients with hepatic impairment were excluded from the randomized trial.

A single dose of 1 mg degarelix administered as an intravenous infusion over 1 hour was studied in 16 non-prostate cancer patients with either mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment. Compared to non-prostate cancer patients with normal liver function, the exposure of degarelix decreased by 10% and 18% in patients with mild and moderate hepatic impairment, respectively. Therefore, dose adjustment is not necessary in patients with mild or moderate hepatic impairment. However, since hepatic impairment can lower degarelix exposure, it is recommended that in patients with hepatic impairment testosterone concentrations should be monitored on a monthly basis until medical castration is achieved. Once medical castration is achieved, an every-other-month testosterone monitoring approach could be considered.

Patients with severe hepatic dysfunction have not been studied and caution is therefore warranted in this group.

Overdosage

There have been no reports of overdose with Firmagon. In the case of overdose, however, discontinue Firmagon, treat the patient symptomatically, and institute supportive measures.

As with all prescription drugs, this medicine should be kept out of the reach of children.

SEE Firmagon PATIENT COUNSELING INFORMATION

Firmagon Description

Firmagon is a sterile lyophilized powder for injection containing degarelix (as the acetate) and mannitol. Degarelix is a synthetic linear decapeptide amide containing seven unnatural amino acids, five of which are D-amino acids. The acetate salt of degarelix is a white to off-white amorphous powder of low density as obtained after lyophilization.

The chemical name of degarelix is D-Alaninamide, N-acetyl-3-(2-naphthalenyl)-D-alanyl-4-chloro-D-phenylalanyl-3-(3-pyridinyl)-D-alanyl-L-seryl-4-[[[(4S)-hexahydro-2,6-dioxo-4-pyrimidinyl]carbonyl]amino]-L phenylalanyl-4-[(aminocarbonyl)amino]-D-phenylalanyl-L leucyl-N6–(1-methylethyl)-L-lysyl-L-prolyl. It has an empirical formula of C82H103N18O16Cl and a molecular weight of 1632.3 Da.

Degarelix has the following structural formula:from clipboard


Firmagon delivers degarelix acetate, equivalent to 120 mg of degarelix for the starting dose, and 80 mg of degarelix for the maintenance dose. The 80 mg vial contains 200 mg mannitol and the 120 mg vial contains 150 mg mannitol.

Firmagon - Clinical PharmacologyMechanism of Action

Degarelix is a GnRH receptor antagonist. It binds reversibly to the pituitary GnRH receptors, thereby reducing the release of gonadotropins and consequently testosterone.

Pharmacodynamics

A single dose of 240 mg Firmagon causes a decrease in the plasma concentrations of luteinizing hormone (LH) and follicle stimulating hormone (FSH), and subsequently testosterone.

Firmagon is effective in achieving and maintaining testosterone suppression below the castration level of 50 ng/dL.

Figure 1: Plasma Testosterone Levels from Day 0 to 364 for Degarelix 240 mg/80 mg (Median with Interquartile Ranges)

from clipboard

Pharmacokinetics



Absorption

Firmagon forms a depot upon subcutaneous administration, from which degarelix is released to the circulation. Following administration of Firmagon 240 mg at a product concentration of 40 mg/mL, the mean Cmax was 26.2 ng/mL (coefficient of variation, CV 83%) and the mean AUC was 1054 ng∙day/mL (CV 35%). Typically Cmax occurred within 2 days after subcutaneous administration. In prostate cancer patients at a product concentration of 40 mg/mL, the pharmacokinetics of degarelix were linear over a dose range of 120 to 240 mg. The pharmacokinetic behavior of the drug is strongly influenced by its concentration in the injection solution.

Distribution

The distribution volume of degarelix after intravenous (> 1 L/kg) or subcutaneous administration (> 1000L) indicates that degarelix is distributed throughout total body water. In vitro plasma protein binding of degarelix is estimated to be approximately 90%.

Metabolism

Degarelix is subject to peptide hydrolysis during the passage of the hepato-biliary system and is mainly excreted as peptide fragments in the feces. No quantitatively significant metabolites were detected in plasma samples after subcutaneous administration. In vitro studies have shown that degarelix is not a substrate, inducer or inhibitor of the CYP450 or p-glycoprotein transporter systems.

Excretion

Following subcutaneous administration of 240 mg Firmagon at a concentration of 40 mg/mL to prostate cancer patients, degarelix is eliminated in a biphasic fashion, with a median terminal half-life of approximately 53 days. The long half-life after subcutaneous administration is a consequence of a very slow release of degarelix from the Firmagon depot formed at the injection site(s). Approximately 20-30% of a given dose of degarelix was renally excreted, suggesting that approximately 70-80% is excreted via the hepato-biliary system in humans. Following subcutaneous administration of degarelix to prostate cancer patients the clearance is approximately 9 L/hr.

Effect of Age, Weight and Race

There was no effect of age, weight or race on the degarelix pharmacokinetic parameters or testosterone concentration.

Nonclinical ToxicologyCarcinogenesis, Mutagenesis, Impairment of Fertility

Degarelix was administered subcutaneously to rats every 2 weeks for 2 years at doses of 2, 10 and 25 mg/kg (about 9, 45 and 120% of the recommended human loading dose on a mg/m2 basis). Long term treatment with degarelix at 25 mg/kg caused an increase in the combined incidence of benign hemangiomas plus malignant hemangiosarcomas in females.

Degarelix was administered subcutaneously to mice every 2 weeks for 2 years at doses of 2, 10 and 50 mg/kg (about 5, 22 and 120% of the recommended human loading dose (240 mg) on a mg/m2 basis). There was no statistically significant increase in tumor incidence associated with this treatment.

Degarelix did not cause genetic damage in standard in vitro assays (bacterial mutation, human lymphocyte chromosome aberration) nor in in vivo rodent bone marrow micronucleus tests.

Single degarelix doses of ≥ 1 mg/kg (about 5% of the clinical loading dose on a mg/m2 basis) caused reversible infertility in male rats. Single doses of ≥ 0.1 mg/kg (about 0.5% of the clinical loading dose on a mg/m2 basis) caused a decrease in fertility in female rats.

Clinical Studies

The safety and efficacy of Firmagon were evaluated in an open-label, multi-center, randomized, parallel-group study in patients with prostate cancer A total of 620 patients were randomized to receive one of two Firmagon dosing regimens or leuprolide for one year:

1.     Firmagon at a starting dose of 240 mg (40 mg/mL) followed by monthly doses of 160 mg (40 mg/mL) subcutaneously,

2.    Firmagon at a starting dose of 240 mg (40 mg/mL) followed by monthly doses of 80 mg (20 mg/mL) subcutaneously,

3.    leuprolide 7.5 mg intramuscularly monthly.

Serum levels of testosterone were measured at screening, on Day 0, 1, 3, 7, 14, and 28 in the first month, and then monthly until the end of the study.

The clinical trial population (n=610) across all treatment arms had an overall median age of approximately 73 (range 50 to 98). The ethnic/racial distribution was 84% white, 6% black and 10% others. Disease stage was distributed approximately as follows: 20% metastatic, 29% locally advanced (T3/T4 Nx M0 or N1 M0), 31% localized (T1 or T2 N0 M0) and 20% classified as other (including patients whose disease metastatic status could not be determined definitively - or patients with PSA relapse after primary curative therapy). In addition, the median testosterone baseline value across treatment arms was approximately 400 ng/dL.

The primary objective was to demonstrate that Firmagon is effective with respect to achieving and maintaining testosterone suppression to castration levels (T ≤ 50 ng/dL), during 12 months treatment. The results are shown in Table 2.

Table 2: Medical Castration Rates (Testosterone ≤ 50 ng/dL) from Day 28 to Day 364

Firmagon
240/160 mg
N=202

Firmagon
240/80 mg
N=207

Leuprolide
7.5 mg
N=201

*

Kaplan Meier estimates within group

No. of Responders

199

202

194

Castration Rate
(95% CIs)*

98.3%
(94.8; 99.4)

97.2%
(93.5; 98.8)

96.4%
(92.5; 98.2)

Percentage changes in testosterone from baseline to Day 28 (median with interquartile ranges) are shown in Figure 2 and the percentages of patients who attained the medical castration of testosterone ≤ 50 ng/dL are summarized in Table 3.


Figure 2: Percentage Change in Testosterone from Baseline by Treatment Group until Day 28 (Median with Interquartile Ranges)




from clipboard


Table 3: Percentage of Patients Attaining Testosterone ≤ 50 ng/dL within the First 28 Days

Firmagon
240/160 mg
N=202

Firmagon
240/80 mg
N=207

Leuprolide
7.5 mg
N=201

Day 1

44%

52%

0%

Day 3

96%

96%

0%

Day 7

99%

99%

1%

Day 14

99%

99%

18%

Day 28

99%

100%

100%

In the clinical trial, PSA levels were monitored as a secondary endpoint. PSA levels were lowered by 64% two weeks after administration of Firmagon, 85% after one month, 95% after three months, and remained suppressed throughout the one year of treatment. These PSA results should be interpreted with caution because of the heterogeneity of the patient population studied. No evidence has shown that the rapidity of PSA decline is related to a clinical benefit.

How Supplied/Storage and Handling

Firmagon is available as:

NDC 55566-8403-1, Starting dose – One carton contains:
Two vials each with 120 mg powder for injection
Two prefilled syringes containing 3 mL of sterile water for injection, USP
Two vial adapters
Two administration needlesNDC 55566-8303-1, Maintenance dose – One carton contains:
One vial with 80 mg powder for injection
One prefilled syringe containing 4.2 mL of sterile water for injection, USP
One vial adapter
One administration needle

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).

Discard all components safely in an appropriate biohazard container.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Patient Information).

-

Patients should be informed of the possible side effects of androgen deprivation therapy, including hot flashes, flushing of the skin, increased weight, decreased sex drive, and difficulties with erectile function. Possible side effects related to therapy with Firmagon include redness, swelling, and itching at the injection site; these are usually mild, self limiting, and decrease within three days.

MANUFACTURED FOR:

FERRING PHARMACEUTICALS INC., PARSIPPANY, NJ 07054
Manufactured in Germany

2009054575
Rev. 07/2016

Patient Information

Firmagon (FIRM-uh-gahn)
(degarelix for injection)

What is Firmagon?

Firmagon is a prescription medicine used in the treatment of advanced prostate cancer.

It is not known if Firmagon is safe or effective in children.

Who should not receive Firmagon?

Do not receive Firmagon if you are:

·         allergic to degarelix or any ingredient in Firmagon. See the end of this leaflet for a complete list of ingredients in Firmagon.

·         a female who is pregnant or may become pregnant. Firmagon can harm your unborn baby.

Talk to your healthcare provider before receiving Firmagon if you have any of these conditions.

Before receiving Firmagon, tell your healthcare provider about all your medical conditions, including if you:

·         have any heart problems including a condition called long QT syndrome.

·         have problems with blood levels such as sodium, potassium, calcium, and magnesium

·         have kidney or liver problems

·         are breastfeeding or plan to breastfeed. It is not known if Firmagon passes into your breast milk. You and your healthcare provider should decide if you will receive Firmagon or breastfeed. You should not do both.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.

How will I receive Firmagon?

You will receive an injection of Firmagon from your healthcare provider.

·         The injection site will always be in the stomach (abdominal area). The injection site will change within the stomach area each time you receive a dose of Firmagon.

·         Two injections are given as a first dose. The following monthly doses are one injection.

·         Do not rub or scratch the injection site. Make sure your injection site is free of any pressure from belts, waistbands or other types of clothing.

·         Always set up an appointment for your next injection.

What are the possible side effects of Firmagon?

Firmagon can cause serious side effects, including:

·         Serious allergic reactions. Get medical help right away if you get any of these symptoms:

o    trouble breathing or wheezing

o    severe itching

o    swelling of your face, lips, mouth, or tongue

·         Disorder of the heart's electrical activity. Your healthcare provider may do tests during treatment with Firmagon to check your heart for a condition called long QT syndrome.

The common side effects of Firmagon include:

·         injection site pain, redness, and swelling

·         hot flashes

·         weight gain

·         increase in some liver enzymes

Other side effects include decreased sex drive and erectile function problems.

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General information about the safe and effective use of Firmagon.

Medicines are sometimes prescribed for conditions that are not mentioned in a Patient Information leaflet. Do not use Firmagon for a condition for which it was not prescribed. Do not give Firmagon to other people, even if they have the same symptoms that you have. It may harm them.

You can ask your pharmacist or healthcare provider for information about Firmagon that is written for health professionals.

What are the ingredients in Firmagon?

Active ingredient: degarelix (as acetate)

Inactive ingredient: mannitol

MANUFACTURED FOR:

FERRING PHARMACEUTICALS INC., PARSIPPANY, NJ 07054
Manufactured in Germany

For more information, go to www.Firmagon.com or call -1-888-337-7464.

This Patient Information has been approved by the U.S. Food and Drug Adminstration.

2009054575
Rev. 07/2016

PRINCIPAL DISPLAY PANEL - 240 mg Kit Carton

NDC 55566-8403-1

FERRING
PHARMACEUTICALS

Firmagon® 240mg*
(degarelix for injection)

* 240 mg dose administered from
two vials each containing 120 mg

For single use subcutaneous injection only
Discard unused portion

Kit contents:

2

vials each with 120 mg powder for injection

2

syringes with sterile water for injection, USP
for reconstitution/administration

2

vial adapters

2

administration needles

Initiation Dose
Rx only

from clipboard


PRINCIPAL DISPLAY PANEL - 80 mg Kit Carton

NDC 55566-8303-1

FERRING
PHARMACEUTICALS

Firmagon® 80mg
(degarelix for injection)

For single use subcutaneous injection only
Discard unused portion

Kit contents:

1

vial with 80 mg powder for injection

1

syringe with sterile water for injection, USP
for reconstitution/administration

1

vial adapter

1

administration needle

Maintenance Dose (28 Days)
Rx only

from clipboard


Firmagon degarelix kit

Product Information

Product Type

HUMAN PRESCRIPTION DRUG LABEL

Item Code (Source)

NDC:55566-8403

Packaging

#

Item Code

Package Description

1

NDC:55566-8403-1

1 KIT in 1 CARTON

Quantity of Parts

Part #

Package Quantity

Total Product Quantity

Part 1

2 VIAL, GLASS

6 mL

Part 2

2 SYRINGE

6 mL

Part 1 of 2

Firmagon degarelix powder, metered

Product Information

Route of Administration

SUBCUTANEOUS

DEA Schedule

    

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Strength

Degarelix (Degarelix)

Degarelix

40 mg  in 1 mL

Inactive Ingredients

Ingredient Name

Strength

Mannitol

50 mg  in 1 mL

Product Characteristics

Color

WHITE

Score

    

Shape

Size

Flavor

Imprint Code

Contains

    

Packaging

#

Item Code

Package Description

1

3 mL in 1 VIAL, GLASS

Marketing Information

Marketing Category

Application Number or Monograph Citation

Marketing Start Date

Marketing End Date

NDA

NDA022201

03/02/2009

Part 2 of 2

STERILE WATER water injection, solution

Product Information

Route of Administration

SUBCUTANEOUS

DEA Schedule

    

Inactive Ingredients

Ingredient Name

Strength

Water

 

Packaging

#

Item Code

Package Description

1

3 mL in 1 SYRINGE

Marketing Information

Marketing Category

Application Number or Monograph Citation

Marketing Start Date

Marketing End Date

NDA

NDA022201

03/02/2009

Marketing Information

Marketing Category

Application Number or Monograph Citation

Marketing Start Date

Marketing End Date

NDA

NDA022201

03/02/2009

Firmagon degarelix kit

Product Information

Product Type

HUMAN PRESCRIPTION DRUG LABEL

Item Code (Source)

NDC:55566-8303

Packaging

#

Item Code

Package Description

1

NDC:55566-8303-1

1 KIT in 1 CARTON

Quantity of Parts

Part #

Package Quantity

Total Product Quantity

Part 1

2 VIAL, GLASS

8 mL

Part 2

1 SYRINGE

4.2 mL

Part 1 of 2

Firmagon degarelix powder, metered

Product Information

Route of Administration

SUBCUTANEOUS

DEA Schedule

    

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Strength

Degarelix (Degarelix)

Degarelix

20 mg  in 1 mL

Inactive Ingredients

Ingredient Name

Strength

Mannitol

50 mg  in 1 mL

Product Characteristics

Color

WHITE

Score

    

Shape

Size

Flavor

Imprint Code

Contains

    

Packaging

#

Item Code

Package Description

1

4 mL in 1 VIAL, GLASS

Marketing Information

Marketing Category

Application Number or Monograph Citation

Marketing Start Date

Marketing End Date

NDA

NDA022201

03/02/2009

Part 2 of 2

STERILE WATER water injection, solution

Product Information

Route of Administration

SUBCUTANEOUS

DEA Schedule

    

Inactive Ingredients

Ingredient Name

Strength

Water

 

Packaging

#

Item Code

Package Description

1

4.2 mL in 1 SYRINGE

Marketing Information

Marketing Category

Application Number or Monograph Citation

Marketing Start Date

Marketing End Date

NDA

NDA022201

03/02/2009

Marketing Information

Marketing Category

Application Number or Monograph Citation

Marketing Start Date

Marketing End Date

NDA

NDA022201

03/02/2009


Labeler - Ferring Pharmaceuticals Inc. (103722955)

Establishment

Name

Address

ID/FEI

Operations

Rentschler Biotechnologie GmbH

332952766

MANUFACTURE(55566-8403, 55566-8303), PACK(55566-8403, 55566-8303), ANALYSIS(55566-8403, 55566-8303)


Establishment

Name

Address

ID/FEI

Operations

Ferring International Center SA

481210362

PACK(55566-8403, 55566-8303)

Establishment

Name

Address

ID/FEI

Operations

Ferring Gmbh - Kiel

328609615

MANUFACTURE(55566-8403, 55566-8303), ANALYSIS(55566-8403, 55566-8303), PACK(55566-8403, 55566-8303)


Establishment

Name

Address

ID/FEI

Operations

PolyPeptide Laboratories

356580779

API MANUFACTURE(55566-8403, 55566-8303)

Revised: 08/2016


Ferring Pharmaceuticals Inc.