2016年5月31日,肺癌新药Portrazza(necitumumab)获欧盟委员会(EC)批准,联合吉西他滨(gemcitabine)和顺铂(cisplatin),用于既往未接受过化疗治疗的局部晚期或转移性、表达表皮生长因子受体(EGFR)的鳞状非小细胞肺癌(squamous NSCLC)患者的一线治疗。
b Once the infusion rate has been reduced for a Grade 1 or 2 hypersensitivity/infusion-related reaction, it is recommended that the lower infusion rate be utilized for all subsequent infusions. The infusion duration should not exceed 2 hours. Skin reactions Table 2 – Management recommendations for skin reactions
Special populations Paediatric population There is no relevant use of necitumumab in the paediatric population in the non-small cell lung cancer indication. Elderly No dose reductions other than those recommended for all patients are necessary (see sections 4.4 and 5.1). Renal impairment No dose adjustments are required in patients with mild or moderate renal impairment (see section 5.2). There are no data regarding necitumumab administration in patients with severe renal impairment. No dose reductions are recommended. Hepatic impairment There are no data regarding necitumumab administration in patients with moderate or severe hepatic impairment (see section 5.2). No dose reductions are recommended. Method of administration Portrazza is for intravenous use only. It is administered as an intravenous infusion over approximately 60 minutes via an infusion pump. Portrazza must not be administered as an intravenous bolus or push. In case of previous hypersensitivity or infusion-related reaction, recommendations for management of hypersensitivity/infusion-related reactions should be followed, as for Table 1. Only sodium chloride 9 mg/mL (0.9 %) solution for injection should be used as a diluent. Portrazza infusions should not be administered or mixed with glucose solutions. For instructions on dilution of the medicinal product before administration, see section 6.6. 4.3 Contraindications Patients with a history of severe or life-threatening hypersensitivity to the active substance or to any of the excipients listed in section 6.1 (see section 4.4). 4.4 Special warnings and precautions for use Thromboembolic events Venous thromboembolic events (VTE) and arterial thromboembolic events (ATE), including fatal cases, were observed with necitumumab in combination with gemcitabine and cisplatin (see also section 4.8). Administration of necitumumab should be carefully considered in those patients with a history of thromboembolic events (such as pulmonary embolism, deep vein thrombosis, myocardial infarction, stroke) or preexisting risk factors for thromboembolic events (such as advanced age, patients with prolonged periods of immobilisation, severely hypovolemic patients, patients with acquired or inherited thrombophilic disorders). The relative risk of VTE or ATE was approximately three-fold higher in patients with a reported history of VTE or ATE. Necitumumab should not be administered to patients with multiple risk factors for thromboembolic events unless the benefits outweigh the risks to the patient. Thromboprophylaxis should be considered after careful assessment of a patient's risk factors (including the increased risk of serious bleeding in patients with tumour cavitation or tumour involvement of large central blood vessels). Patients and physicians should be aware of signs and symptoms of thromboembolism. Patients should be instructed to seek medical care if they develop symptoms such as shortness of breath, chest pain, arm or leg swelling. Discontinuation of necitumumab in patients who experience a VTE or ATE should be considered after a thorough benefit risk assessment for the individual patient. In a clinical trial in advanced non-squamous NSCLC, patients experienced an increased rate of serious thromboembolic events (including fatal events) in the necitumumab plus pemetrexed and cisplatin arm as compared to the pemetrexed and cisplatin arm (see also section 4.8). The addition of necitumumab did not improve the efficacy outcome over pemetrexed and cisplatin alone in advanced non-squamous NSCLC. Cardiorespiratory disorders An increased frequency of cardiorespiratory arrest or sudden death was observed with necitumumab. Cardiorespiratory arrest or sudden death was reported in 2.8% (15/538) of patients treated with necitumumab in combination with gemcitabine and cisplatin compared to 0.6% (3/541) of patients treated with chemotherapy alone. Twelve of the fifteen patients died within 30 days of the last dose of necitumumab and had comorbid conditions including history of coronary artery disease (n=3), hypomagnesemia (n=4), chronic obstructive pulmonary disease (n=7), and hypertension (n=5). Eleven of the 12 patients had an unwitnessed death. Patients with significant coronary artery disease, myocardial infarction within 6 months, uncontrolled hypertension, and uncontrolled congestive heart failure were not enrolled in the pivotal study. The incremental risk of cardiopulmonary arrest or sudden death in patients with a history of coronary artery disease, congestive heart failure, or arrhythmias as compared to those without these comorbid conditions is not known. Hypersensitivity/infusion-related reactions Hypersensitivity/infusion-related reactions (IRRs) were reported with necitumumab. The onset of events usually occurred after the first or second administration of necitumumab. Monitor patients during and following the infusion for signs of hypersensitivity and infusion-related reactions with resuscitation equipment and appropriate medical resources readily available. In patients who have experienced a previous Grade 1 or 2 hypersensitivity or infusion related reaction to Portrazza, premedication with a corticosteroid and an antipyretic in addition to an antihistamine is recommended. For management and dose adjustments, see section 4.2. Skin reactions Skin reactions were reported with necitumumab (see section 4.8). The onset of events occurred mainly during the first cycle of treatment. For management and dose adjustments, see section 4.2. Pre-emptive skin treatment including skin moisturiser, sun screen, topical steroid cream (1 % hydrocortisone) and an oral antibiotic (e.g. doxycycline) may be useful in the management of dermatologic reactions as clinically appropriate. Patients may be advised to apply moisturiser, sunscreen and topical steroid cream to face, hands, feet, neck, back and chest. Electrolyte abnormalities Progressively decreasing serum magnesium levels occur frequently (81.3%) and may lead to severe hypomagnesaemia (18.7%) (see also section 4.8). Hypomagnesaemia may reoccur at the same grade or worse after a dose delay. Patients should be carefully monitored for serum electrolytes, including serum magnesium, potassium, and calcium, prior to each necitumumab administration and after completion of necitumumab treatment, until within normal limits. Prompt electrolyte repletion is recommended, as appropriate. Elderly No overall differences in efficacy between arms were observed in patients above 70 years of age. Cardiovascular comorbidities, performance status and the likely tolerability to chemotherapy with add-on necitumumab should therefore be thoroughly evaluated prior to the initiation of treatment in patients above 70 years of age. Women of childbearing potential/contraception in females Based on its mechanism of action and animal models where EGFR expression is disrupted, necitumumab may cause foetal harm or developmental anomalies. Women of childbearing potential should be advised to avoid becoming pregnant while on necitumumab. Effective contraception has to be used during necitumumab treatment and up to 3 months after last administration of necitumumab treatment. Contraceptive measures or abstinence are recommended (see section 4.6). Sodium restricted diet This medicinal product contains 244 mg sodium per dose. To be taken into consideration by patients on a controlled sodium diet. 4.5 Interaction with other medicinal products and other forms of interaction No drug-drug interactions were observed between Portrazza and gemcitabine/cisplatin. The pharmacokinetics of gemcitabine/cisplatin were not affected when co-administered with necitumumab and the pharmacokinetics of necitumumab were not affected when co-administered with gemcitabine/cisplatin. No other formal interaction studies with necitumumab have been performed in humans. 4.6 Fertility, pregnancy and lactation Women of childbearing potential/contraception in females Women of childbearing potential should be advised to avoid becoming pregnant while on necitumumab and should be informed of the potential hazard to the pregnancy and foetus. Women of childbearing potential have to use effective contraception during necitumumab treatment and up to 3 months after last administration of necitumumab treatment. Contraceptive measures or abstinence are recommended. Pregnancy There are no data from the use of necitumumab in pregnant women. Animal reproduction studies have not been conducted with necitumumab. Based on animal models, epidermal growth factor receptor (EGFR) is involved in prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Portrazza should not be used during pregnancy or in women not using effective contraception, unless the potential benefit justifies the potential risk to the foetus. Breast-feeding It is unknown whether necitumumab is excreted in human milk. Excretion in milk and oral absorption is expected to be low. A risk to newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with Portrazza and for at least 4 months after the last dose. Fertility There are no data on the effect of necitumumab on human fertility. Animal studies to assess fertility directly have not been conducted (see section 5.3). 4.7 Effects on ability to drive and use machines Portrazza has no known influence on the ability to drive and use machines. If patients experience treatment-related symptoms affecting their ability to concentrate and react, it is recommended that they do not drive or use machines until the effect subsides. 4.8 Undesirable effects Summary of the safety profile The most common serious adverse reactions (Grade ≥3) observed in necitumumab-treated patients are skin reactions (6.3 %) and venous thromboembolic events (4.3 %). The most common adverse reactions were skin reactions, venous thromboembolic events and laboratory abnormalities (hypomagnesaemia and albumin-corrected hypocalcaemia). Tabulated list of adverse reactions Adverse drug reactions (ADRs) which were reported in patients with squamous non-small cell lung cancer are listed below in MedDRA body system organ class, frequency and grade of severity. The following convention has been used for classification of frequency: Very common (≥1/10) Common (≥1/100 to <1/10) Uncommon (≥1/1,000 to <1/100) Rare (≥1/10,000 to <1/1,000) Very rare (<1/10,000) Within each frequency grouping, ADRs are presented in order of decreasing seriousness. The following table provides the frequency and severity of ADRs based on results from SQUIRE, a global, multicenter, two-arm, randomized Phase 3 study in adult patients with squamous NSCLC randomised to treatment with necitumumab in combination with gemcitabine/cisplatin or gemcitabine/cisplatin. Table 3. ADRs reported in ≥ 1 % of necitumumab treated patients in SQUIRE
a MedDRA preferred term (Version 16). b The table reflects the frequency of ADRs during the chemotherapy phase of study treatment in which Portrazza+GC was directly compared with GC. c Based on laboratory assessments. Only patients with baseline and at least one post-baseline result are included. Description of selected adverse reactions Thromboembolic events Venous thromboembolic events (VTEs) were reported in approximately 8 % of patients and mainly present as pulmonary embolism and deep vein thrombosis. Severe VTEs were reported in approximately 4 % of patients. The incidence of fatal VTEs was similar between arms (0.2%). Arterial thromboembolic events (ATEs) were reported in approximately 4 % of patients and mainly present as stroke and myocardial infarction. Severe ATEs were reported in 3 % of patients. The incidence of fatal ATEs was 0.6% in the experimental arm versus 0.2% in the control arm (see also section 4.4). In a clinical trial in advanced non-squamous NSCLC, venous thromboembolic events (VTEs) were reported in approximately 11 % of patients treated with necitumumab in combination with pemetrexed and cisplatin (versus 8 % in the pemetrexed and cisplatin alone arm) and mainly presented as pulmonary embolism and deep vein thrombosis. Severe VTEs were reported in approximately 6 % of patients treated with necitumumab in combination with pemetrexed and cisplatin (versus 4 % in the pemetrexed and cisplatin alone arm). Arterial thromboembolic events (ATEs) were reported in approximately 4 % of patients treated with necitumumab in combination with pemetrexed and cisplatin (versus 6 % in the pemetrexed and cisplatin alone arm) and mainly present as stroke and myocardial infarction. Severe ATEs were reported in approximately 3 % of patients treated with necitumumab in combination with pemetrexed and cisplatin (versus 4 % in the pemetrexed and cisplatin alone arm). Skin reactions Skin reactions were reported in approximately 78 % of patients and mainly presented as acneiform rash, dermatitis acneiform, dry skin, pruritus, skin fissures, paronychia and palmar-plantar erythrodysaesthesia syndrome. Severe skin reactions were reported in approximately 6 % of patients while 1.7 % of patients discontinued due to skin reactions. The majority of skin reactions developed during the first cycle of treatment and resolved within 17 weeks after onset (see also section 4.4). Infusion-related reactions Infusion-related reactions were reported in 1.5 % of patients and mainly present as chills, fever or dyspnoea. Severe infusion-related reactions were reported in 0.4 % of patients. The majority of infusion-related reactions developed after the first or second administration of necitumumab. Toxicity in the elderly or in patients with ECOG PS 2 Clinically relevant toxicities with respect to the elderly and those patients with Eastern Cooperative Oncology Group (ECOG) performance status score 2 (ECOG PS2) were similar to the overall population in patients receiving necitumumab plus chemotherapy consisting of gemcitabine and cisplatin. Eyelash trichomegaly Isolated cases of Grade 1 trichomegaly have been reported in patients treated with necitumumab. 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 Ireland: HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517, website: www.hpra.ie, e-mail: medsafety@hpra.ie, United Kingdom: Yellow Card Scheme, website: www.mhra.gov.uk/yellowcard. 4.9 Overdose There has been limited experience with necitumumab overdose in human clinical trials. The highest dose of necitumumab studied clinically in a human dose-escalation Phase 1 study is 1,000 mg once a week or once every other week. Adverse events observed included headache, vomiting and nausea and were consistent with the safety profile at the recommended dose. There is no known antidote for necitumumab overdose. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01XC22 Mechanism of action Necitumumab is a recombinant human IgG1 monoclonal antibody that binds with high affinity and specificity to the human epidermal growth factor receptor 1 (EGFR) and blocks the ligand binding site, blocking activation by all known ligands and inhibiting relevant biological consequences in vitro. Activation of EGFR has been correlated with malignant progression, induction of angiogenesis and inhibition of apoptosis or cell death. In addition, necitumumab induces EGFR internalization and degradation in vitro. In vivo studies in cell line-derived xenograft models of human cancer, including non-small cell lung carcinoma, demonstrate that necitumumab has antitumor activity both in monotherapy and in combination with gemcitabine and cisplatin. Immunogenicity As with all therapeutic proteins, there is the potential for immunogenicity. Overall, there was a low incidence of both treatment-emergent anti-drug antibodies and neutralizing antibodies among necitumumab-treated patients, and no correlation with safety outcomes in these patients. There was no relationship between immunogenicity and IRRs or treatment emergent adverse events. Clinical efficacy SQUIRE, a global, multicenter, two-arm, randomized study of Portrazza, was conducted in 1,093 patients with stage IV (American Joint Committee on Cancer Version 7) squamous NSCLC, including patients with ECOG PS2, who had received no prior anticancer therapy for metastatic disease. Patients were randomised to receive first-line Portrazza at 800 mg plus chemotherapy consisting of gemcitabine at 1,250 mg/m2 and cisplatin at 75 mg/m2 (Portrazza+GC Arm), or gemcitabine-cisplatin chemotherapy alone (GC Arm). Portrazza and gemcitabine were administered on days 1 and 8 of each 3-week treatment cycle, and cisplatin was administered on day 1 of each 3-week treatment cycle. There was no premedication for Portrazza mandated by the study. Pre-emptive treatment for skin reaction was not permitted prior to the beginning of the second treatment cycle. Patients received a maximum of six cycles of chemotherapy in each arm; patients in the Portrazza+GC arm who had no progression continued to receive single-agent Portrazza until disease progression, unacceptable toxicity, or withdrawal of consent. The major efficacy outcome measure was overall survival (OS) and the supportive efficacy outcome measure was progression-free survival (PFS). Patients underwent radiographic assessment of disease status every six weeks, until radiographic documentation of progressive disease (PD). Demographics and baseline characteristics were balanced between arms. Median age was 62 (32-86), 83 % of patients were men; 83.5 % were Caucasian; and 91 % were smokers. The ECOG PS was 0 for 31.5 %, 1 for 59.7 %, and 2 for 9 % of patients; over 50 % had metastatic disease at more than 2 sites. In the Portrazza+GC arm, 51 % of patients continued with single-agent Portrazza after completing chemotherapy. Use of post-study systemic therapy was similar in the 2 arms (47.3 % in the Portrazza+GC arm and 44.7 % in the GC arm). Efficacy results are shown in Table 4. Table 4. Summary of efficacy data (ITT population)
b Hazard ratio is expressed as treatment/control and estimated from Cox model c Stratified by the randomization strata (ECOG PS [0-1 vs. 2], and geographic region [North America, Europe, and Australia vs. South America, South Africa, and India vs. Eastern Asia]) Figure 1. Kaplan Meier plot of overall survival (ITT population)
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Portrazza(necitumumab solution infusion)简介:
2016年5月31日,肺癌新药Portrazza(necitumumab)获欧盟委员会(EC)批准,联合吉西他滨(gemcitabine)和顺铂(cisplatin),用于既往未接受过化疗治疗的局部晚期或转移性、表达表皮生长因子受体(EG ... 责任编辑:admin
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