耐昔妥珠单抗，耐昔妥珠单抗注射剂（Portrazza 800mg infusion）

药店国别：无 产地国家：荷兰 处方药：是 所属类别： 800毫克/50毫升/瓶 包装规格： 800毫克/50毫升/瓶 计价单位：瓶 生产厂家中文参考译名：无 生产厂家英文名：Eli Lilly Nederland B.V. 原产地英文商品名：Portrazza  800mg/50mL/bottle 原产地英文药品名：necitumumab 中文参考商品译名：Portrazza  800毫克/50毫升/瓶 中文参考药品译名：necitumumab 曾用名：无

简介

近日,单抗药物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。 此次批准，使Portrazza成为欧洲治疗鳞状NSLCLC的首个生物制剂。Portrazza是一种靶向性抗癌药，旨在干扰某些癌细胞中一种名为表皮生长因子受体（EGFR）的蛋白。EGFR的激活与恶性进展、诱导血管生成、抑制凋亡或细胞死亡相关。阻断EGFR能够从根本上饿死癌细胞，并引发细胞的毁灭。 作用机制 Necitumumab是一种重组人lgG1单克隆抗体结合至人表皮生长因子受体(EGFR)和阻断EGFR与其配体的结合。EGFR的表达和激活曾与恶性进展，血管生成的诱导，和凋亡的抑制作用相关。在体外Necitumumab的结合诱导EGFR内化和降解。 在体外，在EGFR-表达细胞中necitumumab的结合还导致抗体-依赖性细胞细胞毒性(ADCC)。在体内研究中使用人类癌的异种移植模型，包括非-小细胞肺癌，necitumumab的给予至被移植小鼠导致与吉西他滨和顺铂联用抗肿瘤活性与单独接受吉西他滨和顺铂比较增加抗肿瘤活性。 适应证和用途 PORTRAZZA™是一种表皮生长因子受体(EGFR)拮抗剂适用与吉西他滨和顺铂联用，为有转移鳞状非-小细胞肺癌患者首次线治疗。使用限制：PORTRAZZA不适用为非-鳞状非-小细胞肺癌的治疗。 剂量和给药方法：PORTRAZZA的推荐剂量是800 mg(绝对剂量)为每3-周疗程在第1和8天在历时60分钟静脉输注。 剂型和规格注射液：在单剂量小瓶中800mg/50mL(16mg/mL)溶液。

英文版说明

Portrazza 800mg concentrate for solution for infusion1. Name of the medicinal productPortrazza* 800 mg concentrate for solution for infusion2. Qualitative and quantitative compositionEach 50 mL vial contains 800 mg of necitumumab.Each mL of concentrate for solution for infusion contains 16 mg of necitumumab.The concentrate must be diluted before use (see section 6.6).Necitumumab is a human IgG1 monoclonal antibody produced in murine (NS0) cells by recombinant DNA technology.Excipient with known effectEach 50 mL vial contains approximately 244.4 mg sodium.For the full list of excipients, see section 6.1.3. Pharmaceutical formConcentrate for solution for infusion (sterile concentrate).Clear to slightly opalescent and colourless to slightly yellow liquid, with pH 6.0.4. Clinical particulars4.1 Therapeutic indicationsPortrazza in combination with gemcitabine and cisplatin chemotherapy is indicated for the treatment of adult patients with locally advanced or metastatic epidermal growth factor receptor (EGFR) expressing squamous non-small cell lung cancer who have not received prior chemotherapy for this condition.4.2 Posology and method of administrationNecitumumab therapy must be administered under the supervision of a physician qualified in the use of anti-cancer chemotherapy.Appropriate medical resources for the treatment of severe infusion reactions should be available during necitumumab infusions. Availability of resuscitation equipment must be ensured.PosologyPortrazza is administered in addition to gemcitabine and cisplatin-based chemotherapy for up to 6 cycles of treatment followed by Portrazza as a single agent in patients whose disease has not progressed, until disease progression or unacceptable toxicity.The recommended dose of Portrazza is 800 mg (flat dose) administered as an intravenous infusion over 60 minutes on Days 1 and 8 of each 3-week cycle. If a decreased infusion rate is indicated, the infusion duration should not exceed 2 hours.Patients should be monitored during infusion for signs of infusion-related reactions (see section 4.4).PremedicationIn patients who have experienced a previous Grade 1-2 hypersensitivity or infusion-related reaction to Portrazza, premedication with a corticosteroid and an antipyretic in addition to an antihistamine is recommended.Prior to each necitumumab infusion, premedication for possible skin reactions must be considered (see section 4.4).Posology adjustmentsRecommendations for the management of infusion-related and skin reactions are provided in tables 1 and 2.Hypersensitivity/Infusion-related reactionsTable 1 – Management recommendations for hypersensitivity/infusion-related reactionsa Grade per NCI-CTCAE, Version 3.0b 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 reactionsTable 2 – Management recommendations for skin reactionsa Grade per NCI-CTCAE, Version 3.0Special populationsPaediatric populationThere is no relevant use of necitumumab in the paediatric population in the non-small cell lung cancer indication.ElderlyNo dose reductions other than those recommended for all patients are necessary (see sections 4.4 and 5.1).Renal impairmentNo 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 impairmentThere 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 administrationPortrazza 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 ContraindicationsPatients 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 useThromboembolic eventsVenous 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 disordersAn 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 reactionsHypersensitivity/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 reactionsSkin 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 abnormalitiesProgressively 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.ElderlyNo 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 eva luated prior to the initiation of treatment in patients above 70 years of age.Women of childbearing potential/contraception in femalesBased 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 dietThis 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 interactionNo 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 lactationWomen of childbearing potential/contraception in femalesWomen 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.PregnancyThere 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-feedingIt 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.FertilityThere 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 machinesPortrazza 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 effectsSummary of the safety profileThe 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 reactionsAdverse 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 SQUIREAbbreviations: GC = gemcitabine and cisplatin alone; Portrazza+GC = necitumumab plus gemcitabine and cisplatin; MedDRA = Medical Dictionary for Regulatory Activities.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 reactionsThromboembolic eventsVenous 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 reactionsSkin 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 reactionsInfusion-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 2Clinically 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 trichomegalyIsolated cases of Grade 1 trichomegaly have been reported in patients treated with necitumumab.Reporting of suspected adverse reactionsReporting 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 OverdoseThere 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 properties5.1 Pharmacodynamic propertiesPharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01XC22Mechanism of actionNecitumumab 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.ImmunogenicityAs 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 efficacySQUIRE, 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)a Abbreviations: CI = confidence intervalb Hazard ratio is expressed as treatment/control and estimated from Cox modelc 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)Abbreviations: C = cisplatin; G = gemcitabine.An improvement was observed in subgroups for OS and PFS including the pre-specified stratification factors [ECOG PS score (0-1 vs. 2) and geographic region (North America, Europe, and Australia vs. South America, South Africa, and India vs. Eastern Asia)]; in patients age 70 and over, the hazard ratio for overall survival was 1.03 (0.75, 1.42) (see Figure 2).Figure 2. Forest plot for subgroup analysis of overall survival (ITT population)Abbreviations: C = cisplatin; G = gemcitabine; ITT = intent-to-treat.A pre-planned exploratory analysis performed after the primary analysis, determined clinical efficacy outcome according to the level of tumour EGFR protein expression.Of the ITT population, 982 patients (89.8%) were eva luable for an EGFR protein expression analysis by immunohistochemistry (IHC) using Dako PharmDx Kit. A tumour was considered to be EGFR-expressing if at least one stained cell could be identified. The large majority of patients (95.2% of eva luable patients; n = 935) had tumor samples expressing EGFR protein; 4.8% (n = 47) were not detectable for EGFR protein expression. There were no relevant differences in the distribution of demographics, disease characteristics, or the use of post-study systemic therapy between the subset of patients with detectable EGFR protein expression and the ITT population.In patients with detectable EGFR protein expression (indicated patient population), overall survival was statistically significantly improved in the Portrazza+GC Arm as compared to the GC Arm with an estimated reduction in risk of death of 21% (hazard ratio [HR] = 0.79 [0.69, 0.92]; p = 0.002) and a median OS of 11.7 months in the Portrazza+GC Arm and 10.0 months in the GC Arm.A statistically significant improvement in progression-free survival was also observed (HR = 0.84 [0.72, 0.97]; p = 0.018), with a median PFS of 5.7 months in the Portrazza+GC Arm and 5.5 months in the GC Arm.In patients with detectable EGFR protein expression, there was no trend observed for increased efficacy with increasing levels of EGFR expression.In patients with no detectable EGFR protein expression, no improvement in overall survival (hazard ratio [HR] = 1.52 [0.74, 3.12]) or progression free survival (hazard ratio [HR] = 1.33 [0.65, 2.70] was observed.Paediatric populationThe European Medicines Agency has waived the obligation to submit the results of studies with Portrazza in all subsets of the paediatric population in non-small cell lung cancer (see section 4.2 for information on paediatric use).5.2 Pharmacokinetic propertiesFollowing the dose regimen of 800 mg necitumumab on day 1 and day 8 of a 21 day schedule, the geometric mean of necitumumab Cmin was 98.5 μg/mL (Coefficient of Variation 80 %) in serum from patients with squamous NSCLC after five cycles of treatment in combination with gemcitabine and cisplatin.AbsorptionPortrazza is administered as an intravenous infusion. There have been no studies performed with other routes of administration.DistributionDistribution of Portrazza follow a biphasic decline. Based on population pharmacokinetic approach (PopPK), the mean volume of distribution at steady state (Vss) for necitumumab was 6.97 L (CV 31 %).EliminationNecitumumab exhibits concentration-dependent clearance. Mean total systemic clearance (CLtot) at steady state following 800 mg on Day 1 and Day 8 of a 21-day cycle was 0.014 l/hr (CV 39 %). This corresponds to a half-life of approximately 14 days. The predicted time to reach steady state was approximately 70 days.Special populationsPopulation pharmacokinetic analysis suggested age, gender, and race had no effect on the pharmacokinetics of necitumumab, while CL and volume of distribution had a less than proportional positive correlation with body weight. Although modeling results suggest that the disposition of necitumumab was statistically dependent on body weight, simulations indicated that weight-based dosing would not significantly decrease PK variability. No dose adjustment is necessary for these sub-populations.ElderlyBased on the results of the population pharmacokinetic analysis, there was no impact of age on necitumumab exposure.Renal impairmentNo formal studies have been conducted to eva luate the effect of renal impairment on the PK of necitumumab. Based on the results of the population pharmacokinetic analysis, there was no impact of renal function as assessed by creatinine clearance [CrCl] on the pharmacokinetics of necitumumab.Hepatic impairmentNo formal studies have been conducted to eva luate the effect of hepatic impairment on the PK of necitumumab. Based on the results of the population pharmacokinetic analysis, hepatic status (as assessed by alanine aminotransferase, aspartate transaminase and total bilirubin) had no significant effect on the pharmacokinetics of necitumumab.5.3 Preclinical safety dataDose dependent reversible skin toxicity was observed in the 26-week monkey study. The skin effects were consistent with the known class effects of EGFR inhibitors.Specific animal studies to test necitumumab for carcinogenic potential or potential to impair fertility have not been performed. The risk of fertility impairment is unknown. However, no adverse effects on male or female reproductive organs were observed in monkeys treated for 26 weeks with necitumumab.Human IgG1 is known to cross the placenta; therefore, necitumumab has the potential to be transmitted from the mother to the developing foetus. No animal studies have been specifically conducted to eva luate the effect of necitumumab on reproduction and foetal development; however, based on its mechanism of action and animal models where EGFR expression is disrupted, necitumumab may cause foetal harm or developmental anomalies.6. Pharmaceutical particulars6.1 List of excipientsSodium citrate dihydrate (E331)Citric acid anhydrous (E330)Sodium chlorideGlycine (E640)Mannitol (E421)Polysorbate 80 (E433)Water for injections6.2 IncompatibilitiesPortrazza infusions should not be administered or mixed with glucose solutions. This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.6.3 Shelf lifeUnopened vial2 years.After dilutionWhen prepared as directed, infusion solutions of Portrazza contain no antimicrobial preservatives.It is recommended that the prepared dosing solution be used immediately in order to minimize the risk of microbial contamination. If not used immediately, the prepared necitumumab dosing solution must be stored at 2°C to 8°C for a duration not to exceed 24 hours, or may be held at 9°C to 25°C for up to 4 hours. Store protected from light. Brief exposure to ambient light is acceptable while preparation and administration is taking place.6.4 Special precautions for storageStore in a refrigator (2˚C - 8˚C).Do not freeze.Keep the vial in the outer carton in order to protect from light.For storage conditions after dilution of the medicinal product, see section 6.3.6.5 Nature and contents of container50 mL solution in a vial (Type I glass) with a chlorobutyl elastomer stopper, an aluminium seal and a polypropylene cap.Pack of 1 vial.6.6 Special precautions for disposal and other handlingPrepare the infusion solution using aseptic technique to ensure the sterility of the prepared solution.Each vial is intended for single use only. Inspect the contents of the vials for particulate matter and discolouration. The concentrate for solution for infusion must be clear to slightly opalescent and colourless to slightly yellow prior to dilution. If particulate matter or discolouration is identified, discard the vial.Vials contain 800 mg as a 16 mg/mL solution of necitumumab; one 50 mL vial contains the complete dose. Only use sodium chloride 9 mg/mL (0.9 %) solution for injection as a diluent.To administer using pre-filled intravenous infusion containersAseptically remove 50 mL of sodium chloride 9 mg/mL (0.9 %) solution for injection from the prefilled 250 mL container and transfer 50 mL of necitumumab medicinal product into the container to bring the final volume in the container back to 250 mL. Gently invert the container to mix. DO NOT FREEZE OR SHAKE the infusion solution. DO NOT dilute with other solutions or co-infuse with other electrolytes or medicines.To administer using empty intravenous infusion containersAseptically transfer 50 mL of necitumumab medicinal product into an empty intravenous container and add 200 mL of sodium chloride 9 mg/mL (0.9 %) solution for injection to the container to bring the total volume to 250 mL. Gently invert the container to mix. DO NOT FREEZE OR SHAKE the infusion solution. DO NOT dilute with other solutions or co-infuse with other electrolytes or medicines.Administer via an infusion pump. A separate infusion line must be used and the line must be flushed with sodium chloride 9 mg/mL (0.9 %) solution for injection at the end of the infusion.Parenteral medicinal products should be inspected visually for particulate matter prior to administration. If particulate matter is identified, discard the infusion solution.Discard any unused portion of necitumumab left in a vial, as the product contains no antimicrobial preservatives.Any unused medicinal product or waste material should be disposed of in accordance with local requirements.7. Marketing authorisation holderEli Lilly Nederland B.V.Papendorpseweg 833528 BJ UtrechtThe Netherlands8. Marketing authorisation number(s)EU/1/15/1084/0019. Date of first authorisation/renewal of the authorisationDate of first authorisation: 15 February 201610. Date of revision of the text01 March 2016Detailed information on this medicinal product is available on the website of the European Medicines Agency https://www.ema.europa.eu.