近日,欧盟委员会批准EMPLICITI(ELOTUZUMAB)INJECTABLE INJECTION以合并用药形式用于多发性骨髓瘤治疗。Empliciti被批准与来那度胺及地塞米松合并用于既往至少接受过一种治疗的患者。这次的批准代表了首个也是唯一在欧盟获批用于多发性骨髓瘤的免疫刺激性抗体。
See Method of administration below for instruction on infusion rates. Dose delay, interruption, or discontinuation If the dose of one medicine in the regimen is delayed, interrupted, or discontinued, the treatment with the other medicinal products may continue as scheduled. However, if oral or intravenous dexamethasone is delayed or discontinued, the administration of Empliciti should be based on clinical judgment (e.g. risk of hypersensitivity) (see section 4.4). Special populations Paediatric population There is no relevant use of Empliciti in the paediatric population for the indication of multiple myeloma. Elderly No dose adjustment is required for elotuzumab in patients over 65 years of age (see section 5.2). Data on the efficacy and safety of elotuzumab in patients ≥ 85 years of age are very limited. Renal impairment No dose adjustment of Empliciti is required for patients with mild (CrCl = 60 - 89 mL/min), moderate (CrCl = 30 - 59 mL/min), severe (CrCl < 30 mL/min) renal impairment or end stage renal disease requiring dialysis (see section 5.2). Hepatic impairment No dose adjustment for Empliciti is required for patients with mild hepatic impairment (total bilirubin [TB] ≤ to the upper limit of normal [ULN] and AST > ULN or TB < 1 to 1.5 × ULN and any AST). Empliciti has not been studied in patients with moderate (TB > 1.5 to 3 × ULN and any AST) or severe (TB > 3 × ULN and any AST) hepatic impairment (see section 5.2). Method of administration Empliciti is for intravenous use only. The administration of the reconstituted and diluted solution must be initiated at an infusion rate of 0.5 mL/min. If the infusion is well tolerated the infusion rate may be increased in a stepwise fashion as described in Table 2. The maximum infusion rate should not exceed 5 mL/min. Table 2: Infusion rate for Empliciti
For instructions on reconstitution and dilution of Empliciti before administration, see section 6.6. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. The Summary of Product Characteristics for all medicinal products used in combination with Empliciti must be consulted before starting therapy. 4.4 Special warnings and precautions for use Infusion reaction Infusion reactions have been reported in patients receiving elotuzumab (see section 4.8). Premedication consisting of dexamethasone, H1 blocker, H2 blocker, and paracetamol must be administered prior to Empliciti infusion (see section 4.2 Premedication). The rate of infusion reactions was much higher in patients who were not premedicated. If any of the symptoms of infusion reaction reach Grade ≥ 2, Empliciti infusion must be interrupted and appropriate medical and supportive measures instituted. Vital signs should be monitored every 30 minutes for 2 hours after the end of the Empliciti infusion. Once the reaction has resolved (symptoms ≤ Grade 1), Empliciti can be restarted at the initial infusion rate of 0.5 mL/min. If symptoms do not recur, the infusion rate may be gradually escalated every 30 minutes to a maximum of 5 mL/min (see section 4.2 Method of administration). Very severe infusion reactions may require permanent discontinuation of Empliciti therapy and emergency treatment. Patients with mild or moderate infusion reactions may receive Empliciti with a reduced infusion rate and close monitoring (see section 4.2 Method of administration). Conditions for use of medicinal products used with Empliciti Empliciti is used in combination with other medicinal products; therefore, the conditions for use applicable to those medicinal products also apply to the combination therapy. The Summary of Product Characteristics for all medicinal products used in combination with Empliciti must be consulted before starting therapy. Infections In clinical trials of patients with multiple myeloma, the incidence of all infections, including pneumonia, were higher in patients treated with Empliciti (see section 4.8). Patients should be monitored and infections should be managed with standard treatment. Second primary malignancies (SPMs) In a clinical trial of patients with multiple myeloma that compared Empliciti combined with lenalidomide and dexamethasone treatment to lenalidomide and dexamethasone treatment (Study 1), the incidence of SPMs, and specifically of solid tumours and non-melanoma skin cancer, was higher in patient treated with Empliciti (see section 4.8). SPMs are known to be associated with lenalidomide exposure, which was extended in patients treated with Empliciti combined with lenalidomide and dexamethasone vs. lenalidomide and dexamethasone. The rate of haematologic malignancies was the same between the two treatment arms. Patients should be monitored for the development of SPMs. 4.5 Interaction with other medicinal products and other forms of interaction Pharmacokinetic interaction studies have not been conducted. Empliciti, as a humanised monoclonal antibody, is not expected to be metabolised by cytochrome P450 (CYP) enzymes or other drug metabolising enzymes, inhibition or induction of these enzymes by co-administered medicinal products is not anticipated to affect the pharmacokinetics of Empliciti. Empliciti may be detected in the serum protein electrophoresis (SPEP) and serum immunofixation assays of myeloma patients and could interfere with correct response classification. The presence of elotuzumab in patient's serum may cause a small peak in the early gamma region on SPEP that is IgGƙ on serum immunofixation. This interference can impact the determination of complete response and possibly relapse from complete response in patients with IgG kappa myeloma protein. In case of detection of additional peaks on serum immunofixation, the possibility of a biclonal gammopathy should be excluded. The Summary of Product Characteristics for all medicinal products used in combination with Empliciti must be consulted before starting therapy. 4.6 Fertility, pregnancy and lactation Woman of childbearing potential/Contraception in the males and females Empliciti should not be used in women of childbearing potential, unless the clinical condition of the woman requires treatment with elotuzumab. Women of childbearing potential should use effective contraception. Male patients must use effective contraception measures during and for 180 days following treatment if their partner is pregnant or of childbearing potential and not using effective contraception. Pregnancy There is no human experience with elotuzumab during pregnancy. Elotuzumab will be given in combination with lenalidomide, which is contraindicated during pregnancy. No animal data are present regarding the effect on reproductive toxicity because of the lack of an adequate animal model. Empliciti should not be used during pregnancy unless the clinical condition of the woman requires treatment with elotuzumab. The Summary of Product Characteristics for all medicinal products used in combination with Empliciti must be consulted before starting therapy. When Empliciti is used with lenalidomide there is a risk of foetal harm, including severe life-threatening human birth defects associated with these agents and the need to follow requirements regarding pregnancy avoidance, including testing and contraception. Lenalidomide is present in the blood and sperm of patients receiving the medicine. Refer to the Summary of Product Characteristics for requirements regarding contraception due to presence and transmission in sperm and for additional detail. Patients receiving Empliciti in combination with lenalidomide should adhere to the pregnancy prevention programme of lenalidomide. Breast-feeding Elotuzumab is not expected to be excreted into human milk. Elotuzumab will be given in combination with lenalidomide and breast-feeding should be stopped because of the use of lenalidomide. Fertility Studies to evaluate the effect of elotuzumab on fertility have not been performed. Thus, the effect of elotuzumab on male and female fertility is unknown. 4.7 Effects on ability to drive and use machines On the basis of reported adverse reactions, Empliciti is not expected to influence the ability to drive or use machines. Patients experiencing infusion reactions should be advised not to drive and use machines until symptoms abate. 4.8 Undesirable effects Summary of safety profile The safety data of elotuzumab have been assessed from a total of 554 patients with multiple myeloma treated with elotuzumab in combination with lenalidomide and dexamethasone (451 patients) or bortezomib and dexamethasone (103 patients) pooled across 6 clinical trials. The majority of adverse reactions were mild to moderate (Grade 1 or 2). The most serious adverse reaction that may occur during elotuzumab treatment is pneumonia. The most common adverse reactions (occurring in > 10% of patients) with elotuzumab treatment were infusion related reactions, diarrhoea, herpes zoster, nasopharyngitis, cough, pneumonia, upper respiratory tract infection, lymphopenia and weight decreased. Tabulated list of adverse reactions Adverse reactions reported in 554 patients with multiple myeloma who were treated with elotuzumab in 6 clinical trials are presented in Table 3. These reactions are presented by system organ class and by frequency. Frequencies are defined as: 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); and not known (cannot be estimated from available data). Table 3: Adverse reactions in patients with multiple myeloma treated with Empliciti
b The term pneumonia is a grouping of the following terms: pneumonia, atypical pneumonia, bronchopneumonia, lobar pneumonia, bacterial pneumonia, fungal pneumonia, pneumonia influenza, and pneumococcal pneumonia. c The term lymphopenia includes the following terms: lymphopenia and lymphocyte count decreased. d The term cough includes the following terms: cough, productive cough, and upper airway cough syndrome. Exposure-adjusted rates for adverse reactions (all Grades and Grade 3/4) in Study 1, a clinical trial in patients with multiple myeloma comparing Empliciti combined with lenalidomide and dexamethasone treatment (N = 318) to lenalidomide and dexamethasone treatment (N = 317), is shown in Table 4. Table 4: Exposure-adjusted rates for adverse reactions for Empliciti-treated patients versus lenalidomide and dexamethasone-treated patients [includes multiple occurrences of all treated patients]
b The term lymphopenia includes the following terms: lymphopenia and lymphocyte count decreased. c The term pneumonia is a grouping of the following terms: pneumonia, atypical pneumonia, bronchopneumonia, lobar pneumonia, bacterial pneumonia, fungal pneumonia, pneumonia influenza, and pneumococcal pneumonia. d The term herpes zoster is a grouping of the following terms: herpes zoster, oral herpes, and herpes virus infection. Description of selected adverse reactions Infusion reactions In a clinical trial of patients with multiple myeloma (Study 1), infusion reactions were reported in approximately 10% of premedicated patients treated with Empliciti combined with lenalidomide and dexamethasone (N = 318) (see section 4.4). The rate of mild to moderate infusion reactions was > 50% in patients who were not premedicated. All reports of infusion reaction were ≤ Grade 3. Grade 3 infusion reactions occurred in 1% of patients. The most common symptoms of an infusion reaction included fever, chills, and hypertension. Five percent (5%) of patients required interruption of the administration of Empliciti for a median of 25 minutes due to infusion reaction, and 1% of patients discontinued due to infusion reactions. Of the patients who experienced an infusion reaction, 70% (23/33) had the reaction during the first dose. Infections The incidence of infections, including pneumonia, was higher with Empliciti treatment than with control (see section 4.4). In a clinical trial of patients with multiple myeloma (Study 1), infections were reported in 81.4% of patients in the Empliciti combined with lenalidomide and dexamethasone arm (N = 318) and 74.4% in lenalidomide and dexamethasone arm (N = 317). Grade 3-4 infections were noted in 28% and 24.3% of Empliciti combined with lenalidomide and dexamethasone and lenalidomide and dexamethasone treated patients, respectively. Fatal infections were infrequent and were reported in 2.5% of Empliciti combined with lenalidomide and dexamethasone and 2.2% of lenalidomide and dexamethasone treated patients. The incidence of pneumonia was higher in the Empliciti combined with lenalidomide and dexamethasone arm compared to lenalidomide and dexamethasone arm reported at 15.1% vs. 11.7% with a fatal outcome at 0.6% vs. 0%, respectively. Second Primary Malignancies The incidence of SPMs was higher with Empliciti treatment than with control (see section 4.4). In a clinical trial of patients with multiple myeloma (Study 1), invasive SPMs have been observed in 6.9% of patients treated with Empliciti combined with lenalidomide and dexamethasone (N = 318) and 4.1% of patients treated with lenalidomide and dexamethasone (N = 317). Second Primary Malignancies are known to be associated with lenalidomide exposure which was extended in patients treated with Empliciti combined with lenalidomide and dexamethasone vs. lenalidomide and dexamethasone. The rate of haematologic malignancies were the same between the two treatment arms (1.6%). Solid tumours were reported in 2.5% and 1.9% of Empliciti combined with lenalidomide and dexamethasone and lenalidomide and dexamethasone treated patients, respectively. Non-melanoma skin cancer was reported in 3.1% and 1.6% of patients treated with Empliciti combined with lenalidomide and dexamethasone and lenalidomide and dexamethasone, respectively. Deep vein thrombosis In a clinical trial of patients with multiple myeloma (Study 1), deep vein thromboses were reported in 7.2% of patients treated with Empliciti combined with lenalidomide and dexamethasone (N = 318) and 3.8% of patients treated with lenalidomide and dexamethasone (N = 317). Among, patients treated with aspirin, deep vein thromboses were reported in 4.1% of patients treated with Empliciti combined with lenalidomide and dexamethasone (E-Ld) and 1.4% of patients treated with lenalidomide and dexamethasone (Ld). The rates of deep vein thromboses observed between treatment arms were similar for patients given prophylaxis with low molecular weight heparin (2.2% in both treatment arms), and for patients given vitamin K antagonists the rates were 0% for patients treated with E-Ld and 6.7% for patients treated with Ld. Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity to Empliciti. Of 390 patients across four clinical studies who were treated with Empliciti and evaluable for the presence of anti-product antibodies, 72 patients (18.5%) tested positive for treatment-emergent anti-product antibodies by an electrochemiluminescent (ECL) assay. Neutralizing antibodies were detected in 19 of 299 patients in Study 1. In the majority of patients, immunogenicity occurred early in treatment and was transient resolving by 2 to 4 months. There was no clear causal evidence of altered pharmacokinetic, efficacy, or toxicity profiles with anti-product antibody development based on the population pharmacokinetic and exposure-response analyses. 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 (see details below). 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 One patient was reported to be overdosed with 23.3 mg/kg of elotuzumab in combination with lenalidomide and dexamethasone. The patient had no symptoms, did not require any treatment for the overdose, and was able to continue on elotuzumab therapy. In clinical studies, approximately 78 patients were evaluated with elotuzumab at 20 mg/kg without apparent toxic effects. In case of overdose, patients should be closely monitored for signs or symptoms of adverse reactions, and appropriate symptomatic treatment instituted. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies. ATC code: L01XC23. Mechanism of action Elotuzumab is an immunostimulatory humanised, IgG1 monoclonal antibody that specifically targets the SLAMF7 (signaling lymphocyte activation molecule family member 7) protein. SLAMF7 is highly expressed on multiple myeloma cells independent of cytogenetic abnormalities. SLAMF7 is also expressed on natural killer cells, normal plasma cells, and other immune cells including some T cell subsets, monocytes, B cells, and pDCs (plasmacytoid dendritic cells), but is not detected on normal solid tissues or haematopoietic stem cells. Elotuzumab directly activates natural killer cells through both the SLAMF7 pathway and Fc receptors enhancing anti-myeloma activity in vitro. Elotuzumab also targets SLAMF7 on myeloma cells and facilitates the interaction with natural killer cells to mediate the killing of myeloma cells through antibody-dependent cellular cytotoxicity (ADCC). In nonclinical models, elotuzumab has demonstrated synergistic activity when combined with lenalidomide or bortezomib. Clinical efficacy and safety Two randomised, open-label studies were conducted to evaluate the efficacy and safety of Empliciti (elotuzumab) in adult patients with multiple myeloma who have received one or more prior therapies. Study 1 provided the pivotal data for the indication for Empliciti in combination with lenalidomide and dexamethasone. Study 1 A randomised, open-label study was conducted to evaluate the efficacy and safety of Empliciti in combination with lenalidomide and dexamethasone in patients with multiple myeloma who have received one to three prior therapies. All patients had documented progression following their most recent therapy. Patients who were refractory to lenalidomide were excluded and 6% of patients had prior lenalidomide treatment. Patients had to recover after transplant for a minimum of 12 weeks from autologous stem cell transplant (SCT), and 16 weeks from allogeneic SCT. Patients with cardiac amyloidosis or plasma cell leukemia were excluded from this study. Eligible patients were randomised in a 1:1 ratio to receive either Empliciti in combination with lenalidomide and dexamethasone or lenalidomide and dexamethasone. Treatment was administered in 4-week cycles until disease progression or unacceptable toxicity. Elotuzumab 10 mg/kg was administered intravenously each week for the first 2 cycles and every 2 weeks thereafter. Prior to Empliciti infusion, dexamethasone was administered as a divided dose: an oral dose of 28 mg and an intravenous dose of 8 mg. In the control group and on weeks without Empliciti, dexamethasone 40 mg was administered as a single oral dose weekly. Lenalidomide 25 mg was taken orally once daily for the first 3 weeks of each cycle. Assessment of tumour response was conducted every 4 weeks. A total of 646 patients were randomised to receive treatment: 321 to Empliciti in combination with lenalidomide and dexamethasone and 325 to lenalidomide and dexamethasone. Demographics and baseline characteristics were well balanced between treatment arms. The median age was 66 years (range 37 to 91); 57% of patients were older than 65 years; 60% of patients were male; Whites comprised 84% of the study population, Asians 10%, and blacks 4%. The International Staging System (ISS) Stage was I in 43%, II in 32% and III in 21% of patients. The high risk cytogenetic categories of del17p and t(4;14) were present in 32% and 9% of patients, respectively. The median number of prior therapies was 2. Thirty-five percent (35%) of patients were refractory (progression during or within 60 days of last therapy) and 65% were relapsed (progression after 60 days of last therapy). Prior therapies included: stem cell transplant (55%), bortezomib (70%) melphalan (65%), thalidomide (48%), and lenalidomide (6%). The primary endpoints of this study, progression-free survival (PFS), as assessed by hazard ratio, and overall response rate (ORR) were determined based on assessments made by a blinded Independent Review Committee. Efficacy results are presented in Table 5 and Figure 1. The median number of treatment cycles was 19 for the Empliciti arm and 14 for the comparator arm. Table 5: Efficacy results for Study 1
b A pre-specified analysis for 3-year PFS rate was performed based on a minimum follow-up time of 33 months. c European Group for Blood and Marrow Transplantation (EBMT) criteria. d p-value based on the Cochran-Mantel-Haenszel chi-square test stratified by B2 microglobulins (<3.5 mg/L versus ≥ 3.5 mg/L), number of prior lines of therapy (1 versus 2 or 3), and prior immunomodulatory therapy (no versus prior thalidomide only versus other). e Complete response (CR) + stringent complete response (sCR). f Complete response rates in Empliciti group may be underestimated due to interference of elotuzumab monoclonal antibody with immunofixation assay and serum protein electrophoresis assay. g A pre-specified interim analysis for OS was performed based on a minimum follow-up time of 35.4 months. h The interim OS analysis did not meet the protocol-specified early stopping boundary for OS (p ≤ 0.014). Figure 1: Progression free survival
Figure 2: Overall survival
• After the remaining solids are completely dissolved, allow the reconstituted solution to stand for 5 to 10 minutes. The reconstituted solution is colourless to slightly yellow, and clear to very opalescent. Empliciti should be inspected visually for particulate matter and discolouration prior to administration. Discard the solution if any particulate matter or discolouration is observed. • Once the reconstitution is completed, withdraw the necessary volume for the calculated dose from each vial, up to a maximum of 16 mL from 400 mg vial and 12 mL from 300 mg vial. Dilute the reconstituted solution with 230 mL of either sodium chloride 9 mg/mL (0.9%) solution for injection or 5% glucose injection, into an infusion bag made of polyvinyl chloride or polyolefin. The volume of sodium chloride 9 mg/mL (0.9%) solution for injection or 5% glucose injection should be adjusted so as not to exceed 5 mL/kg of patient weight at any given dose of Empliciti. Administration The entire Empliciti infusion should be administered with an infusion set and a sterile, non-pyrogenic, low-protein-binding filter (with a pore size of 0.2-1.2 µm) using an automated infusion pump. Empliciti infusion is compatible with: • PVC and polyolefin containers • PVC infusion sets • polyethersulfone and nylon in-line filters with pore sizes of 0.2 μm to 1.2 μm. Empliciti should be initiated at an infusion rate of 0.5 mL/min. If well tolerated, the infusion rate may be increased stepwise as described in Table 2 (see section 4.2 Method of administration). The maximum infusion rate should not exceed 5 mL/min. The Empliciti infusion solution should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C − 8°C protected from light. Do not freeze the reconstituted or diluted solution. The solution for infusion may be stored for a maximum of 8 hours of the total 24 hours at 20°C − 25°C and room light. This 8-hour period should be inclusive of the product administration period. Disposal Do not store any unused portion of the infusion solution for reuse. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. Marketing authorisation holder Bristol-Myers Squibb Pharma EEIG Uxbridge Business Park Sanderson Road Uxbridge UB8 1DH United Kingdom 8. Marketing authorisation number(s) EU/1/16/1088/001-002 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 11 May 2016 10. Date of revision of the text 11 May 2016 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. |
Empliciti powder solution(埃罗妥珠单抗冻干粉末注射剂)简介:
近日,欧盟委员会批准EMPLICITI(ELOTUZUMAB)INJECTABLE INJECTION以合并用药形式用于多发性骨髓瘤治疗。Empliciti被批准与来那度胺及地塞米松合并用于既往至少接受过一种治疗的患者。这次的批准代表了首 ... 责任编辑:admin |
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