欧盟委员会（EC）批准Kyprolis联合地塞米松，治疗既往接受过治疗的多发性骨髓瘤患者 作用机制 Carfilzomib是一种四肽基环氧骨架蛋白酶体抑制剂不可逆地结合至20S蛋白酶体含苏氨酸N-端活性部位，26S蛋白酶体内蛋白水解核心颗粒。Carfilzomib有抗增殖和凋亡活性在体外在实体和血液学中粒细胞。在动物中，carfilzomib抑制 蛋白酶体活性在血液和组织和在多发性骨髓瘤，血液学，和实体瘤模型中延迟肿瘤生长。 适应症和用途 Kyprolis是一种蛋白酶体抑制剂适用为治疗多发性骨髓瘤患者，患者曾接收至少两种既往治疗包括硼替佐米和一种免疫调节药和曾证实疾病进展或末次治疗完成的60天内。批准是根据反应率。尚未证明临床获益，例如活存或症状改善。 剂量和给药方法 （1）每周连续2天历时2至10分钟静脉给药共三周（第1，2，8，9，15，和16天），接着12-天休息期（第17至28天）。 （2）推荐疗程1剂量是20mg/m2/day和如果耐受增加第2疗程剂量和随后疗程剂量至27mg/m2/day。 （3）给药前和后水化患者。 （4）在所有第1疗程剂量前用地塞米松预先给药。在第一疗程剂量递增期，和如果发生或再次出现输注反应症状时。 （5）根据毒性修改给药。 剂型和规格 单次使用小瓶：60mg无菌冻干粉。 Kyprolis® 10mg 30mg 60mg powder for solution for infusion 1. Name of the medicinal product Kyprolis® 10 mg powder for solution for infusion Kyprolis® 30 mg powder for solution for infusion Kyprolis® 60 mg powder for solution for infusion 2. Qualitative and quantitative composition Kyprolis 10 mg powder for solution for infusion Each vial contains 10 mg of carfilzomib. Kyprolis 30 mg powder for solution for infusion Each vial contains 30 mg of carfilzomib. Kyprolis 60 mg powder for solution for infusion Each vial contains 60 mg of carfilzomib. After reconstitution, 1 mL of solution contains 2 mg of carfilzomib. Excipient with known effect Each mL of reconstituted solution contains 7 mg of sodium. For the full list of excipients, see section 6.1. 3. Pharmaceutical form Powder for solution for infusion. White to off-white lyophilised powder. 4. Clinical particulars 4.1 Therapeutic indications Kyprolis in combination with either lenalidomide and dexamethasone or dexamethasone alone is indicated for the treatment of adult patients with multiple myeloma who have received at least one prior therapy (see section 5.1). 4.2 Posology and method of administration Kyprolis treatment should be supervised by a physician experienced in the use of anti-cancer therapy. Posology The dose is calculated using the patient's baseline body surface area (BSA). Patients with a BSA greater than 2.2 m2 should receive a dose based upon a BSA of 2.2 m2. Dose adjustments do not need to be made for weight changes of less than or equal to 20%. Kyprolis in combination with lenalidomide and dexamethasone When combined with lenalidomide and dexamethasone, Kyprolis is administered intravenously as a 10 minute infusion, on two consecutive days, each week for three weeks (days 1, 2, 8, 9, 15, and 16), followed by a 12-day rest period (days 17 to 28) as shown in table 1. Each 28-day period is considered one treatment cycle. Kyprolis is administered at a starting dose of 20 mg/m2 (maximum dose 44 mg) in cycle 1 on days 1 and 2. If tolerated, the dose should be increased on day 8 of cycle 1 to 27 mg/m2 (maximum dose 60 mg). From cycle 13, the day 8 and 9 doses of Kyprolis are omitted. Treatment may be continued until disease progression or until unacceptable toxicity occurs. Treatment with Kyprolis combined with lenalidomide and dexamethasone for longer than 18 cycles should be based on an individual benefit-risk assessment, as the data on the tolerability and toxicity of carfilzomib beyond 18 cycles are limited (see section 5.1). In combination with Kyprolis, lenalidomide is administered as 25 mg orally on days 1–21 and dexamethasone is administered as 40 mg orally or intravenously on days 1, 8, 15, and 22 of the 28 day cycles. Appropriate dose reduction for the starting dose of lenalidomide should be considered according to the recommendations in the current lenalidomide summary of product characteristics, for example for patients with baseline renal impairment. Dexamethasone should be administered 30 minutes to 4 hours before Kyprolis. Table 1 Kyprolis in combination with lenalidomide and dexamethasonea Cycle 1 Week 1 Week 2 Week 3 Week 4 Day 1 Day 2 Days 3–7 Day 8 Day 9 Days 10–14 Day 15 Day 16 Days 17–21 Day 22 Days 23-28 Kyprolis (mg/m2) 20 20 - 27 27 - 27 27 - - - Dexamethasone (mg) 40 - - 40 - - 40 - - 40 - Lenalidomide 25 mg daily - -   Cycles 2-12 Week 1 Week 2 Week 3 Week 4 Day 1 Day 2 Days 3–7 Day 8 Day 9 Days 10–14 Day 15 Day 16 Days 17–21 Day 22 Days 23-28 Kyprolis (mg/m2) 27 27 - 27 27 - 27 27 - - - Dexamethasone (mg) 40 - - 40 - - 40 - - 40 - Lenalidomide 25 mg daily - -   Cycles 13 on Week 1 Week 2 Week 3 Week 4 Day 1 Day 2 Days 3–7 Day 8 Day 9 Days 10–14 Day 15 Day 16 Days 17–21 Day 22 Days 23-28 Kyprolis (mg/m2) 27 27 - - - - 27 27 - - - Dexamethasone (mg) 40 - - 40 - - 40 - - 40 - Lenalidomide 25 mg daily - - a Infusion time is 10 minutes and remains consistent throughout the regimen Kyprolis in combination with dexamethasone When combined with dexamethasone, Kyprolis is administered intravenously as a 30-minute infusion on two consecutive days, each week for three weeks (days 1, 2, 8, 9, 15, and 16) followed by a 12-day rest period (days 17 to 28) as shown in table 2. Each 28-day period is considered one treatment cycle. Kyprolis is administered at a starting dose of 20 mg/m2 (maximum dose 44 mg) in cycle 1 on days 1 and 2. If tolerated, the dose should be increased on day 8 of cycle 1 to 56 mg/m2 (maximum dose 123 mg). Treatment may be continued until disease progression or until unacceptable toxicity occurs. When Kyprolis is combined with dexamethasone alone, dexamethasone is administered as 20 mg orally or intravenously on days 1, 2, 8, 9, 15, 16, 22, and 23 of the 28 day cycles. Dexamethasone should be administered 30 minutes to 4 hours before Kyprolis. Table 2 Kyprolis in combination with dexamethasone alonea Cycle 1 Week 1 Week 2 Week 3 Week 4 Day 1 Day 2 Days 3–7 Day 8 Day 9 Days 10–14 Day 15 Day 16 Days 17–21 Day 22 Day 23 Days 24-28 Kyprolis (mg/m2) 20 20 - 56 56 - 56 56 - - - - Dexamethasone (mg) 20 20 - 20 20 - 20 20 - 20 20 -   Cycle 2 and all subsequent cycles Week 1 Week 2 Week 3 Week 4 Day 1 Day 2 Days 3–7 Day 8 Day 9 Days 10–14 Day 15 Day 16 Days 17–21 Day 22 Day 23 Days 24-28 Kyprolis (mg/m2) 56 56 - 56 56 - 56 56 - - - - Dexamethasone (mg) 20 20 - 20 20 - 20 20 - 20 20 - a Infusion time is 30 minutes and remains consistent throughout the regimen Concomitant medicinal products Antiviral prophylaxis should be considered in patients being treated with Kyprolis to decrease the risk of herpes zoster reactivation. The majority of patients included in studies with Kyprolis received antiviral prophylaxis; due to this fact it is not possible to calculate the true incidence of herpes zoster infection in patients treated with Kyprolis. Thromboprophylaxis is recommended in patients being treated with Kyprolis in combination with dexamethasone or with lenalidomide and dexamethasone, and should be based on an assessment of the patient's underlying risks and clinical status. For other concomitant medicinal products that may be required, such as the use of antacid prophylaxis, refer to the current lenalidomide and dexamethasone summary of product characteristics. Hydration, fluid and electrolyte monitoring Adequate hydration is required before dose administration in cycle 1, especially in patients at high risk of tumour lysis syndrome or renal toxicity. All patients should be monitored for evidence of volume overload and fluid requirements should be tailored to individual patient needs. The total volume of fluids may be adjusted as clinically indicated in patients with baseline cardiac failure or who are at risk for cardiac failure (see section 4.4). Recommended hydration includes both oral fluids (30 mL/kg/day for 48 hours before day 1 of cycle 1) and intravenous fluids (250 mL to 500 mL of appropriate intravenous fluid before each dose in cycle 1). Give an additional 250 mL to 500 mL of intravenous fluids as needed following Kyprolis administration in cycle 1. Oral and/or intravenous hydration should be continued, as needed, in subsequent cycles. Serum potassium levels should be monitored monthly, or more frequently during treatment with Kyprolis as clinically indicated and will depend on the potassium levels measured before the start of treatment, concomitant therapy used (e.g. medicinal products known to increase the risk of hypokalaemia) and associated comorbidities. Recommended dose modifications Dosing should be modified based on Kyprolis toxicity. Recommended actions and dose modifications are presented in table 3. Dose level reductions are presented in table 4. Table 3 Dose modifications during Kyprolis treatment Haematologic toxicity Recommended action • Absolute neutrophil count < 0.5 x 109/L (see section 4.4) • Stop dose - If recovered to ≥ 0.5 x 109/L, continue at same dose level • For subsequent drops to < 0.5 x 109/L, follow the same recommendations as above and consider 1 dose level reduction when restarting Kyprolisa • Febrile neutropenia • Absolute neutrophil count < 0.5 x 109/L and an oral temperature > 38.5°C or two consecutive readings of > 38.0°C for 2 hours • Stop dose • If absolute neutrophil count returns to baseline grade and fever resolves, resume at the same dose level • Platelet count < 10 x 109/L or evidence of bleeding with thrombocytopenia (see section 4.4) • Stop dose - If recovered to ≥ 10 x 109/L and/or bleeding is controlled continue at same dose level • For subsequent drops to < 10 x 109/L, follow the same recommendations as above and consider 1 dose level reduction when restarting Kyprolisa Non-haematologic toxicity (renal) Recommended action • Serum creatinine equal to or greater than 2 × baseline; or • Creatinine clearance < 15 mL/min (or creatinine clearance decreases to ≤ 50% of baseline) or need for dialysis (see section 4.4) • Stop dose and continue monitoring renal function (serum creatinine or creatinine clearance) - Kyprolis should be resumed when renal function has recovered to within 25% of baseline; consider resuming at 1 dose level reductiona • For patients on dialysis receiving Kyprolis, the dose is to be administered after the dialysis procedure Other non-haematologic toxicity Recommended action • All other grade 3 or 4 non-haematologic toxicities (see section 4.4) • Stop until resolved or returned to baseline • Consider restarting the next scheduled treatment at 1 dose level reductiona a See table 4 for dose level reductions Table 4 Dose level reductions for Kyprolis Regimen Kyprolis Dose First Kyprolis dose reduction Second Kyprolis dose reduction Third Kyprolis dose reduction Kyprolis, lenalidomide, and dexamethasone 27 mg/m2 20 mg/m2 15 mg/m2 a —  Kyprolis and dexamethasone 56 mg/m2 45 mg/m2 36 mg/m2 27 mg/m2 a Note: Kyprolis infusion times remain unchanged during dose reduction(s) a If symptoms do not resolve, discontinue Kyprolis treatment Special populations Renal impairment Patients with moderate or severe renal impairment were excluded from Kyprolis-lenalidomide combination studies. Appropriate dose reduction for the starting dose of lenalidomide in patients with baseline renal impairment should be considered according to the recommendations in the lenalidomide summary of product characteristics. No starting dose adjustment for Kyprolis is required in patients with baseline mild, moderate, or severe renal impairment or patients on chronic dialysis. Since dialysis clearance of Kyprolis concentrations has not been studied, the medicinal product should be administered after the dialysis procedure (see section 5.2). In phase 3 clinical studies the incidence of adverse events of acute renal failure was higher in subjects with lower baseline creatinine clearance than that among subjects with higher baseline creatinine clearance. Renal function should be monitored at least monthly or in accordance with accepted clinical practice guidelines, particularly in patients with lower baseline creatinine clearance. Hepatic impairment Patients with hepatic impairment have not been systematically evaluated (see section 5.2). Liver enzymes and bilirubin should be monitored at treatment initiation and monthly during treatment with carfilzomib, regardless of baseline values. Elderly patients Overall, the subject incidence of certain adverse events (including cardiac failure) in clinical trials was higher for patients who were ≥ 75 years of age compared to patients who were < 75 years of age (see section 4.4). Paediatric population The safety and efficacy of Kyprolis in paediatric patients have not been established. No data are available. Method of administration Kyprolis is to be administered by intravenous infusion. The 20/27 mg/m2 dose is administered over 10 minutes. The 20/56 mg/m2 dose must be administered over 30 minutes. Kyprolis must not be administered as a bolus. The intravenous administration line should be flushed with normal sodium chloride solution or 5% glucose solution for injection immediately before and after Kyprolis administration. Do not mix Kyprolis with or administer as an infusion with other medicinal products. For instructions on reconstitution of the medicinal product 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. • Women who are breast-feeding (see section 4.6). As Kyprolis is administered in combination with other medicinal products, refer to their summaries of product characteristics for additional contraindications. 4.4 Special warnings and precautions for use As Kyprolis is administered in combination with other medicinal products, the summary of product characteristics of these other medicinal products must be consulted prior to initiation of treatment with Kyprolis. As lenalidomide may be used in combination with Kyprolis, particular attention to the lenalidomide pregnancy testing and prevention requirements is needed (see section 4.6). Cardiac disorders New or worsening cardiac failure (e.g. congestive cardiac failure, pulmonary oedema, decreased ejection fraction), myocardial ischaemia and infarction have occurred following administration of Kyprolis. Death due to cardiac arrest has occurred within a day of Kyprolis administration and fatal outcomes have been reported with cardiac failure and myocardial infarction. While adequate hydration is required prior to dosing in cycle 1, all patients should be monitored for evidence of volume overload, especially patients at risk for cardiac failure. The total volume of fluids may be adjusted as clinically indicated in patients with baseline cardiac failure or who are at risk for cardiac failure (see section 4.2). Stop Kyprolis for grade 3 or 4 cardiac events until recovery and consider whether to restart Kyprolis at 1 dose level reduction based on a benefit/risk assessment (see section 4.2). The risk of cardiac failure is increased in elderly patients (≥ 75 years). Patients with New York Heart Association (NYHA) Class III and IV heart failure, recent myocardial infarction, and conduction abnormalities uncontrolled by medicinal products were not eligible for the clinical trials. These patients may be at greater risk for cardiac complications. Patients with signs or symptoms of NYHA Class III or IV cardiac failure, recent history of myocardial infarction (in the last 4 months), and in patients with uncontrolled angina or arrhythmias, should have a comprehensive medical assessment, prior to starting treatment with Kyprolis. This assessment should optimise the patient's status, with particular attention to blood pressure and fluid management. Subsequently patients should be treated with caution and remain under close follow-up. Electrocardiographic changes There have been cases of QT interval prolongation reported in clinical studies. An effect of Kyprolis on QT interval cannot be excluded (see section 5.1). Pulmonary toxicity Acute respiratory distress syndrome (ARDS), acute respiratory failure, and acute diffuse infiltrative pulmonary disease such as pneumonitis and interstitial lung disease have occurred in patients receiving Kyprolis. Some of these events have been fatal. Evaluate and stop Kyprolis until resolved and consider whether to restart Kyprolis based on a benefit/risk assessment (see section 4.2). Pulmonary hypertension Pulmonary hypertension has been reported in patients treated with Kyprolis. Some of these events have been fatal. Evaluate as appropriate. Stop Kyprolis for pulmonary hypertension until resolved or returned to baseline and consider whether to restart Kyprolis based on a benefit/risk assessment (see section 4.2). Dyspnoea Dyspnoea was commonly reported in patients treated with Kyprolis. Evaluate dyspnoea to exclude cardiopulmonary conditions including cardiac failure and pulmonary syndromes. Stop Kyprolis for grade 3 and 4 dyspnoea until resolved or returned to baseline and consider whether to restart Kyprolis based on a benefit/risk assessment (see section 4.2 and 4.8). Hypertension Hypertension, including hypertensive crisis and hypertensive emergency, has been observed with Kyprolis. Some of these events have been fatal. All patients should be routinely evaluated for hypertension and treated as needed. If the hypertension cannot be controlled, the Kyprolis dose should be reduced. In case of hypertensive crises, stop Kyprolis until resolved or returned to baseline and consider whether to restart Kyprolis based on a benefit/risk assessment (see section 4.2). Acute renal failure Cases of acute renal failure have been reported in patients who received Kyprolis. Acute renal failure was reported more frequently in patients with advanced relapsed and refractory multiple myeloma who received Kyprolis monotherapy. In phase 3 clinical studies the incidence of adverse events of acute renal failure was higher in subjects with lower baseline creatinine clearance than that among subjects with higher baseline creatinine clearance. Creatinine clearance was stable over time for the majority of patients. Renal function should be monitored at least monthly or in accordance with accepted clinical practice guidelines, particularly in patients with lower baseline creatinine clearance. Reduce or stop dose as appropriate (see section 4.2). Tumour lysis syndrome Cases of tumour lysis syndrome (TLS), including with fatal outcome, have been reported in patients who received Kyprolis. Patients with a high tumour burden should be considered to be at greater risk for TLS. Ensure that patients are well hydrated before administration of Kyprolis in cycle 1, and in subsequent cycles as needed (see section 4.2). Uric acid lowering medicinal products should be considered in patients at high risk for TLS. Evidence of TLS during treatment should be monitored for, including regular measurement of serum electrolytes, and managed promptly. Stop Kyprolis until TLS is resolved (see section 4.2). Infusion reactions Infusion reactions, including life-threatening reactions, have been reported in patients who received Kyprolis. Symptoms may include fever, chills, arthralgia, myalgia, facial flushing, facial oedema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration of Kyprolis. Dexamethasone should be administered prior to Kyprolis to reduce the incidence and severity of reactions (see section 4.2). Haemorrhage and thrombocytopenia Cases of haemorrhage (e.g. gastrointestinal, pulmonary and intracranial haemorrhage) have been reported in patients treated with Kyprolis, often associated with thrombocytopenia. Some of these events have been fatal (see section 4.8). Kyprolis causes thrombocytopenia with platelet nadirs observed on day 8 or day 15 of each 28-day cycle with recovery to baseline platelet count by the start of the next cycle (see section 4.8). Platelet counts should be monitored frequently during treatment with Kyprolis. Reduce or stop dose as appropriate (see section 4.2). Venous thrombosis Cases of venous thromboembolic events, including deep vein thrombosis and pulmonary embolism with fatal outcomes, have been reported in patients who received Kyprolis. Patients with known risk factors for thromboembolism – including prior thrombosis – should be closely monitored. Action should be taken to try to minimise all modifiable risk factors (e.g. smoking, hypertension and hyperlipidaemia). Caution should be used in the concomitant administration of other agents that may increase the risk of thrombosis (e.g. erythropoietic agents or hormone replacement therapy). Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Patients should be instructed to seek medical care if they develop symptoms such as shortness of breath, chest pain, haemoptysis, arm or leg swelling or pain. Thromboprophylaxis should be considered based on an individual benefit/risk assessment. Hepatic toxicity Cases of hepatic failure, including fatal cases, have been reported. Kyprolis can cause elevations of serum transaminases (see section 4.8). Reduce or stop dose as appropriate (see section 4.2). Liver enzymes and bilirubin should be monitored at treatment initiation and monthly during treatment with carfilzomib, regardless of baseline values. Thrombotic microangiopathy Cases of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome (TTP/HUS) have been reported in patients who received Kyprolis. Some of these events have been fatal. Signs and symptoms of TTP/HUS should be monitored for. If the diagnosis is suspected, stop Kyprolis and evaluate patients for possible TTP/HUS. If the diagnosis of TTP/HUS is excluded, Kyprolis can be restarted. The safety of reinitiating Kyprolis therapy in patients previously experiencing TTP/HUS is not known. Posterior reversible encephalopathy syndrome Cases of posterior reversible encephalopathy syndrome (PRES) have been reported in patients receiving Kyprolis. PRES, formerly termed reversible posterior leukoencephalopathy syndrome (RPLS), is a rare, neurological disorder, which can present with seizure, headache, lethargy, confusion, blindness, altered consciousness, and other visual and neurological disturbances, along with hypertension, and the diagnosis is confirmed by neuro-radiological imaging. Kyprolis should be discontinued if PRES is suspected. The safety of reinitiating Kyprolis therapy in patients previously experiencing PRES is not known. Contraception Female patients of child bearing potential (and/or their partners) must use effective contraception measures during and for one month following treatment. Male patients must use effective contraception measures during and for 3 months following treatment if their partner is pregnant or of childbearing potential and not using effective contraception (refer to section 4.6). Carfilzomib may decrease the efficacy of oral contraceptives (refer to section 4.5). Sodium content This medicinal product contains 0.3 mmols (7 mg) of sodium. This should be taken into consideration for patients on a controlled sodium diet. 4.5 Interaction with other medicinal products and other forms of interaction Carfilzomib is primarily metabolised via peptidase and epoxide hydrolase activities, and as a result, the pharmacokinetic profile of carfilzomib is unlikely to be affected by concomitant administration of cytochrome P450 inhibitors and inducers. In vitro studies indicated that carfilzomib did not induce human CYP3A4 in cultured human hepatocytes. A clinical trial using oral midazolam as a CYP3A probe conducted with carfilzomib at a dose of 27 mg/m2 (2-10 minute infusion) demonstrated that the pharmacokinetics of midazolam were unaffected by concomitant carfilzomib administration, indicating that carfilzomib is not expected to inhibit the metabolism of CYP3A4/5 substrates and is not a CYP3A4 inducer in human subjects. No clinical trial was conducted with a dose of 56 mg/m2. However, it is unknown whether carfilzomib is an inducer of CYP1A2, 2C8, 2C9, 2C19 and 2B6 at therapeutic concentrations. Caution should be observed when carfilzomib is combined with medicinal products that are substrates of these enzymes, such as oral contraceptives. Effective measures to avoid pregnancy should be taken (see section 4.6, and refer also to the current lenalidomide summary of product characteristics), an alternative method of effective contraception should be used if the patient is using oral contraceptives. Carfilzomib does not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19 and 2D6 in vitro and is therefore not expected to influence exposure of medicinal products that are substrates of these enzymes as a result of inhibition. Carfilzomib is a P-glycoprotein (P-gp) but not a BCRP substrate. However, given that Kyprolis is administrated intravenously and is extensively metabolised, the pharmacokinetic profile of carfilzomib is unlikely to be affected by P-gp or BCRP inhibitors or inducers. In vitro, at concentrations (3 µM) lower than those expected at therapeutic doses, carfilzomib inhibits the efflux transport of digoxin, a P-gp substrate, by 25%. Caution should be observed when carfilzomib is combined with substrates of P-gp (e.g. digoxin, colchicine). In vitro, carfilzomib inhibits OATP1B1 with an IC50 = 2.01 µM whereas it is unknown whether carfilzomib may or not inhibit other transporters OATP1B3, OAT1, OAT3, OCT2 and BSEP, at the systemic level. Carfilzomib does not inhibit human UGT2B7 but inhibits human UGT1A1 with an IC50 of 5.5 µM. Nonetheless, considering the fast elimination of carfilzomib, notably a rapid decline in systemic concentration 5 minutes after the end of infusion, the risk of clinically relevant interactions with substrates of OATP1B1 and UGT1A1 is probably low. 4.6 Fertility, pregnancy and lactation Women of childbearing potential/Contraception in males and females Female patients of child bearing potential (and/or their partners) must use effective contraception measures during and for one month following treatment. It cannot be excluded that the efficacy of oral contraceptives may be reduced during carfilzomib treatment (see section 4.5). In addition, due to an increased risk of venous thromboembolic events associated with carfilzomib, females should avoid the use of hormonal contraceptives that are associated with a risk of thrombosis during treatment with carfilzomib (see section 4.4 and 4.8). If a patient is currently using oral contraceptives or a hormonal method of contraception that is associated with a risk of thrombosis, the patient should switch to an alternative method of effective contraception. Male patients must use effective contraception measures during and for 3 months following treatment if their partner is pregnant or of childbearing potential not using effective contraception. Pregnancy There are no data from the use of carfilzomib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Based on its mechanism of action and findings in animals, Kyprolis can cause foetal harm when administered to a pregnant woman. Kyprolis should not be used during pregnancy unless the potential benefit outweighs the potential risk to the foetus. If Kyprolis is used during pregnancy, or if the patient becomes pregnant while taking this medicinal product, the patient should be apprised of the potential hazard to the foetus. Lenalidomide is structurally related to thalidomide. Thalidomide is a known human teratogenic active substance that causes severe life-threatening birth defects. If lenalidomide is taken during pregnancy, a teratogenic effect of lenalidomide in humans is expected. The conditions of the Pregnancy Prevention Programme for lenalidomide must be fulfilled for all patients unless there is reliable evidence that the patient does not have childbearing potential. Please refer to the current lenalidomide summary of product characteristics. Breast-feeding It is unknown whether carfilzomib or its metabolites are excreted in human milk. Based on its pharmacological properties, a risk to the suckling child cannot be excluded. Consequently, as a precautionary measure, breast-feeding is contra-indicated during and for at least 2 days after treatment with Kyprolis. Fertility No fertility studies have been performed in animals (see section 5.3). 4.7 Effects on ability to drive and use machines Kyprolis has minor influence on the ability to drive and use machines. Fatigue, dizziness, fainting, blurred vision, somnolence and/or a drop in blood pressure have been observed in clinical trials. Patients being treated with Kyprolis should be advised not to drive or operate machines in the event that they experience any of these symptoms. 4.8 Undesirable effects Summary of safety profile The most serious adverse reactions that may occur during Kyprolis treatment include: cardiac toxicity, pulmonary toxicities, pulmonary hypertension, dyspnoea, hypertension including hypertensive crises, acute renal failure, tumour lysis syndrome, infusion reactions, thrombocytopenia, hepatic toxicity, PRES and TTP/HUS. In clinical studies with Kyprolis, cardiac toxicity and dyspnoea typically occurred early in the course of Kyprolis therapy (see section 4.4). The most common adverse reactions (occurring in > 20% of subjects) were: anaemia, fatigue, diarrhoea, thrombocytopenia, nausea, pyrexia, dyspnoea, respiratory tract infection, cough and peripheral oedema. Following initial doses of carfilzomib at 20 mg/m2, the dose was increased to 27 mg/m2 in study PX-171-009 and to 56 mg/m2 in study 2011-003 (see section 5.1). A cross-study comparison of the adverse reactions occurring in the Kyprolis and dexamethasone (Kd) arm of study 2011-003 vs the Kyprolis, lenalidomide and dexamethasone (KRd) arm of study PX-171-009 suggest that there may be a potential dose relationship for the following adverse reactions: cardiac failure (Kd 8.2%, KRd 6.4%), dyspnoea (Kd 30.9%, KRd 22.7%), hypertension (Kd 25.9%, KRd 15.8%), and pulmonary hypertension (Kd 1.3%, KRd 0.8%). Tabulated list of adverse reactions Adverse reactions are presented below by system organ class and frequency category (table 5). Frequency categories were determined from the crude incidence rate reported for each adverse reaction in a dataset of pooled clinical studies (n = 2,044). Within each system organ class and frequency category, adverse reactions are presented in order of decreasing seriousness. Table 5 Tabulated list of adverse reactions MedDRA system organ class  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) Infections and infestations  Pneumonia Respiratory tract infection Nasopharyngitis  Sepsis Influenza Urinary tract infection Bronchitis Viral infection Rhinitis  Lung infection Immune system disorders      Drug hypersensitivity Blood and lymphatic system disorders  Thrombocytopenia Neutropenia Anaema Lymphopenia  Febrile neutropenia Leukopenia  HUS  TTP Thrombotic microangiopathy Metabolism and nutrition disorders  Hypokalaemia Hyperglycaemia Decreased appetite  Dehydration Hyperkalaemia Hypomagnesaemia Hyponatraemia Hypercalcaemia Hypocalcaemia Hypophosphataemia Hyperuricaemia Hypoalbuminaemia  Tumour lysis syndrome Psychiatric disorders  Insomnia  Anxiety   Nervous system disorders  Dizziness Peripheral neuropathy Headache  Paraesthesia Hypoaesthesia  Intracranial haemorrhage Cerebrovascular accident  PRES Eye disorders    Cataract Blurred vision   Cardiac disorders    Cardiac failure Atrial fibrillation Tachycardia Palpitations  Cardiac arrest Myocardial infarction Myocardial ischaemia Ejection fraction decreased Pericarditis Pericardial effusion  Vascular disorders  Hypertension  Deep vein thrombosis Hypotension Flushing  Hypertensive crisis Haemorrhage  Hypertensive emergency Respiratory, thoracic, and mediastinal disorders  Dyspnoea Cough  Pulmonary embolism Pulmonary oedema Epistaxis Oropharyngeal pain Dysphonia Wheezing Pulmonary hypertension  ARDS Acute respiratory failure Pulmonary haemorrhage Interstitial lung disease Pneumonitis Gastrointestinal disorders  Vomiting Diarrhoea Constipation Abdominal pain Nausea  Dyspepsia Toothache  Gastrointestinal haemorrhage Gastrointentestinal perforation Hepatobiliary disorders    Increased alanine aminotransferase Increased aspartate aminotransferase Gamma-glutamyltransferase increased Hyperbilirubinaemia  Hepatic failure Cholestasis Skin and subcutaneous tissue disorders    Rash Pruritus Erythema Hyperhidrosis     Musculoskeletal and connective tissue disorders  Back pain Arthralgia Pain in extremity Muscle spasms  Musculoskeletal pain Musculoskeletal chest pain Bone pain Myalgia Muscular weakness Renal and urinary disorders  Increased blood creatinine  Acute renal failure Renal failure Renal impairment Decreased creatinine renal clearance General disorders and administration site conditions  Infusion reaction Pyrexia Peripheral oedema Asthenia Fatigue  Chest pain Pain Infusion site reaction Chills  Multi-organ failure Investigations    Increased c-reactive protein Increased blood uric acid Description of selected adverse reactions Cardiac failure, myocardial infarction and myocardial ischaemia In clinical studies with Kyprolis, cardiac failure was reported in approximately 7% of subjects (< 5% of subjects had grade ≥ 3 events), myocardial infarction was reported in approximately 2% of subjects (< 1.5% of subjects had grade ≥ 3 events) and myocardial ischaemia was reported in approximately 1% of subjects (< 1% of subjects had grade ≥ 3 events). These events typically occurred early in the course of Kyprolis therapy (< 5 cycles). For clinical management of cardiac disorders during Kyprolis treatment, see section 4.4. Dyspnoea Dyspnoea was reported in approximately 30% of subjects in clinical studies with Kyprolis. The majority of dyspnoea adverse reactions were non-serious (< 5% of subjects had grade ≥ 3 events), resolved, rarely resulted in treatment discontinuation, and had an onset early in the course of study (< 3 cycles). For clinical management of dyspnoea during Kyprolis treatment, see section 4.4. Hypertension including hypertensive crises Hypertensive crises (hypertensive urgency or hypertensive emergency) have occurred following administration of Kyprolis. Some of these events have been fatal. In clinical studies, hypertension adverse events occurred in approximately 20% of subjects and approximately 6% of subjects had grade ≥ 3 hypertension events, but hypertensive crises occurred in < 0.5% of subjects. The incidence of hypertension adverse events was similar between those with or without a prior medical history of hypertension. For clinical management of hypertension during Kyprolis treatment, see section 4.4. Thrombocytopenia Thrombocytopenia was reported in approximately 40% of subjects in clinical studies with Kyprolis and approximately 20% of subjects had grade ≥ 3 events. Kyprolis causes thrombocytopenia through inhibition of platelet budding from megakaryocytes resulting in a classic cyclical thrombocytopenia with platelet nadirs occurring on day 8 or 15 of each 28-day cycle and usually associated with recovery to baseline by the start of the next cycle. For clinical management of thrombocytopenia during Kyprolis treatment, see section 4.4. Venous thromboembolic events Cases of venous thromboembolic events, including deep vein thrombosis and pulmonary embolism with fatal outcomes, have been reported in patients who received Kyprolis (see section 4.4). The overall incidence of venous thromboembolic events was higher in the Kyprolis arms of two phase 3 studies. In study PX 171 009 the incidence of venous thromboembolic events was 15.3% in the KRd arm and 9.0% in the Rd arm. Grade ≥ 3 venous thromboembolic events were reported in 5.6% of patients in the KRd arm and 3.9% of patients in the Rd arm. In study 2011 003 the incidence of venous thromboembolic events was 10.6% in the Kd arm and 3.1% in the bortezomib plus dexamethasone (Vd) arm. Grade ≥ 3 venous thromboembolic events were reported in 3.0% of patients in the Kd arm and 1.5% of patients in the Vd arm. Hepatic failure Cases of hepatic failure, including fatal cases, have been reported in < 1% of subjects in clinical studies with Kyprolis. For clinical management of hepatic toxicity during Kyprolis treatment, see section 4.4. Peripheral neuropathy In a randomised, open-label multicentre study in patients receiving Kyprolis 20/56 mg/m2 infused over 30 minutes in combination with dexamethasone (Kd, n = 464) vs bortezomib plus dexamethasone (Vd, n = 465), cases of grade 2 and higher peripheral neuropathy were reported in 6% of patients with relapsed multiple myeloma in the Kd arm, compared with 32% in the Vd arm. Other special populations Elderly patients (≥ 75 years) Overall, the subject incidence of certain adverse events (including cardiac arrhythmias, cardiac failure (see section 4.4), dyspnoea, leukopenia and thrombocytopenia) in clinical trials with Kyprolis was higher for patients who were ≥ 75 years of age compared to patients who were < 75 years of age. 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: United Kingdom Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard 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 4.9 Overdose There is currently insufficient information to draw conclusions about the safety of doses higher than those evaluated in clinical studies. Acute onset of chills, hypotension, renal insufficiency, thrombocytopenia and lymphopenia has been reported following a dose of 200 mg of Kyprolis administered in error. There is no known specific antidote for carfilzomib overdose. In the event of an overdose, the patient should be monitored, specifically for the adverse reactions to Kyprolis listed in section 4.8. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antineoplastic agents, ATC code: L01XX45 Mechanism of action Carfilzomib is a tetrapeptide epoxyketone proteasome inhibitor that selectively and irreversibly binds to the N terminal threonine containing active sites of the 20S proteasome, the proteolytic core particle within the 26S proteasome, and displays little to no activity against other protease classes. Carfilzomib had antiproliferative and proapoptotic activities in preclinical models in haematologic tumours. In animals, carfilzomib inhibited proteasome activity in blood and tissue and delayed tumour growth in models of multiple myeloma. In vitro, carfilzomib was found to have minimal neurotoxicity and minimal reaction to non-proteasomal proteases. Pharmacodynamic effects Intravenous carfilzomib administration resulted in suppression of proteasome chymotrypsin-like (CT-L) activity when measured in blood 1 hour after the first dose. Doses of ≥ 15 mg/m2 consistently induced an (≥ 80%) inhibition of the CT-L activity of the proteasome. In addition, carfilzomib administration resulted in inhibition of the latent membrane protein 2 (LMP2) and multicatalytic endopeptidase complex-like 1 (MECL1) subunits of the immunoproteasome ranging from 26% to 32% and 41% to 49%, respectively, at 20 mg/m2. Proteasome inhibition was maintained for ≥ 48 hours following the first dose of carfilzomib for each week of dosing. Combination dosing with lenalidomide and dexamethasone did not affect proteasome inhibition. At the higher dose of 56 mg/m2, there was not only a greater inhibition of CT-L subunits (≥ 90%) compared to those at 15 to 20 mg/m2, but also a greater inhibition of other proteasome subunits (LMP7, MECL1, and LMP2). There was an approximately 8%, 23% and 34% increase in the inhibition of LMP7, MECL1, and LMP2 subunits respectively at the dose of 56 mg/m2compared to those at 15 to 20 mg/m2. Similar proteasome inhibition by carfilzomib was achieved with 2- to 10-minute and 30-minute infusions at the 2 dose levels (20 and 36 mg/m2) at which it was tested. Clinical efficacy and safety Kyprolis in combination with lenalidomide and dexamethasone for the treatment of patients with relapsed multiple myeloma – study PX-171-009 (ASPIRE) The safety and efficacy of Kyprolis were evaluated in a randomised, open-label, multicentre study of 792 patients with relapsed multiple myeloma, which evaluated the combination of Kyprolis with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone, randomised 1:1. This study evaluated Kyprolis at an initial dose of 20 mg/m2, which was increased to 27 mg/m2 on cycle 1, day 8, administered twice weekly for 3 out of 4 weeks as a 10 minute infusion. Kyprolis treatment was administered for a maximum of 18 cycles unless discontinued early for disease progression or unacceptable toxicity. Lenalidomide and dexamethasone administration could continue until progression or unacceptable toxicity. Patients who had the following were excluded from the trial: creatinine clearance rates < 50 mL/min, NYHA Class III to IV congestive heart failure, or myocardial infarction within the last 4 months, disease progression during the treatment with a bortezomib-containing regimen, or progression during the first 3 months of initiating treatment with lenalidomide and dexamethasone, or progression at any time during treatment with lenalidomide and dexamethasone if this was the subject's most recent line of therapy. Study eligibility criteria allowed a small subset of patients with myeloma refractory to bortezomib (n = 118) or lenalidomide (n = 57) to be enrolled. Enrolled subjects were defined as refractory to a therapy if they met any of the following 3 criteria: nonresponsive (< minimal response) to any regimen; progression during any regimen; or progression within 60 days of completion of any regimen. This study did not evaluate the benefit/risk ratio in the broader refractory population. The disease status and other baseline characteristics were well-balanced between the two arms, including age (64 years, range 31-91 years), gender (56% male), ECOG performance status (48% with performance status 1), high-risk genetic mutations, consisting of the genetic subtypes t(4;14), t(14;16), or deletion 17p in ≥ 60% of plasma cells (13%), unknown-risk genetic mutations, which included subjects with results not collected or not analysed (47%), and baseline ISS stage III disease (20%). Subjects had received 1 to 3 prior lines of therapy (median of 2), including prior treatment with bortezomib (66%), thalidomide (44%) and lenalidomide (20%). The results of study PX-171-009 are summarised in table 6 and in figure 1 and figure 2. Table 6 Summary of efficacy analysis in relapsed multiple myeloma study PX-171-009 KRd combination therapy KRd arma (N = 396) Rd arma (N = 396) PFS months median (95% CI) 26.3 (23.3, 30.5) 17.6 (15.0, 20.6) HR (95% CI); 1-sided p-valueb 0.69 (0.57, 0.83); < 0.0001 OS months median (95% CI) NE (NE, NE) NE (32.1, NE) HR (95% CI); 1-sided p-valuec 0.79 (0.63, 0.99); 0.0182 ORR n (%) 345 (87.1) 264 (66.7) sCR 56 (14.1) 17 (4.3) CR 70 (17.7) 20 (5.1) VGPR 151 (38.1) 123 (31.1) PR 68 (17.2) 104 (26.3) 95% CI of ORR 83.4, 90.3 61.8, 71.3 1-sided p-valuec < 0.0001 KRd = Kyprolis, lenalidomide and dexamethasone; Rd = lenalidomide and dexamethasone; PFS = progression-free survival; HR = hazard ratio; CI = confidence interval; OS = overall survival; ORR = overall response rate; NE = not estimable; sCR = stringent complete response; CR = complete response; VGPR = very good partial response; PR = partial response; IMWG = international myeloma working group EBMT = European blood and marrow transplantation a As determined by an Independent Review Committee using standard objective IMWG/EBMT response criteria b Statistically significant c The interim OS analysis did not meet the protocol-specified early stopping boundary for OS (p = 0.0051); hence, due to the hierarchical nature of the study design all subsequent p-values are provided for descriptive purposes only Patients in the Kyprolis, lenalidomide, and dexamethasone (KRd) arm demonstrated improved progression-free survival (PFS) compared with those in the lenalidomide and dexamethasone (Rd) arm, (HR = 0.69, with 1-sided p value < 0.0001) which represents a 45% improvement in PFS or a 31% reduction in the risk of event as determined using standard objective International Myeloma Working Group (IMWG)/European Blood and Marrow Transplantation (EBMT) response criteria by an Independent Review Committee (IRC). The PFS benefit of KRd was consistently observed in all subgroups, including patients ≥ 75 years of age (n = 96), patients with high risk (n = 100) or unknown (n = 375) risk genetic mutations, and patients with baseline creatinine clearance of 30 - < 50mL/min (n = 56). Figure 1 Kaplan-Meier curve of progression-free survival in relapsed multiple myelomaa KRd = Kyprolis, lenalidomide and dexamethasone; Rd = lenalidomide, dexamethasone; PFS = progression-free survival; HR = hazard ratio; CI = confidence interval; IMWG = International Myeloma Working Group; EBMT = European blood and marrow transplantation Note: The response and PD outcomes were determined using standard objective IMWG/EBMT response criteria. a Study PX-171-009 The Kaplan-Meier event-free rate for OS at 24 months was 73.3% (95% CI: 68.6% to 77.5%) in the KRd arm and 65.0% (95% CI: 59.9% to 69.5%) in the Rd arm. Figure 2 Kaplan-Meier curve of interim overall survival in relapsed multiple myelomaa KRd = Kyprolis, lenalidomide and dexamethasone; Rd = lenalidomide and dexamethasone; OS = overall survival; NE = not estimable; HR = hazard ratio; CI = confidence interval Note: The interim OS analysis did not meet the protocol-specified early stopping boundary for OS (p = 0.0051). a Study PX-171-009 Patients treated with KRd reported improved Global Health Status, with higher Global Health Status/Quality of Life (QoL) scores compared with Rd over 18 cycles of treatment (multiplicity unadjusted 1 sided p-value = 0.0001) measured with the EORTC QLQ-C30, an instrument validated in multiple myeloma. The p-values for ORR and Global Health Status/Quality of Life (QoL) scores are descriptive based on the pre-specified multiplicity adjustment plan. Kyprolis in combination with dexamethasone for the treatment of patients with relapsed multiple myeloma – study 2011-003 (ENDEAVOR) The safety and efficacy of Kyprolis were evaluated in a phase 3, randomised, open-label, multicentre study of Kyprolis plus dexamethasone (Kd) versus bortezomib plus dexamethasone (Vd). A total of 929 patients with relapsed or refractory multiple myeloma who had received 1 to 3 prior lines of therapy were enrolled and randomised (464 in the Kd arm; 465 in the Vd arm). This study evaluated Kyprolis at an initial dose of 20 mg/m2, which was increased to 56 mg/m2 on cycle 1, day 8, administered twice weekly for 3 out of 4 weeks as a 30 minute infusion until progression or unacceptable toxicity. Patients randomised to the Vd arm could receive bortezomib either by the intravenous (n = 108) or subcutaneous (n = 357) route. Patients who had the following were excluded from the trial: creatinine clearance rates < 15 mL/min, NYHA Class III to IV congestive heart failure, myocardial infarction within the last 4 months or those with left ventricular ejection fraction (LVEF) < 40%. Study eligibility criteria allowed patients previously treated with carfilzomib (n = 3) or bortezomib (n = 502) to be enrolled as long as patients had at least a partial response (PR) to prior proteasome inhibitor therapy, were not removed from proteasome inhibitor therapy due to toxicity, and had at least a 6-month proteasome inhibitor treatment-free interval from last dose. The demographics and baseline characteristics for study 2011-003 were well-balanced between the two arms, including prior treatment with bortezomib (54%), prior treatment with lenalidomide (38%), lenalidomide refractory (25%), age (65 years, range 30-89 years), gender (51% male), ECOG performance status (45% with performance status 1), high-risk genetic mutations, consisting of the genetic subtypes t(4;14), t(14;16), or deletion 17p in ≥ 60% of plasma cells (23%) unknown-risk genetic mutations, which included subjects with results not collected or not analysed (9%) and baseline ISS stage III disease (24%). The results of study 2011-003 are summarised in table 7. Table 7 Summary of efficacy analysis in relapsed multiple myeloma study 2011-003 Kd Arm (N = 464) Vd Arm (N = 465) PFS months median (95% CI)a 18.7 (15.6, NE) 9.4 (8.4, 10.4) HR (95% CI); 1-sided p-valueb 0.533 (0.44, 0.65); < 0.0001 ORR n (%)a, c 357 (76.9) 291 (62.6) ≥ CRd 58 (12.5) 29 (6.2) ≥ VGPRe 252 (54.3) 133 (28.6) 95% CI of ORR 72.8, 80.7 58.0, 67.0 1-sided p-valueb < 0.0001 Kd = Kyprolis plus dexamethasone; Vd = bortezomib and dexamethasone; CI = confidence interval; NE = not estimable; HR = Hazard Ratio; ORR = overall response rate; CR = complete response; VGPR = very good partial response a These endpoints were determined by an Independent Review Committee b Statistically significant c Overall response is defined as achieving a best overall response of PR, VGPR, CR, or sCR. d Statistically significant, 1-sided p value = 0.0005 e Statistically significant, 1-sided p value = 0.0001 The study showed significant improvement in PFS for patients in the Kd arm over those in the Vd arm (HR: 0.53, 95% CI: 0.44, 0.65 [p value = 0.0001]) (see figure 3). Similar PFS results were observed in patients who had received prior treatment with bortezomib (HR 0.56, 95% CI: 0.44, 0.73) and patients who had not received prior treatment with bortezomib (HR 0.48, 95% CI: 0.36, 0.66). The PFS benefit of Kd was consistently observed in all subgroups, including patients ≥ 75 years of age (n = 143), patients with high risk (n = 210) genetic mutations, and patients with baseline creatinine clearance of 30 - < 50mL/min (n = 128). In patients who received prior bortezomib (54%), median PFS was 15.6 months in the Kd arm versus 8.1 months in the Vd arm (HR = 0.56, 95% CI = [0.44, 0.73]), ORR was 71.2% versus 60.3%. In patients who received prior lenalidomide (38%), median PFS was 12.9 months in the Kd arm versus 7.3 months in the Vd arm (HR = 0.69, 95% CI = [0.52, 0.92]), ORR was 70.1% versus 59.3%. In patients refractory to lenalidomide (25%), median PFS was 8.6 months in the Kd arm versus 6.6 months in the Vd arm (HR = 0.80, 95% CI = [0.57, 1.11]), ORR was 61.9% versus 54.9%. Figure 3 Kaplan-Meier plot of progression-free survival as determined by the IRC (intent-to-treat population) study 2011-003 Kd = Kyprolis plus dexamethasone; Vd = bortezomib plus dexamethasone; PFS = progression-free survival; mo = months; HR = hazard ratio; CI = confidence interval; As of the data cutoff date of the interim analysis, 75 (16.2%) subjects in the Kd arm and 88 (18.9%) subjects in the Vd arm had died, corresponding to 33% of total 496 events required for the final analysis (HR = 0.786, 95% CI: 0.575, 1.075) (see figure 4). Figure 4 Kaplan-Meier curve of interim overall survival in relapsed multiple myeloma study 2011-003 Kd = Kyprolis plus dexamethasone; Vd = bortezomib plus dexamethasone; OS = overall survival; mo = months; NE = Not Estimable; HR = hazard ratio; CI = confidence interval Kyprolis monotherapy in patients with relapsed and refractory multiple myeloma Additional clinical experience has been generated with Kyprolis monotherapy in patients with relapsed and refractory multiple myeloma. Study PX-171-011 was an open-label randomised phase 3 study (N = 315; exposure to ≥ 3 prior therapies required). Patients enrolled to study PX 171-011 were more heavily pre-treated with lower organ and marrow function as compared to those enrolled in study PX 171-009. PX 171-011 evaluated Kyprolis monotherapy versus a control arm (corticosteroids and cyclophosphamide). The study did not meet its primary efficacy endpoint of demonstrating superiority of Kyprolis monotherapy over the active control arm in overall survival (HR = 0.975 [95% CI: 0.760-1.249]). PX 171-003A1 was a single-arm phase 2 study (N = 266; exposure to ≥ 2 prior therapies required), which met its primary efficacy endpoint of IRC-assessed ORR (22.9%). Cardiac electrophysiology An evaluation of possible effects of carfilzomib on cardiac function was performed by analyzing, via central blind reading, triplicate ECG in 154 subjects with advanced malignancies, including multiple myeloma. The effect of carfilzomib on cardiac repolarization using the QT interval with Fridericia's correction (QTcF interval) and the analysis of concentration-QTc relationships show no clear signal of any dose-related effect. The upper bound of one-sided 95% confidence interval (CI) for predicted effect on QTcF at Cmax was 4.8 msec. With Bazett's correction (QTcB interval), the upper bound of one-sided 95% confidence interval (CI) for predicted effect on QTcB at Cmax was 5.9 msec. Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies with Kyprolis in all subsets of the paediatric population in multiple myeloma (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties Absorption The Cmax and AUC following a 2- to 10-minute intravenous infusion of 27 mg/m2 was 4,232 ng/mL and 379 ng•hr/mL, respectively. Following repeated doses of Kyprolis at 15 and 20 mg/m2, systemic exposure (AUC) and half-life were similar on days 1 and 15 or 16 of cycle 1, suggesting there was no systemic carfilzomib accumulation. At doses between 20 and 56 mg/m2, there was a dose-dependent increase in exposure. A 30-minute infusion resulted in a similar half-life and AUC, but 2- to 3-fold lower Cmax compared to that observed with a 2- to 10-minute infusion of the same dose. Following a 30-minute infusion of the 56 mg/m2 dose, the AUC (948 ng•hr/mL) was approximately 2.5-fold that observed at the 27 mg/m2 level, and Cmax (2079 ng/mL) was lower compared to that of 27 mg/m2 over the 2- to 10-minute infusion. Distribution The mean steady-state volume of distribution of a 20 mg/m2 dose of carfilzomib was 28 L. When tested in vitro, the binding of carfilzomib to human plasma proteins averaged 97% over the concentration range of 0.4 to 4 micromolar. Biotransformation Carfilzomib was rapidly and extensively metabolised. The predominant metabolites measured in human plasma and urine, and generated in vitro by human hepatocytes, were peptide fragments and the diol of carfilzomib, suggesting that peptidase cleavage and epoxide hydrolysis were the principal pathways of metabolism. Cytochrome P450 mediated mechanisms played a minor role in overall carfilzomib metabolism. The metabolites have no known biologic activity. Elimination Following intravenous administration of doses ≥ 15 mg/m2, carfilzomib was rapidly cleared from the systemic circulation with a half-life of ≤ 1 hour on day 1 of cycle 1. The systemic clearance ranged from 151 to 263 L/hour, and exceeded hepatic blood flow, suggesting that carfilzomib was largely cleared extrahepatically. Carfilzomib is eliminated primarily via metabolism with subsequent excretion of its metabolites in urine. Special populations Population pharmacokinetic analyses indicate there are no effects of age, gender or race on the pharmacokinetics of carfilzomib. No dedicated pharmacokinetic studies have been completed in patients with hepatic impairment (see section 4.4). Renal function status had no effect on the clearance or exposure of carfilzomib following single or repeat-dose administration at doses up to 20 mg/m2 (see section 4.2). 5.3 Preclinical safety data Carfilzomib was clastogenic in the in vitro chromosomal aberration test in peripheral blood lymphocytes. Carfilzomib was not mutagenic in the in vitro bacterial reverse mutation (Ames) test and was not clastogenic in the in vivo mouse bone marrow micronucleus assay. Monkeys administered a single bolus intravenous dose of carfilzomib at 3 mg/kg (which corresponds to 36 mg/m2 and is similar to the recommended dose in humans of 27 mg/m2 based on BSA) experienced hypotension, increased heart rate, and increased serum levels of troponin T. The repeated bolus intravenous administration of carfilzomib at ≥ 2 mg/kg/dose in rats and 2 mg/kg/dose in monkeys using dosing schedules similar to those used clinically resulted in mortalities that were due to toxicities occurring in the cardiovascular (cardiac failure, cardiac fibrosis, pericardial fluid accumulation, cardiac haemorrhage/degeneration), gastrointestinal (necrosis/haemorrhage), renal (glomerulonephropathy, tubular necrosis, dysfunction), and pulmonary (haemorrhage/inflammation) systems. The dose of 2 mg/kg/dose in rats is approximately half the recommended dose in humans of 27 mg/m2 based on BSA. The highest non-severely toxic dose of 0.5 mg/kg in monkeys resulted in interstitial inflammation in the kidney along with slight glomerulopathy and slight heart inflammation. Those findings were reported at 6 mg/m2 which are below the recommended dose in humans of 27 mg/m2. Fertility studies with carfilzomib have not been conducted. No effects on reproductive tissues were noted during 28-day repeat-dose rat and monkey toxicity studies or in 6-month rat and 9-month monkey chronic toxicity studies. Carfilzomib caused embryo-foetal toxicity in pregnant rabbits at doses that were lower than in patients receiving the recommended dose. Carfilzomib administered to pregnant rats during the period of organogenesis was not teratogenic at doses up to 2 mg/kg/day, which is approximately half the recommended dose in humans of 27 mg/m2 based on BSA. 6. Pharmaceutical particulars 6.1 List of excipients Betadex sulfobutyl ether sodium Anhydrous citric acid (E330) Sodium hydroxide (for pH adjustment) 6.2 Incompatibilities In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. Kyprolis powder for solution for infusion must not be mixed with sodium chloride 9 mg/mL (0.9%) solution for injection. 6.3 Shelf life Powder vial 3 years. Reconstituted solution Chemical and physical in-use stability of reconstituted solutions in the vial, syringe or intravenous bag has been demonstrated for 24 hours at 2°C - 8°C or for 4 hours at 25°C. The elapsed time from reconstitution to administration should not exceed 24 hours. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user and should not be longer than 24 hours at 2°C – 8°C. 6.4 Special precautions for storage Store in a refrigerator (2°C – 8°C). Do not freeze. Store in the original carton in order to protect from light. For storage conditions after reconstitution of the medicinal product, see section 6.3. 6.5 Nature and contents of container Kyprolis 10 mg powder for solution for infusion 10 mL type I clear glass vial, closed with fluoropolymer laminated elastomeric stopper and aluminium seal with a light blue plastic flip off cap. Kyprolis 30 mg powder for solution for infusion 30 mL type I clear glass vial, closed with fluoropolymer laminated elastomeric stopper and aluminium seal with an orange plastic flip off cap. Kyprolis 60 mg powder for solution for infusion 50 mL type I clear glass vial, closed with fluoropolymer laminated elastomeric stopper and aluminium seal with a purple plastic flip off cap. Pack size of one vial. Not all presentations may be marketed. 6.6 Special precautions for disposal and other handling Reconstitution and preparation for intravenous administration Kyprolis vials contain no antimicrobial preservatives and are intended for single use only. Proper aseptic technique must be observed. The reconstituted solution contains carfilzomib at a concentration of 2 mg/mL. Read the complete preparation instructions prior to reconstitution. 1. Remove vial from refrigerator just prior to use. 2. Calculate the dose (mg/m2) and number of vials of Kyprolis required using the patient's BSA at baseline. Patients with a BSA greater than 2.2 m2 should receive a dose based upon a BSA of 2.2 m2. Dose adjustments do not need to be made for weight changes of ≤ 20%. 3. Aseptically reconstitute each vial by slowly injecting 5 mL (for 10 mg vial), 15 mL (for 30 mg vial) or 29 mL (for 60 mg vial) sterile water for injections through the stopper and directing the solution onto the INSIDE WALL OF THE VIAL to minimise foaming. 4. Gently swirl and/or invert the vial slowly for approximately 1 minute, or until complete dissolution. DO NOT SHAKE. If foaming occurs, allow the solution to settle in the vial until foaming subsides (approximately 5 minutes) and the solution is clear. 5. Visually inspect for particulate matter and discolouration prior to administration. The reconstituted product should be a clear, colourless to slightly yellow solution and should not be administered if any discolouration or particulate matter is observed. 6. Discard any unused portion left in the vial. 7. Optionally, Kyprolis can be administered in an intravenous bag. 8. When administering in an intravenous bag, withdraw the calculated dose from the vial and dilute into a 50 or 100 mL intravenous bag containing 5% glucose solution for injection. Disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. Marketing authorisation holder Amgen Europe B.V. Minervum 7061 NL-4817 ZK Breda The Netherlands 8. Marketing authorisation number(s) EU/1/15/1060/002 EU/1/15/1060/003 EU/1/15/1060/001 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 19 November 2015 10. Date of revision of the text August 2016 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. Kyprolis用于多发性骨髓瘤的新适应证获欧盟批准 近日，欧盟委员会（EC）已允许安进公司的Kyprolis（carfilzomib）联合地塞米松用于治疗既往接受过至少一种疗法的多发性骨髓瘤成人患者。 欧盟委员会这次新适应证的批准依据的是3期直接对比ENDEAVOR试验数据，患者使用Kyprolis联合地塞米松（Kd 组）治疗多发性骨髓瘤，无进展生存期（PFS）达到了18.7个月，相比硼替佐米+地塞米松（Vd组）为9.4个月。在次要终点上Kd组也表现出比Vd组的改善，包括完全缓解或更好缓解的比例，KD组是VD组的两倍。 耐受性方面Kd组合Vd组是类似的，但Kd组的患者发生2级及以上神经性疾病的概率相比Vd组显著较低，硼替佐米治疗的患者使用常用的毒性限制剂量。Kyprolis治疗的患者有20%以上出现最常见的不良反应是贫血、疲劳、腹泻、血小板减少、恶心、发烧、呼吸困难、呼吸道感染、咳嗽和外周水肿。 椐安进公司研发执行副总裁 Harper表示，在三期直接比较试验中，Kyprolis 联合地塞米松治疗的患者癌症无进展生存期相比完全响应硼替佐米联合地塞米松的患者延长了一倍。针对复发多发性骨髓瘤患者，基于Kyprolis的治疗方案现在已经表现出对以前两种标准治疗方案的优势，加强Kyprolis成为此类患者的基础疗法的地位。 Kyprolis最早由欧盟在2015年11月批准联合来那度胺和地塞米松使用治疗既往接受过至少一种疗法的成年多发性骨髓瘤患者，该批准基于ASPIRE研究的结果。 欧盟这次最新的批准是基于美国食品和药品监督管理局根据2016年1月ENDEAVOR 研究结果批准的补充新药申请。 --------------------------------------------------- 产地国家: 荷兰 原产地英文商品名: Kyprolis Powder 10mg/Vial 原产地英文药品名: Carfilzomib 中文参考商品译名: Kyprolis 粉剂 10毫克/支 中文参考药品译名: 卡非佐米 生产厂家英文名: Amgen Ltd --------------------------------------------------- 产地国家: 荷兰 原产地英文商品名: Kyprolis Powder 30mg/Vial 原产地英文药品名: Carfilzomib 中文参考商品译名: Kyprolis 粉剂 30毫克/支 中文参考药品译名: 卡非佐米 生产厂家英文名: Amgen Ltd --------------------------------------------------- 产地国家: 荷兰 原产地英文商品名: Kyprolis Powder 60mg/Vial 原产地英文药品名: Carfilzomib 中文参考商品译名: Kyprolis 粉剂 60毫克/支 中文参考药品译名: 卡非佐米 生产厂家英文名: Amgen Ltd