新型激酶抑制剂Zydelig（idelalisib）薄膜片再获欧盟批准上市，用于治疗复发的慢性淋巴细胞白血病（CLL）、复发性滤泡B细胞非霍奇金淋巴瘤（FL）和复发性小淋巴细胞淋巴瘤（SLL）。 ZYDELIG(艾代拉里斯 idelalisib)薄膜片，供口服使用 初次批准：2014 作用机制 Idelalisib是一种在正常和恶性B-细胞内表达的PI3Kδ激酶的抑制剂。Idelalisib诱导凋亡和抑制来自恶性B-细胞细胞株和原代肿瘤细胞增殖。Idelalisib抑制几条细胞信号通路，包括B-细胞受体(BCR)信号和CXCR4和CXCR5信号，这参与B-细胞交易和归巢[trafficking和homing]至淋巴结和骨髓。淋巴瘤细胞用idelalisib治疗导致趋化和黏附的抑制，和减低细胞活力。 适应证和用途 Zydelig是一种激酶抑制剂适用为以下患者的治疗： ⑴复发慢性淋巴细胞性白血病(CLL)，与利妥昔单抗联用，在由于其他共患病将考虑对单独利妥昔单抗 适当治疗患者。 ⑵复发滤泡B-细胞非霍奇金淋巴瘤(FL)接受至少2次既往全身治疗患者。 ⑶复发性小淋巴细胞淋巴瘤(SLL)曾至少接受2次既往全身治疗患者。 被授权加速批准对FL和SLL根据总体反应率。未确定改善患者生存或疾病相关症状。继续批准这些适应证，取决于在验证试验中证实临床获益。 剂量和给药方法 推荐起始剂量：150mg口服，每天2次。 剂型和规格 片：150mg，100mg。 禁忌证 严重过敏性反应包括过敏反应和毒性表皮细胞坏死病史。 警告和注意事项 ⑴严重皮肤反应：对患者严重皮肤反应的发展监视和终止Zydelig。 ⑵过敏反应：患者对过敏反应监视和终止Zydelig。 ⑶中性粒细胞减少：监视血细胞计数。 ⑷胚胎-胎儿毒性：可能致胎儿危害。忠告妇女对胎儿潜在风险和服用Zydelig时避免妊娠。 不良反应 最常见不良反应(发生率≥20%)是腹泻，发热，疲劳，恶心，咳嗽，肺炎，腹痛，畏寒，和皮疹。 最常见实验室异常(发生率≥30%)是中性粒细胞减少，高三酸甘油血症，高血糖，ALT升高，和AST升高。 药物相互作用 CYP3A诱导剂：避免强CYP3A诱导剂与Zydelig共同给药。 CYP3A底物：避免CYP3A底物与Zydelig共同给药。 特殊人群中使用 哺乳母亲：终止药物或哺乳。 Zydelig (idelalisib film-coated tablets)150mg/100mg 1. Name of the medicinal product Zydelig 150 mg film-coated tablets 2. Qualitative and quantitative composition Each film-coated tablet contains 150 mg of idelalisib. For the full list of excipients, see section 6.1. 3. Pharmaceutical form Film-coated tablet. Pink, oval-shaped, film-coated tablet of dimensions 10.0 mm by 6.8 mm, debossed on one side with “GSI” and “150” on the other side. 4. Clinical particulars 4.1 Therapeutic indications Zydelig is indicated in combination with rituximab for the treatment of adult patients with chronic lymphocytic leukaemia (CLL): • who have received at least one prior therapy, or • as first line treatment in the presence of 17p deletion or TP53 mutation in patients unsuitable for chemo-immunotherapy. Zydelig is indicated as monotherapy for the treatment of adult patients with follicular lymphoma (FL) that is refractory to two prior lines of treatment. 4.2 Posology and method of administration Treatment with Zydelig should be conducted by a physician experienced in the use of anticancer therapies. Posology The recommended dose of Zydelig is 150 mg, taken orally, twice daily. Treatment should be continued until disease progression or unacceptable toxicity. If the patient misses a dose of Zydelig within 6 hours of the time it is usually taken, the patient should take the missed dose as soon as possible and resume the normal dosing schedule. If a patient misses a dose by more than 6 hours, the patient should not take the missed dose and simply resume the usual dosing schedule. Dose modification Elevated liver transaminases Treatment with Zydelig must be withheld in the event of a Grade 3 or 4 aminotransferase elevation (alanine aminotransferase [ALT]/aspartate aminotransferase [AST] > 5 x upper limit of normal [ULN]). Once values have returned to Grade 1 or below (ALT/AST ≤ 3 x ULN), treatment can be resumed at 100 mg twice daily. If the event does not recur, the dose can be re-escalated to 150 mg twice daily at the discretion of the treating physician. If the event recurs, treatment with Zydelig must be withheld until the values return to Grade 1 or less, after which re-initiation at 100 mg twice daily may be considered at the discretion of the physician (see sections 4.4 and 4.8). Diarrhoea/colitis Treatment with Zydelig must be withheld in the event of Grade 3 or 4 diarrhoea/colitis. Once diarrhoea/colitis has returned to Grade 1 or below, treatment can be resumed at 100 mg twice daily. If diarrhoea/colitis does not recur, the dose can be re-escalated to 150 mg twice daily at the discretion of the treating physician (see section 4.8). Pneumonitis Treatment with Zydelig must be withheld in the event of suspected pneumonitis. Once pneumonitis has resolved and if re-treatment is appropriate, resumption of treatment at 100 mg twice daily can be considered (see sections 4.4 and 4.8). Rash Treatment with Zydelig must be withheld in the event of Grade 3 or 4 rash. Once rash has returned to Grade 1 or below, treatment can be resumed at 100 mg twice daily. If rash does not recur, the dose can be re-escalated to 150 mg twice daily at the discretion of the treating physician (see section 4.8). Special patient populations Elderly No specific dose adjustment is required for elderly patients (aged ≥ 65 years) (see section 5.2). Renal impairment No dose adjustment is required for patients with mild, moderate, or severe renal impairment (see section 5.2). Hepatic impairment No dose adjustment is required when initiating treatment with Zydelig in patients with mild or moderate hepatic impairment, but an intensified monitoring of adverse reactions is recommended (see sections 4.4 and 5.2). There is insufficient data to make dose recommendations for patients with severe hepatic impairment. Therefore, caution is recommended when administering Zydelig in this population and an intensified monitoring of adverse reactions is recommended (see sections 4.4 and 5.2). Paediatric population The safety and efficacy of Zydelig in children under the age of 18 years have not been established. No data are available. Method of administration Zydelig is for oral use. Patients should be instructed to swallow the tablet whole. The film-coated tablet should not be chewed or crushed. The film-coated tablet can be taken with or without food (see section 5.2). 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 4.4 Special warnings and precautions for use Transaminase elevations Elevations in ALT and AST of Grade 3 and 4 (> 5 x ULN) have been observed in clinical studies of idelalisib. These laboratory findings were generally observed within the first 12 weeks of treatment, were generally asymptomatic, and were reversible with dose interruption. Most patients resumed treatment at a lower dose without recurrence (see section 4.2). ALT, AST, and total bilirubin must be monitored in all patients every 2 weeks for the first 3 months of treatment, then as clinically indicated. If Grade 2 or higher elevations in ALT and/or AST are observed, patients must be monitored weekly until the values return to Grade 1 or below. Diarrhoea/colitis Cases of severe drug-related colitis occurred relatively late (months) after the start of therapy, sometimes with rapid aggravation, but resolved within a few weeks with dose interruption and additional symptomatic treatment (e.g., anti-inflammatory agents such as enteric budesonide). There is very limited experience from the treatment of patients with a history of inflammatory bowel disease. Pneumonitis Cases of pneumonitis have been reported in clinical studies with idelalisib. Patients presenting with serious lung events that do not respond to conventional antimicrobial therapy should be assessed for drug-induced pneumonitis. If pneumonitis is suspected, idelalisib should be interrupted and the patient treated accordingly. Treatment must be discontinued for moderate or severe symptomatic pneumonitis. CYP3A inducers Idelalisib exposure may be reduced when co-administered with CYP3A inducers such as rifampicin, phenytoin, St. John's wort (Hypericum perforatum), or carbamazepine. Since a reduction in idelalisib plasma concentrations may result in decreased efficacy, co-administration of Zydelig with moderate or strong CYP3A inducers should be avoided (see section 4.5). CYP3A substrates The primary metabolite of idelalisib, GS-563117, is a strong CYP3A4 inhibitor. Thus, idelalisib has the potential to interact with medicinal products that are metabolised by CYP3A, which may lead to increased serum concentrations of the other product (see section 4.5). When idelalisib is co-administered with other medicinal products, the Summary of Product Characteristics (SmPC) for the other product must be consulted for the recommendations regarding co-administration with CYP3A4 inhibitors. Concomitant treatment of idelalisib with CYP3A substrates with serious and/or life-threatening adverse reactions (e.g., alfuzosin, amiodarone, cisapride, pimozide, quinidine, ergotamine, dihydroergotamine, quetiapine, lovastatin, simvastatin, sildenafil, midazolam, triazolam) should be avoided and alternative medicinal products that are less sensitive to CYP3A4 inhibition should be used if possible. Hepatic impairment Intensified monitoring of adverse reactions is recommended in patients with impaired hepatic function as exposure is expected to be increased in this population, in particular in patients with severe hepatic impairment. No patients with severe hepatic impairment were included in clinical studies of idelalisib. Caution is recommended when administering Zydelig in this population. Chronic hepatitis Idelalisib has not been studied in patients with chronic active hepatitis including viral hepatitis. Caution should be exercised when administering Zydelig in patients with active hepatitis. Women of childbearing potential Women of childbearing potential must use highly effective contraception while taking idelalisib and for 1 month after stopping treatment (see section 4.6). Women using hormonal contraceptives should add a barrier method as a second form of contraception since it is currently unknown whether idelalisib may reduce the effectiveness of hormonal contraceptives. 4.5 Interaction with other medicinal products and other forms of interaction Idelalisib is metabolised primarily via aldehyde oxidase, and to a lesser extent via CYP3A and glucuronidation (UGT1A4). Its primary metabolite is GS-563117, which is not pharmacologically active. Idelalisib and GS-563117 are substrates of P-gp and BCRP. Effect of other medicinal products on idelalisib pharmacokinetics CYP3A inducers A clinical drug interaction study found that co-administration of a single dose of 150 mg idelalisib with rifampicin (a strong CYP3A inducer) resulted in a ~75% reduction in idelalisib AUCinf. Co-administration of Zydelig with moderate or strong CYP3A inducers such as rifampicin, phenytoin, St. John's wort, or carbamazepine should be avoided as this may result in decreased efficacy (see section 4.4). CYP3A/P-gp inhibitors A clinical drug interaction study found that co-administration of a single dose of 400 mg idelalisib with 400 mg once daily ketoconazole (a strong CYP3A, P-gp and BCRP inhibitor) resulted in a 26% increase in Cmax and a 79% increase in AUCinf of idelalisib. No initial dose adjustment of idelalisib is considered necessary when administered with CYP3A/P-gp inhibitors, but an intensified monitoring of adverse reactions is recommended. Effect of idelalisib on the pharmacokinetics of other medicinal products CYP3A substrates The primary metabolite of idelalisib, GS-563117, is a strong CYP3A inhibitor. A clinical drug interaction study found that co-administration of idelalisib with midazolam (a sensitive CYP3A substrate) resulted in a ~140% increase in Cmax and a ~440% increase in AUCinf of midazolam due to the CYP3A inhibition by GS-563117. Co-administration of idelalisib with CYP3A substrates may increase their systemic exposures and increase or prolong their therapeutic activity and adverse reactions. In vitro, the CYP3A4 inhibition was irreversible, and return to normal enzyme activity is therefore expected to take several days after stopping idelalisib administration. Potential interactions between idelalisib and co-administered medicinal products that are CYP3A substrates are listed in Table 1 (increase is indicated as “↑”). This list is not exhaustive and is intended to serve as guidance only. In general, the SmPC for the other product must be consulted for the recommendations regarding co-administration with CYP3A4 inhibitors (see section 4.4). Table 1: Interactions between idelalisib and other medicinal products that are CYP3A substrates Medicinal product Expected effect of idelalisib on drug levels Clinical recommendation upon co-administration with idelalisib ALPHA-1 ADRENORECEPTOR ANTAGONISTS Alfuzosin ↑ serum concentrations Idelalisib should not be co-administered with alfuzosin. ANALGESICS Fentanyl, alfentanil, methadone, buprenorphine/naloxone ↑ serum concentrations Careful monitoring of adverse reactions (e.g., respiratory depression, sedation) is recommended. ANTIARRHYTHMICS Amiodarone, quinidine Bepridil, disopyramide, lidocaine ↑ serum concentrations ↑ serum concentrations Idelalisib should not be co-administered with amiodarone or quinidine. Clinical monitoring is recommended. ANTI-CANCER AGENTS Tyrosine kinase inhibitors such as dasatinib and nilotinib, also vincristine and vinblastine ↑ serum concentrations Careful monitoring of the tolerance to these anti-cancer agents is recommended. ANTICOAGULANTS Dabigatran, rivaroxaban, warfarin ↑ serum concentrations It is recommended that the international normalised ratio (INR) be monitored upon co-administration and following ceasing treatment with idelalisib. ANTICONVULSANTS Carbamazepine ↑ serum concentrations Anticonvulsant drug levels should be monitored. ANTIDEPRESSANTS Trazodone ↑ serum concentrations Careful dose titration of the antidepressant and monitoring for antidepressant response is recommended. ANTI-GOUT Colchicine ↑ serum concentrations Dose reductions of colchicine may be required. Idelalisib should not be co-administered with colchicine to patients with renal or hepatic impairment. ANTI-HYPERTENSIVES Amlodipine, diltiazem, felodipine, nifedipine, nicardipine ↑ serum concentrations Clinical monitoring of therapeutic effect and adverse reactions is recommended. ANTI-INFECTIVES Antifungals Ketoconazole, itraconazole, posaconazole, voriconazole ↑ serum concentrations Clinical monitoring is recommended. Antimycobacterials Rifabutin ↑ serum concentrations Increased monitoring for rifabutin-associated adverse reactions including neutropenia and uveitis is recommended. HCV protease inhibitors Boceprevir, telaprevir ↑ serum concentrations Clinical monitoring is recommended. Macrolide antibiotics Clarithromycin, telithromycin ↑ serum concentrations No dose adjustment of clarithromycin is required for patients with normal renal function or mild renal impairment (creatinine clearance [CrCl] 60-90 mL/min). Clinical monitoring is recommended for patients with CrCl < 90 mL/min. For patients with CrCl < 60 mL/min, alternative antibacterials should be considered. Clinical monitoring is recommended for telithromycin. ANTI-PSYCHOTICS/NEUROLEPTICS Quetiapine, pimozide ↑ serum concentrations Idelalisib should not be co-administered with quetiapine or pimozide. Alternative medicinal products, such as olanzapine, may be considered. ENDOTHELIN RECEPTOR ANTAGONISTS Bosentan ↑ serum concentrations Caution should be exercised and patients closely observed for bosentan-related toxicity. ERGOT ALKALOIDS Ergotamine, dihydroergotamine ↑ serum concentrations Idelalisib should not be co-administered with ergotamine or dihydroergotamine. GASTROINTESTINAL MOTILITY AGENTS Cisapride ↑ serum concentrations Idelalisib should not be co-administered with cisapride. GLUCOCORTICOIDS Inhaled/nasal corticosteroids: Budesonide, fluticasone Oral budesonide ↑ serum concentrations ↑ serum concentrations Clinical monitoring is recommended. Clinical monitoring is recommended for increased signs/symptoms of corticosteroid effects. HMG CO-A REDUCTASE INHIBITORS Lovastatin, simvastatin Atorvastatin ↑ serum concentrations ↑ serum concentrations Idelalisib should not be co-administered with lovastatin or simvastatin. Clinical monitoring is recommended and a lower starting dose of atorvastatin may be considered. Alternatively, switching to pravastatin, rosuvastatin, or pitavastatin may be considered. IMMUNOSUPPRESSANTS Ciclosporin, sirolimus, tacrolimus ↑ serum concentrations Therapeutic monitoring is recommended. INHALED BETA AGONIST Salmeterol ↑ serum concentrations Concurrent administration of salmeterol and idelalisib is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia. PHOSPHODIESTERASE INHIBITORS Sildenafil Tadalafil Sildenafil, tadalafil ↑ serum concentrations ↑ serum concentrations ↑ serum concentrations For pulmonary arterial hypertension: Idelalisib should not be co-administered with sildenafil. Caution should be exercised, including consideration of dose reduction, when co-administering tadalafil with idelalisib. For erectile dysfunction: Particular caution must be used and dose reduction may be considered when prescribing sildenafil or tadalafil with idelalisib with increased monitoring for adverse events. SEDATIVES/HYPNOTICS Midazolam (oral), triazolam Buspirone, clorazepate, diazepam, estazolam, flurazepam, zolpidem ↑ serum concentrations ↑ serum concentrations Idelalisib should not be co-administered with midazolam (oral) or triazolam. Concentration monitoring of sedatives/hypnotics is recommended and dose reduction may be considered. CYP2C8 substrates In vitro, idelalisib both inhibited and induced CYP2C8, but it is not known whether this translates to an in vivo effect on CYP2C8 substrates. Caution is advised if Zydelig is used together with narrow therapeutic index drugs that are substrates of CYP2C8 (paclitaxel). Substrates of inducible enzymes (e.g., CYP2C9, CYP2C19, CYP2B6 and UGT) In vitro, idelalisib was an inducer of several enzymes, and a risk for decreased exposure and thereby decreased efficacy of substrates of inducible enzymes such as CYP2C9, CYP2C19, CYP2B6 and UGT cannot be excluded. Caution is advised if Zydelig is used together with narrow therapeutic index drugs that are substrates of these enzymes (warfarin, phenytoin, S-mephenytoin). BCRP, OATP1B1, OATP1B3 and P-gp substrates Co-administration of multiple doses of idelalisib 150 mg twice daily to healthy subjects resulted in comparable exposures for rosuvastatin (AUC 90% CI: 87, 121) and digoxin (AUC 90% CI: 98, 111), suggesting no clinically relevant inhibition of BCRP, OATP1B1/1B3 or systemic P-gp by idelalisib. A risk for P-gp inhibition in the gastrointestinal tract, that could result in increased exposure of sensitive substrates for intestinal P-gp such as dabigatran etexilate, cannot be excluded. Paediatric population Interaction studies have only been performed in adults. 4.6 Fertility, pregnancy and lactation Women of childbearing potential Based on findings in animals, idelalisib may cause foetal harm. Women should avoid becoming pregnant while taking Zydelig, and for up to 1 month after ending treatment. Therefore, women of childbearing potential must use highly effective contraception while taking Zydelig and for 1 month after stopping treatment. It is currently unknown whether idelalisib may reduce the effectiveness of hormonal contraceptives, and therefore women using hormonal contraceptives should add a barrier method as a second form of contraception. Pregnancy There are no or limited amount of data from the use of idelalisib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Zydelig is not recommended during pregnancy and in women of childbearing potential not using contraception. Breast-feeding It is not known whether idelalisib and its metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with Zydelig. Fertility No human data on the effect of idelalisib on fertility are available. Animal studies indicate the potential for harmful effects of idelalisib on fertility and foetal development (see section 5.3). 4.7 Effects on ability to drive and use machines Zydelig has no or negligible influence on the ability to drive and use machines. 4.8 Undesirable effects Summary of the safety profile Assessment of adverse reactions is based on one Phase 3 study and seven Phase 1 and 2 studies. Phase 3 study 312-0116 was a randomised, double-blind, placebo-controlled study in which 220 patients with previously treated CLL were randomised 1:1 to receive idelalisib + rituximab or placebo + rituximab. The Phase 1 and 2 studies assessed the safety of idelalisib in 490 patients with haematologic malignancies, including 354 subjects who received idelalisib (any dose) as a single agent and 136 subjects who received idelalisib in combination with anti-CD20 monoclonal antibodies. During treatment with idelalisib, the most frequently reported adverse drug reactions are reported in Table 2. Tabulated list of adverse reactions The adverse drug reactions reported with idelalisib alone or in combination with anti-CD20 monoclonal antibodies are provided in Table 2. Adverse reactions are listed by system organ class and frequency. Frequencies are defined as follows: 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 2: Adverse drug reactions reported in clinical studies in patients with haematologic malignancies receiving idelalisib Reaction Any grade Grade ≥ 3 Infections and infestations Infections Very common Very common Blood and lymphatic system disorders Neutropenia Very common Very common Respiratory, thoracic and mediastinal disorders Pneumonitis Common Common Gastrointestinal disorders Diarrhoea/colitis Very common Very common Hepatobiliary disorders Transaminase increased Very common Very common Skin and subcutaneous tissue disorders Rash* Very common Common General disorders and administration site conditions Pyrexia Very common Common Investigations Increased triglycerides Very common Common Includes the preferred terms dermatitis exfoliative, drug eruption, rash, rash erythematous, rash generalised, rash macular, rash maculo-papular, rash papular, rash pruritic, and exfoliative rash. Description of selected adverse reactions Rash Rash was generally mild to moderate and resulted in discontinuation of treatment in about 2% of patients. In study 312-0116, rash (reported as dermatitis exfoliative, drug eruption, rash, rash erythematous, rash generalised, rash macular, rash maculo-papular, rash papular, and rash pruritic) occurred in 24.5% of subjects who received idelalisib + rituximab and 6.5% who received placebo + rituximab. Of these, 3.6% who received idelalisib + rituximab and 0.9% who received placebo + rituximab had rash of Grade 3, and no subjects had an adverse event of Grade 4. Rash typically resolved with treatment (e.g., topical and/or oral steroids, diphenhydramine) and dose interruption for severe cases (see section 5.3, phototoxicity). Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system: 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 Malta ADR Reporting Website: www.medicinesauthority.gov.mt/adrportal 4.9 Overdose If overdose occurs the patient must be monitored for evidence of toxicity (see section 4.8). Treatment of overdose with Zydelig consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: antineoplastic agents, other antineoplastic agents, ATC code: L01XX47 Mechanism of action Idelalisib inhibits phosphatidylinositol 3-kinase p110δ (PI3Kδ), which is hyperactive in B-cell malignancies and is central to multiple signalling pathways that drive proliferation, survival, homing, and retention of malignant cells in lymphoid tissues and bone marrow. Idelalisib is a selective inhibitor of adenosine-5-5'-triphosphate (ATP) binding to the catalytic domain of PI3Kδ, resulting in inhibition of the phosphorylation of the key lipid second messenger phosphatidylinositol and prevention of Akt (protein kinase B) phosphorylation. Idelalisib induces apoptosis and inhibits proliferation in cell lines derived from malignant B-cells and in primary tumour cells. Through inhibition of chemokine receptors CXCR4 and CXCR5 signalling induced by the chemokines CXCL12 and CXCL13, respectively, idelalisib inhibits homing and retention of malignant B-cells in the tumour microenvironment including lymphoid tissues and the bone marrow. Pharmacodynamic effects The effect of idelalisib (150 mg and 400 mg) on the QT/QTc interval was evaluated in a placebo- and positive-controlled (moxifloxacin 400 mg) crossover study in 40 healthy subjects. At a dose 2.7 times the maximum recommended dose, idelalisib did not prolong the QT/QTc interval (i.e.,< 10 ms). Clinical efficacy in chronic lymphocytic leukaemia Idelalisib in combination with immunotherapy Study 312-0116 was a Phase 3, randomised, double-blind, placebo-controlled study in 220 subjects with previously treated CLL who required treatment but were not considered suitable for cytotoxic chemotherapy. Subjects were randomised 1:1 to receive 8 cycles of rituximab (first cycle at 375 mg/m2 body surface area [BSA], subsequent cycles at 500 mg/m2 BSA) in combination with either an oral placebo twice daily or with idelalisib 150 mg taken twice daily until disease progression or unacceptable toxicity. The median age was 71 years (range: 47 to 92) with 78.2% of patients over 65 years; 65.5% were male, and 90.0% were white; 64.1% had a Rai stage of III or IV, and 55.9% had Binet Stage C. Most subjects had adverse cytogenetic prognostic factors: 43.2% had a 17p chromosomal deletion and/or tumour protein 53 (TP53) mutation, and 83.6% had unmutated genes for the immunoglobulin heavy chain variable region (IGHV). The median time from diagnosis of CLL to randomisation was 8.5 years. Subjects had a median Cumulative Illness Rating Score (CIRS) of 8. The median number of prior therapies was 3.0. Nearly all (95.9%) subjects had received prior anti-CD20 monoclonal antibodies. The primary endpoint was progression free survival (PFS). Efficacy results are summarised in Tables 3 and 4. The Kaplan-Meier curve for PFS is provided in Figure 1. Compared with rituximab + placebo, treatment with idelalisib + rituximab resulted in statistically significant and clinically meaningful improvements in physical well-being, social well-being, functional well-being, as well as in the leukaemia-specific subscales of the Functional Assessment of Cancer Therapy: Leukaemia (FACT-LEU) instruments, and in statistically significant and clinically meaningful improvements in anxiety, depression and usual activities as measured by the EuroQoL Five-Dimensions (EQ-5D) instrument. Table 3: Efficacy results from study 312-0116 Idelalisib + R N = 110 Placebo + R N = 110 PFS Median (months) (95% CI) 19.4 (12.3, NR) 6.5 (4.0, 7.3) Hazard ratio (95% CI) 0.15 (0.09, 0.25) P-value < 0.0001 ORR* n (%) (95% CI) 92 (83.6%) (75.4, 90.0) 17 (15.5%) (9.3, 23.6) Odds ratio (95% CI) 27.76 (13.40, 57.49) P-value < 0.0001 LNR** n/N (%) (95% CI) 102/106 (96.2%) (90.6, 99.0) 7/104 (6.7%) (2.7, 13.4) Odds ratio (95% CI) 225.83 (65.56, 777.94) P-value < 0.0001 OS^ Median (months) (95% CI) NR (NR, NR) 20.8 (14.8, NR) Hazard ratio (95% CI) 0.34 (0.19, 0.60) P-value 0.0001 CI: confidence interval; R: rituximab; n: number of responding subjects; N: number of subjects per group; NR: not reached. The analyses of PFS, overall response rate (ORR) and lymph node response rate (LNR) were based on evaluation by an independent review committee (IRC). ORR defined as the proportion of subjects who achieved a complete response (CR) or partial response (PR) based on the 2013 National Comprehensive Cancer Network (NCCN) response criteria and Cheson (2012). LNR defined as the proportion of subjects who achieved a ≥ 50% decrease in the sum of products of the greatest perpendicular diameters of index lesions. Only subjects that had both baseline and ≥ 1 evaluable post-baseline assessments were included in this analysis. ^ Overall survival (OS) analysis includes data from subjects who received placebo + R on study 312-0116 and subsequently received idelalisib in an extension study, based on intent-to-treat analysis. Table 4: Summary of PFS and response rates in pre-specified subgroups from study 312-0116 Idelalisib + R Placebo + R 17p deletion/TP53 mutation N = 46 N = 49 PFS median (months) (95% CI) NR (12.3, NR) 4.0 (3.7, 5.7) Hazard ratio (95% CI) 0.13 (0.07, 0.27) ORR (95% CI) 84.8% (71.1, 93.7) 12.2% (4.6, 24.8) Unmutated IGHV N = 91 N = 93 PFS median (months) (95% CI) 19.4 (13.9, NR) 5.6 (4.0, 7.2) Hazard ratio (95% CI) 0.14 (0.08, 0.23) ORR (95% CI) 82.4% (73.0, 89.6) 15.1% (8.5, 24.0) Age ≥ 65 years N = 89 N = 83 PFS median (months) (95% CI) 19.4 (12.3, NR) 5.7 (4.0, 7.3) Hazard ratio (95% CI) 0.14 (0.08, 0.25) ORR (95% CI) 84.3% (75.0, 91.1) 16.9% (9.5, 26.7) CI: confidence interval; R: rituximab; N: number of subjects per group; NR: not reached Figure 1: Kaplan-Meier curve of PFS from study 312-0116 (intent-to-treat population) Study 101-08/99 enrolled 64 subjects with previously untreated CLL, including 5 subjects with small lymphocytic lymphoma (SLL). Subjects received idelalisib 150 mg twice daily and rituximab 375 mg/m2 BSA weekly. The ORR was 96.9%, with 12 CRs (18.8%) and 50 PRs (78.1%), including 3 CRs and 6 PRs in subjects with a 17p deletion and/or TP53 mutation and 2 CRs and 34 PRs in subjects with unmutated IGHV. The median duration of response (DOR) has not been reached. Clinical efficacy in follicular lymphoma The safety and efficacy of idelalisib were assessed in a single-arm, multicentre clinical study (study 101-09) conducted in 125 subjects with indolent B-cell non-Hodgkin lymphoma (iNHL, including: FL, n = 72; SLL, n = 28; lymphoplasmacytic lymphoma/Waldenström macroglobulinaemia [LPL/WM], n = 10; and marginal zone lymphoma [MZL], n = 15). All subjects were refractory to rituximab and 124 of 125 subjects were refractory to at least one alkylating agent. One hundred and twelve (89.6%) subjects were refractory to their last regimen prior to study entry. Of the 125 subjects enrolled, 80 (64%) were male, the median age was 64 years (range: 33 to 87), and 110 (89%) were white. Subjects received 150 mg of idelalisib orally twice daily until evidence of disease progression or unacceptable toxicity. The primary endpoint was the ORR defined as the proportion of subjects who achieved a CR or PR (based on the Revised Response Criteria for Malignant Lymphoma [Cheson]), and, for subjects with Waldenström macroglobulinaemia, a minor response (MR) (based on the Response Assessment for Waldenström macroglobulinaemia [Owen]). DOR was a secondary endpoint and was defined as the time from the first documented response (CR, PR, or MR) to the first documentation of disease progression or death from any cause. Efficacy results are summarised in Table 5. Table 5: Summary of response in subjects with FL treated with idelalisib (IRC assessment) Characteristic Study subjects n (%) ORR (follicular lymphoma)* 95% CI ORR (all subjects)* 95% CI 39 (54.2) 42.0 – 66.0 71 (56.8) 47.6 – 65.6 Response category (follicular lymphoma)* CR PR 6 (8.3) 33 (45.8) CI: confidence interval; n: number of responding subjects Response as determined by an independent review committee (IRC) where ORR = complete response (CR) + partial response (PR). The median DOR for all subjects was 12.5 months (12.5 months for SLL subjects, and not reached for FL, LPL/WM and MZL subjects). Among the 122 subjects with measurable lymph nodes at both baseline and post-baseline, 67 subjects (54.9%) achieved a ≥ 50% decrease from baseline in the sum of the products of the diameters (SPD) of index lesions. Of the subjects who did not respond, 10 (8.0%) had progressive disease as best response, and 2 (1.6%) were not evaluable. The median OS, including long-term follow-up for all 125 subjects, was 20.3 months. Paediatric population The European Medicines Agency has deferred the obligation to submit the results of studies with idelalisib in one or more subsets of the paediatric population in the treatment of mature B-cell neoplasms (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties Absorption Following oral administration of a single dose of idelalisib, peak plasma concentrations were observed 2 to 4 hours post-dose under fed conditions and after 0.5 to 1.5 hours under fasted conditions. Following 150 mg twice daily administration of idelalisib, average (range) Cmax and AUC at steady-state were 1,953 (272; 3,905) ng/mL and 10,439 (2,349; 29,315) ng•h/mL for idelalisib and 4,039 (669; 10,897) ng/mL and 39,744 (6,002; 119,770) ng•h/mL for GS-563117, respectively. The plasma exposures (Cmax and AUC) of idelalisib are approximately dose proportional between 50 mg and 100 mg and less than dose proportional above 100 mg. Effects of food Relative to fasting conditions, administration of an early capsule formulation of idelalisib with a high-fat meal resulted in no change in Cmax and a 36% increase in mean AUCinf. Idelalisib can be administered without regard to food. Distribution Idelalisib is 93% to 94% bound to human plasma proteins at concentrations observed clinically. The mean blood-to-plasma concentration ratio was approximately 0.5. The apparent volume of distribution for idelalisib (mean) was approximately 96 L. Biotransformation Idelalisib is metabolised primarily via aldehyde oxidase, and to a lesser extent via CYP3A and UGT1A4. The primary and only circulating metabolite, GS-563117, is inactive against PI3Kδ. Elimination The terminal elimination half-life of idelalisib was 8.2 (range: 1.9; 37.2) hours and the apparent clearance of idelalisib was 14.9 (range: 5.1; 63.8) L/h following idelalisib 150 mg twice daily oral administration. Following a single 150 mg oral dose of [14C]-labelled idelalisib, approximately 78% and 15% was excreted in faeces and urine, respectively. Unchanged idelalisib accounted for 23% of total radioactivity recovered in urine over 48 hours and 12% of total radioactivity recovered in faeces over 144 hours. In vitro interaction data In vitro data indicated that idelalisib is not an inhibitor of the metabolising enzymes CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A, or UGT1A1, or of the transporters OAT1, OAT3, or OCT2. GS-563117 is not an inhibitor of the metabolising enzymes CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or UGT1A1, or of the transporters P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, or OCT2. Special populations Gender and race Population pharmacokinetic analyses indicated that gender and race had no clinically relevant effect on the exposures to idelalisib or GS-563117. Elderly Population pharmacokinetic analyses indicated that age had no clinically relevant effect on the exposures to idelalisib or GS-563117, including elderly subjects (65 years of age and older), compared to younger subjects. Renal impairment A study of pharmacokinetics and safety of idelalisib was performed in healthy subjects and subjects with severe renal impairment (estimated CrCl 15 to 29 mL/min). Following a single 150 mg dose, no clinically relevant changes in exposures to idelalisib or GS-563117 were observed in subjects with severe renal impairment compared to healthy subjects. Hepatic impairment A study of pharmacokinetics and safety of idelalisib was performed in healthy subjects and subjects with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment. Following a single 150 mg dose, idelalisib AUC (total, i.e., bound plus unbound) was ~60% higher in moderate and severe impairment compared to matched controls. The idelalisib AUC (unbound), after accounting for differences in protein binding, was ~80% (1.8-fold) higher in moderate and ~152% (2.5-fold) higher in severe impairment compared to matched controls. Paediatric population The pharmacokinetics of idelalisib in paediatric subjects have not been established (see section 4.2). 5.3 Preclinical safety data Repeated dose toxicity Idelalisib induced lymphoid depletion in spleen, thymus, lymph nodes and gut-associated lymphoid tissue. In general, B-lymphocyte dependent areas were more affected than T-lymphocyte dependent areas. In rats, idelalisib has the potential to inhibit T-dependent antibody responses. However, idelalisib did not inhibit the normal host response to Staphylococcus aureus and did not exacerbate the myelosuppressive effect of cyclophosphamide. Idelalisib is not considered to have broad immunosuppressive activity. Idelalisib induced inflammatory changes in both rats and dogs. In studies up to 4 weeks in rats and dogs, hepatic necrosis was observed at 7 and 5 times the human exposure based on AUC, respectively. Serum transaminase elevations correlated with hepatic necrosis in dogs, but were not observed in rats. No hepatic impairment or chronic transaminase elevations were observed in rats or dogs in studies of 13 weeks and longer duration. Genotoxicity Idelalisib did not induce mutations in the microbial mutagenesis (Ames) assay, was not clastogenic in the in vitro chromosome aberration assay using human peripheral blood lymphocytes, and was not genotoxic in the in vivo rat micronucleus study. Carcinogenicity Carcinogenicity studies with idelalisib have not been conducted. Reproductive and developmental toxicity In an embryo-foetal development study in rats, increased post-implantation loss, malformations (absence of caudal vertebrae and in some cases also of sacral vertebrae), skeletal variations and lower foetal body weights were observed. Malformations were observed at exposures from 12 times the human exposure based on AUC. Effects on embryo-foetal development were not investigated in a second species. Degeneration of the seminiferous tubules in the testes was observed in 2- to 13-week repeated dose studies in dogs and rats, but not in studies of 26 weeks and longer duration. In a rat male fertility study, decreases in epididymides and testes weight were observed but no adverse effects on mating or fertility parameters, and no degeneration or loss in spermatogenesis were observed. Female fertility was not affected in rats. Phototoxicity Evaluation of the potential for phototoxicity in the embryonic murine fibroblast cell line BALB/c 3T3 was inconclusive for idelalisib due to cytotoxicity in the in vitro assay. The major metabolite, GS-563117, may enhance phototoxicity when cells are simultaneously exposed to UVA light. There is a potential risk that idelalisib, via its major metabolite, GS-563117, may cause photosensitivity in treated patients. 6. Pharmaceutical particulars 6.1 List of excipients Tablet core Microcrystalline cellulose Hydroxypropyl cellulose (E463) Croscarmellose sodium Sodium starch glycolate Magnesium stearate Film-coating Polyvinyl alcohol (E1203) Macrogol 3350 (E1521) Titanium dioxide (E171) Talc (E553B) Iron oxide red (E172) 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years. 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. 6.5 Nature and contents of container High density polyethylene (HDPE) bottle, capped with a polypropylene child-resistant closure, containing 60 film-coated tablets and a polyester coil. Each carton contains 1 bottle. 6.6 Special precautions for disposal and other handling Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. Marketing authorisation holder Gilead Sciences International Ltd Cambridge CB21 6GT United Kingdom 8. Marketing authorisation number(s) EU/1/14/938/002 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 18 September 2014 10. Date of revision of the text 07/2015 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu Zydelig: targeted B-cell malignancy treatment Zydelig (idelalisib) can be used as monotherapy for follicular lymphoma refractory to two prior lines of treatment, and in combination with rituximab for chronic lymphocytic leukaemia after one prior therapy or first-line in patients with the 17p deletion or TP53 mutation who are unsuitable for chemo-immunotherapy. The usual dose of Zydelig (idelalisib) is 150mg twice daily continued until disease progression or unacceptable toxicity occurs. Idelalisib is a first-in-class oral inhibitor of phosphatidylinositol 3-kinase (PI3K) delta, an enzyme that is overexpressed in B-cell malignancies and has a role in the viability, proliferation and migration of these cancer cells. Twice-daily dosing The usual dose of Zydelig is 150mg twice daily continued until disease progression or unacceptable toxicity occurs. Treatment should be withheld if the patient develops severe diarrhoea/colitis, pneumonitis, rash or if liver enzymes are significantly raised. When the adverse reaction has suitably resolved, patients can restart Zydelig at a reduced dose of 100mg twice daily which can then be increased to 150mg twice daily if appropriate. 'Overwhelming efficacy' Investigators assessed the efficacy and safety of idelalisib in refractory chronic lymphocytic leukaemia in a randomised, double-blind placebo-controlled phase III study. Patients (n=220) were eligible if they were unable to receive cytotoxic chemotherapy because of renal impairment, major co-existing illness or if they had developed myelosuppression from previous therapy. Participants were randomised to receive 8 cycles of rituximab plus continuous idelalisib (150g twice daily) or placebo. The primary endpoint was progression-free survival (PFS). At the first prespecified interim analysis, the study was terminated owing to evidence of overwhelming efficacy with idelalisib. At 24 weeks, the PFS rate was 93% in the idelalisib group compared with 46% in the placebo group (adjusted HR for progression or death in the idelalisib group, 0.15, 95% CI 0.08-0.28, p<0.001). The median duration of PFS was 5.5 months in the placebo group but was not reached in the idelalisib group. The overall survival rate in patients treated with idelalisib was also superior to that in patients who received placebo (92% vs 80% at 12 months). In a single-group, open label phase II study, 125 patients with indolent non-Hodgkin's lymphoma who had not responded to rituximab and an alkylating agent, or had relapsed following treatment, were given idelalisib 150mg twice daily as monotherapy until disease progressed or the patient withdrew from the study. Patients had received a median of four prior therapies and had a median age of 64 years. The response rate (primary endpoint) was 57% (95% CI 48-66%), with 6% of patients meeting the criteria for a complete response. Responses lasted for a median of 12.5 months, and the median duration of PFS was 11 months. 抗癌药Zydelig先获FDA批准后再获欧盟批准上市 吉利德科学（Gilead Sciences）7月25日宣布，抗癌药Zydelig（idelalisib，150mg薄膜衣片）获得了欧洲药品管理局（EMA）人用医药产品委员会（CHMP）的积极意见。 CHMP建议： （1）批准Zydelig联合罗氏美罗华（Rituxan，通用名：rituximab，利妥昔单抗），用于既往接受至少1种疗法的慢性淋巴细胞白血病（CLL）成人患者的治疗，（2）批准Zydelig联合Rituxan作为一线疗法，用于存在17p删除或TP53突变且不适合化疗-免疫疗法的CLL患者的治疗； （3）作为单药疗法，用于既往接受过2种系统治疗方案后复发的滤泡性淋巴瘤（FL）成人患者的治疗。 在美国，FDA于2014年7月23日批准Zydelig用于3种B细胞血癌的治疗，分别为：（1）批准Zydelig联合罗氏（Roche）抗癌药美罗华（Rituxan，通用名：rituximab，利妥昔单抗），用于适合Rituxan单药疗法的复发性慢性淋巴细胞白血病（CLL）患者的治疗；（2）批准Zydelig作为单药疗法，用于既往接受过至少2种系统治疗方案的复发性滤泡B细胞非霍奇金淋巴瘤（FL）患者和小细胞淋巴瘤（SLL）患者的治疗。 慢性淋巴细胞白血病（CLL）和滤泡性淋巴瘤（FL）是2种生长缓慢但无法治愈的血癌，可导致严重危机生命的并发症，如贫血、严重感染和骨髓衰竭。复发通常发生在初始化疗-免疫疗法治疗后，同时，有许多复发型CLL和FL患者对化疗不耐受，可能会限制其治疗方案。 CHMP的积极意见，是基于2项研究（Study 116，Study 101-09）的积极数据。Study 116是一项关键性III期研究，在既往已接受治疗但对标准化疗不耐受的慢性淋巴细胞白血病（CLL）患者中开展，调查了Zydelig联合Rituxan用于经治CLL患者的疗效和安全性。一项既定中期分析数据表明，与安慰剂+美罗华（Rituxan）治疗组相比，Zydelig+Rituxan治疗组在研究的主要终点—疾病无进展生存期（PFS）具有统计学意义的显著改善（PFS：10.7个月 vs 5.5个月，p＜0.0001）。 Study 101-09是一项关键II期研究，在既往经美罗华（Rituxan）和含烷化剂化疗方案治疗的难治性惰性非霍奇金淋巴瘤（iNHL，注：FL和SLL是2种类型的iNHL）患者中开展，评价了Zydelig的疗效和安全性。研究结果表明，Zydelig单药疗法取得了57%的总缓解率（ORR），其中，6%的患者实现了完全缓解，50%的患者实现部分缓解，1%的患者取得轻微缓解。研究中，平均缓解持续时间达12.5个月，距离缓解的平均时长为1.9个月，平均无进展生存期为11.0个月，平均总生存期为20.3个月，90%的患者经历了淋巴结的缩小。 Zydelig（idelalisib）是一种首创的高度选择性、口服有效的磷酸肌醇3-激酶delta（PI3K-delta）抑制剂。PI3K-delta信号对于B淋巴细胞的活化、增殖、生存、迁移（trafficking）至关重要，该信号在多种B细胞恶性肿瘤中过度活动。 目前，吉利德正开发idelalisib作为单一制剂，以及与一些已获批的疗法和实验性疗法配伍，调查用于不同类型血癌的治疗。 Zydelig (idelalisib) 100mg（https://www.medicines.org.uk/emc/medicine/29202） Zydelig (idelalisib) 150mg（https://www.medicines.org.uk/emc/medicine/29201） ----------------------------------------------------- 产地国家: 德国 原产地英文商品名: Zydelig filmcoated tablets 100mg/tab 60tabs/bottle 原产地英文药品名: idelalisib 中文参考商品译名: Zydelig片 100毫克/片 60片/瓶 中文参考药品译名: idelalisib 生产厂家中文参考译名: 吉利德科学 生产厂家英文名: Gilead Sciences GmbH  ----------------------------------------------------- 产地国家: 德国 原产地英文商品名: Zydelig film-coated tablets 150mg/tab 60tabs/bottle 原产地英文药品名: idelalisib 中文参考商品译名: Zydelig薄膜片 150毫克/片 60片/瓶 中文参考药品译名: idelalisib 生产厂家中文参考译名: 吉利德科学 生产厂家英文名: Gilead Sciences GmbH  ----------------------------------------------------- 产地国家: 瑞士 原产地英文商品名: Zydelig Filmtabl 100mg/tab 60tabs/bottle 原产地英文药品名: idelalisib 中文参考商品译名: Zydelig薄膜片 100毫克/片 60片/瓶 中文参考药品译名: idelalisib 生产厂家中文参考译名: 吉利德科学 生产厂家英文名: Gilead Sciences Switzerland Sàrl ----------------------------------------------------- 产地国家: 瑞士 原产地英文商品名: Zydelig Filmtabl 150mg/tab 60tabs/bottle 原产地英文药品名: idelalisib 中文参考商品译名: Zydelig片 150毫克/片 60片/瓶 中文参考药品译名: idelalisib 生产厂家中文参考译名: 吉利德科学 生产厂家英文名: Gilead Sciences Switzerland Sàrl