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白血病新药SYNRIBO(OMACETAXINE MEPESUCCINATE)POWDER SUBCUTANEOUS获FDA批准
Before a decision is made to allow SYNRIBO to be administered by someone other than a healthcare professional, ensure that the patient is an appropriate candidate for self-administration or for administration by a caregiver. Provide training on proper handling, storage conditions, administration, disposal, and clean-up of accidental spillage of the product. Ensure that patients receive the necessary supplies for home administration. At minimum these should include: • Reconstituted SYNRIBO in syringe with a capped needle for subcutaneous injection. Syringe(s) should be filled to the patient-specific dose. • Protective eyewear • Gloves • An appropriate biohazard container • Absorbent pad(s) for placement of administration materials and for accidental spillage • Alcohol swabs • Gauze pads • Ice packs or cooler for transportation of reconstituted SYNRIBO syringes If a patient or caregiver cannot be trained for any reason, then in such patients, SYNRIBO should be administered by a healthcare professional. 2.7 Disposal and Accidental Spillage Procedures After administration, any unused solution should be discarded properly1. Instruct patients planning home administration on the following: do not recap or clip the used needle, and do not place used needles, syringes, vials, and other used supplies in a household trash or recycling bin. Used needles, syringes, vials, and other used supplies should be disposed of in an appropriate biohazard container. If accidental spillage occurs, continue to use protective eyewear and gloves, wipe the spilled liquid with the absorbent pad, and wash the area with water and soap. Then, place the pad and gloves into the biohazard container and wash hands thoroughly. Return the biohazard container to the clinic or pharmacy for final disposal. 3 DOSAGE FORMS AND STRENGTHS SYNRIBO for Injection contains 3.5 mg omacetaxine mepesuccinate; as a sterile, preservative-free, white to off-white lyophilized powder in a single-use vial. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Myelosuppression In uncontrolled trials with SYNRIBO, patients with chronic phase and accelerated phase CML experienced NCI CTC (version 3.0) Grade 3 or 4 thrombocytopenia (85%, 88%), neutropenia (81%, 71%), and anemia (62%, 80%), respectively. Fatalities related to myelosuppression occurred in 3% of patients in the safety population (N=163). Patients with neutropenia are at increased risk for infections, and should be monitored frequently and advised to contact a physician if they have symptoms of infection or fever. Monitor complete blood counts weekly during induction and initial maintenance cycles and every two weeks during later maintenance cycles, as clinically indicated. In clinical trials myelosuppression was generally reversible and usually managed by delaying next cycle and/or reducing days of treatment with SYNRIBO [see Dosage and Administration (2.3) and Adverse Reactions (6.1)]. 5.2 Bleeding SYNRIBO causes severe thrombocytopenia which increases the risk of hemorrhage. In clinical trials with CP and AP CML patients, a high incidence of Grade 3 and 4 thrombocytopenia (85% and 88%, respectively) was observed. Fatalities from cerebral hemorrhage occurred in 2% of patients treated with SYNRIBO in the safety population. Severe, non-fatal, gastrointestinal hemorrhages occurred in 2% of patients in the same population. Most bleeding events were associated with severe thrombocytopenia. Monitor platelet counts as part of the CBC monitoring as recommended [see Warnings and Precautions (5.1)]. Avoid anticoagulants, aspirin, and non-steroidal anti-inflammatory drugs (NSAIDs) when the platelet count is less than 50,000/µL as they may increase the risk of bleeding. 5.3 Hyperglycemia SYNRIBO can induce glucose intolerance. Grade 3 or 4 hyperglycemia was reported in 11% of patients in the safety population. Hyperosmolar non-ketotic hyperglycemia occurred in 1 patient treated with SYNRIBO in the safety population. Monitor blood glucose levels frequently, especially in patients with diabetes or risk factors for diabetes. Avoid SYNRIBO in patients with poorly controlled diabetes mellitus until good glycemic control has been established. 5.4 Embryo-Fetal Toxicity SYNRIBO can cause fetal harm when administered to a pregnant woman. Omacetaxine mepesuccinate caused embryo-fetal death in animals. Females of reproductive potential should avoid becoming pregnant while being treated with SYNRIBO. There are no adequate and well-controlled studies of SYNRIBO in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)]. 6 ADVERSE REACTIONS The following serious adverse reactions have been associated with SYNRIBO in clinical trials and are discussed in greater detail in other sections of the label. • Myelosuppression [see Warnings and Precautions (5.1)] • Bleeding [see Warnings and Precautions (5.2)] • Hyperglycemia [see Warnings and Precautions (5.3)] Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety data for SYNRIBO are from 3 clinical trials which enrolled a total of 163 adult patients with TKI resistant and/or intolerant chronic phase (N=108) and accelerated phase (N=55) CML. All patients were treated with initial induction therapy consisting of a dose of 1.25 mg/m2 administered subcutaneously twice daily for 14 consecutive days every 28 days (induction cycle). Responding patients were then treated with the same dose and a twice daily schedule for 7 consecutive days every 28 days (maintenance cycle). 6.1 Clinical Trials Experience Chronic Phase CML The median duration of exposure for the 108 patients with chronic phase CML was 7.4 months (range 0 to 43 months). The median total cycles of exposure was 6 (range 1 to 41), and the median total dose delivered during the trials was 131 mg/m2 (range 1.2 to 678). Among the patients with chronic phase CML, 87% received 14 days of treatment during cycle 1. By cycles 2 and 3, the percentage of patients receiving 14 days of treatment decreased to 42% and 16% respectively. Of the 91 patients who received at least 2 cycles of treatment, 79 (87%) had at least 1 cycle delay during the trials. The median number of days of cycle delays was greatest for cycle 2 (17 days) and cycle 3 (25 days) when more patients were receiving induction cycles. Adverse reactions were reported for 99% of the patients with chronic phase CML. A total of 18% of patients had adverse reactions leading to withdrawal. The most frequently occurring adverse reactions leading to discontinuation were pancytopenia, thrombocytopenia, and increased alanine aminotransferase (each 2%). A total of 87% of patients reported at least 1 Grade 3 or Grade 4 treatment emergent adverse reaction (Table 2). Table 2: Adverse Reactions Occurring* in at Least 10% of Patients (Chronic Myeloid Leukemia - Chronic Phase)
Includes infusion related reaction, injection site erythema, injection site hematoma, injection site hemorrhage, injection site hypersensitivity, injection site induration, injection site inflammation, injection site irritation, injection site mass, injection site edema, injection site pruritus, injection site rash, and injection site reaction. Infection includes bacterial, viral, fungal, and non-specified. Serious adverse reactions were reported for 51% of patients. Serious adverse reactions reported for at least 5% of patients were bone marrow failure and thrombocytopenia (each 10%), and febrile neutropenia (6%). Serious adverse reactions of infections were reported for 8% of patients. Deaths occurred while on study in five (5%) patients with CP CML. Two patients died due to cerebral hemorrhage, one due to multi-organ failure, one due to progression of disease, and one from unknown causes. Accelerated Phase CML Median total cycles of exposure was 2 (range 1 to 29), and the median total dose delivered during the trials was 70 mg/m2. The median duration of exposure for the 55 patients with accelerated phase CML was 1.9 months (range 0 to 30 months). Of the patients with accelerated phase CML, 86% received 14 days of treatment during cycle 1. By cycles 2 and 3, the percentage of patients receiving 14 days of treatment decreased to 55% and 44% respectively. Of the 40 patients who received at least 2 cycles of treatment, 27 (68%) had at least 1 cycle delay during the trials. The median number of days of cycle delays was greatest for cycle 3 (31 days) and cycle 8 (36 days). Adverse reactions regardless of investigator attribution were reported for 100% patients with accelerated phase CML. A total of 33% of patients had adverse reactions leading to withdrawal. The most frequently occurring adverse reactions leading to withdrawal were leukocytosis (6%), and thrombocytopenia (4%). A total of 84% of patients reported at least 1 Grade 3 or Grade 4 treatment emergent adverse reaction (Table 3). Table 3: Adverse Reactions Occurring* in at Least 10% of Patients (Chronic Myeloid Leukemia - Accelerated Phase)
Includes infusion related reaction, injection site erythema, injection site hematoma, injection site hemorrhage, injection site hypersensitivity, injection site induration, injection site inflammation, injection site irritation, injection site mass, injection site edema, injection site pruritus, injection site rash, and injection site reaction. Infection includes bacterial, viral, fungal, and non-specified. Serious adverse reactions were reported for 60% of patients. Serious adverse reactions reported for at least 5% of patients were febrile neutropenia (18%), thrombocytopenia (9%), anemia (7%), and diarrhea (6%). Serious adverse reactions of infections were reported for 11% of patients. Death occurred while on study in 5 (9%) patients with AP CML. Two patients died due to cerebral hemorrhage and three due to progression of disease. Laboratory Abnormalities in Chronic and Accelerated Phase CML Grade 3/4 laboratory abnormalities reported in patients with chronic and accelerated phase CML are described in Table 4. Myelosuppression occurred in all patients treated with SYNRIBO [see Warnings and Precautions (5.1)]. Five patients with chronic phase CML and 4 patients with accelerated phase CML permanently discontinued SYNRIBO due to pancytopenia, thrombocytopenia, febrile neutropenia, or bone marrow necrosis. An event of hyperosmolar non-ketotic hyperglycemia was reported in one patient in the safety population and a similar case has been reported in the literature. Two patients with chronic phase CML permanently discontinued SYNRIBO due to elevated transaminases. Table 4: Grade 3/4 Laboratory Abnormalities in Clinical Studies in Patients with Chronic Phase and Accelerated Phase CML
The following adverse reactions were reported in patients in the SYNRIBO clinical studies of patients with chronic phase and accelerated phase CML at a frequency of 1% to less than 10%. Within each category, adverse reactions are ranked on the basis of frequency. Cardiac Disorders: tachycardia, palpitations, acute coronary syndrome, angina pectoris, arrhythmia, bradycardia, ventricular extrasystoles. Ear and Labyrinth Disorders: ear pain, ear hemorrhage, tinnitus. Eye Disorders: cataract, vision blurred, conjunctival hemorrhage, dry eye, lacrimation increased, conjunctivitis, diplopia, eye pain, eyelid edema. Gastrointestinal Disorders: stomatitis, mouth ulceration, abdominal distension, dyspepsia, gastroesophageal reflux disease, gingival bleeding, aphthous stomatitis, dry mouth, hemorrhoids, gastritis, gastrointestinal hemorrhage, melena, mouth hemorrhage, oral pain, anal fissure, dysphagia, gingival pain, gingivitis. General Disorders and Administration Site Conditions: mucosal inflammation, pain, chest pain, hyperthermia, influenza-like illness, catheter site pain, general edema, malaise. Immune System Disorders: hypersensitivity. Injury, Poisoning and Procedural Complications: contusion, transfusion reaction. Metabolism and Nutrition Disorders: decreased appetite, diabetes mellitus, gout, dehydration. Musculoskeletal and Connective Tissue Disorders: bone pain, myalgia, muscular weakness, muscle spasms, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal stiffness, musculoskeletal discomfort. Nervous System Disorders: dizziness, cerebral hemorrhage, paresthesia, convulsion, hypoesthesia, lethargy, sciatica, burning sensation, dysgeusia, tremor. Psychiatric Disorders: anxiety, depression, agitation, confusional state, mental status change. Renal and Urinary Disorders: dysuria. Respiratory, Thoracic and Mediastinal Disorders: pharyngolaryngeal pain, nasal congestion, dysphonia, productive cough, rales, rhinorrhea, hemoptysis, sinus congestion. Skin and Subcutaneous Tissue Disorders: erythema, pruritus, dry skin, petechiae, hyperhidrosis, night sweats, ecchymosis, purpura, skin lesion, skin ulcer, rash erythematous, rash papular, skin exfoliation, skin hyperpigmentation. Vascular Disorders: hematoma, hypertension, hot flush, hypotension. 7 DRUG INTERACTIONS Based on the findings from in vitro drug interaction studies with SYNRIBO, no clinical drug interaction trials were warranted [see Clinical Pharmacology (12.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.4)] Risk Summary Based on its mechanism of action and findings from animal studies, SYNRIBO can cause fetal harm when administered to pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Animal Data In an embryo-fetal development study, pregnant mice were administered omacetaxine mepesuccinate subcutaneously during the period of organogenesis at doses of 0.21 or 0.41 mg/kg/day. Drug-related adverse effects included embryonic death, an increase in unossified bones/reduced bone ossification and decreased fetal body weights. Fetal toxicity occurred at doses of 0.41 mg/kg (1.23 mg/m2) which is approximately half the recommended daily human dose on a body surface area basis. 8.3 Nursing Mothers It is not known whether omacetaxine mepesuccinate is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reaction in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of SYNRIBO in pediatric patients have not been established. 8.5 Geriatric Use In the chronic and accelerated phase CML efficacy populations 23 (30%) and 16 (46%) patients were ≥65 years of age. For the age subgroups of <65 years of age and ≥65 years of age, there were differences between the subgroups, with higher rates of major cytogenetic responses (MCyRs) in younger patients with CP CML compared with older patients (23% vs. 9%, respectively) and higher rates of major hematologic responses (MaHRs) in older patients with AP CML compared with younger patients (31% vs. 0%, respectively). Patients ≥65 years of age were more likely to experience toxicity, most notably hematologic toxicity. 8.6 Renal Impairment No formal studies assessing the impact of renal impairment on the pharmacokinetics of omacetaxine mepesuccinate have been conducted. 8.7 Hepatic Impairment No formal studies assessing the impact of hepatic impairment on the pharmacokinetics of omacetaxine mepesuccinate have been conducted. 8.8 Effect of Gender Of the 76 patients included in the chronic phase CML population efficacy analysis, 47 (62%) of the patients were men and 29 (38%) were women. For patients with chronic phase CML, the MCyR rate in men was higher than in women (21% vs. 14%, respectively). There were differences noted in the safety profile of omacetaxine mepesuccinate in men and women with chronic phase CML although the small number of patients in each group prevents a definitive assessment. There were inadequate patient numbers in the accelerated phase subset to draw conclusions regarding a gender effect on efficacy. 10 OVERDOSAGE A patient in the clinical expanded access program received an overdose of 2.5 mg/m2 twice daily for 5 days in the 16th cycle. The patient presented with gastrointestinal disorders, gingival hemorrhage, alopecia, and Grade 4 thrombocytopenia and neutropenia. When SYNRIBO treatment was temporarily interrupted the gastrointestinal disorders and hemorrhagic syndrome resolved, and neutrophil values returned to within normal range. The alopecia and thrombocytopenia (Grade 1) improved, and SYNRIBO was restarted. No specific antidote for SYNRIBO overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters. 11 DESCRIPTION SYNRIBO contains the active ingredient omacetaxine mepesuccinate, a cephalotaxine ester. It is a protein synthesis inhibitor. Omacetaxine mepesuccinate is prepared by a semi-synthetic process from cephalotaxine, an extract from the leaves of Cephalotaxus sp. The chemical name of omacetaxine mepesuccinate is cephalotaxine, 4-methyl (2R)-hydroxyl-2-(4-hydroxyl-4-methylpentyl) butanedioate (ester). Omacetaxine mepesuccinate has the following chemical structure:
Complete: 0% Ph+ cells, Partial > 0% to 35% Ph+ cells The mean time to MCyR onset in the 14 patients was 3.5 months. The median duration of MCyR for the 14 patients was 12.5 months (Kaplan-Meier estimate). 14.2 Accelerated Phase CML (AP CML) A total of 35 patients with accelerated phase CML were included in the efficacy analysis. The demographics were: median age was 63 years, 57% were male, 46% were 65 years of age or older, 68% were Caucasian, 23% were African-American, 3% were Asian and 3% were Hispanic. Twenty-two (63%) of 35 patients with accelerated phase had failed treatment with imatinib, dasatinib, and nilotinib. Most patients had also received prior non-TKI treatments, most commonly hydroxyurea (43%), interferon (31%), and/or cytarabine (29%). The efficacy endpoint was assessed based on MCyR and MaHR (complete hematologic response [CHR] or no evidence of leukemia [NEL]). The efficacy results for the patients with accelerated phase as adjudicated by the DMC are shown in Table 6. Table 6: Efficacy Results Evaluated by DMC for Patients with AP CML
The mean time to response onset in the 5 patients was 2.3 months. The median duration of MaHR for the 5 patients was 4.7 months (Kaplan-Meier estimate). 15 REFERENCES 1. OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html. 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied SYNRIBO (omacetaxine mepesuccinate) for Injection is supplied in 8 mL clear glass single-use vial in individual cartons. Each vial contains 3.5 mg of SYNRIBO (omacetaxine mepesuccinate) for Injection (NDC 63459-177-14). 16.2 Storage and Handling Store unopened vials at 20oC to 25ºC (68o F to 77ºF); excursions permitted from 15ºC to 30ºC (59ºF to 86ºF) [see USP Controlled Room Temperature]. Prior to re-constitution, keep product in carton to protect from light. Omacetaxine mepesuccinate is a cytotoxic drug. Follow special handling and disposal procedures1. 完整资料附件：https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=83a504ef-cf92-467d-9ecf-d251194a3484 FDA于10月26日批准梯瓦新药synribo，用于治疗慢性粒细胞白血病（CML）。患者在接受至少两种酪氨酸激酶抑制剂后病情仍继续发展时，可使用synribo治疗。 Synribo主要通过阻断癌细胞发展过程中的特定蛋白起作用，注射方式为皮下，起初每天两次注射，连续注射14天，28天为一周期，直到白细胞计数正常。接着每天注射两次，连续注射7天，28天为一周期，直到患者仍能从中获益。 “一些患者抵抗或无法耐受其他FDA批准的药物治疗，但是synribo为他们提供了新的选择”，理查德帕兹德（ Richard Pazdur），FDA血液学和肿瘤学产品办公室主管说到，“synribo是近两月来批准的的第二种用于治疗CML药物”。在2012年9月4日，FDA批准bosulif用于治疗无法耐受其他疗法的急慢性费城染色体阳性的CML患者。 synribo的获批得益于FDA的加速审批程序。该程序有帮助于治疗严重疾病，FDA可根据药物在替代终点能否患者有益而批准药物。在公司做了证实药物临床受益和安全性的临床试验之后，该程序为病人更早地提供了使用新药的途径。 梯瓦公司的临床试验在一群经过至少两种酪氨酸激酶抑制剂治疗后仍持续进展的患者中进行，所有患者使用synribo治疗。在CML慢性期，synribo治疗后表达费城染色体基因突变的细胞比例降低。76例中有14例患者（18.4%）的比例减少持续3.5个月，中位数为12.5个月。在急性期，通过测定白细胞计数正常或没有白血病证据的患者人数来证实synribo的疗效。结果显示35例中有5例患者（14.3%）在平均维持2.3个月出现重大血液学反应，中位数是4.7个月。 在临床试验中，synribo主要副作用是血液血小板、红细胞、中性粒细胞及淋巴细胞数目减少，可能导致感染、发烧、腹泻、恶心、虚弱、疲劳、注射部位反应等不良反应。 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
