英文品名：Evoltra Concentrate for solution for infusion
适应症：至少使用过两种常用投药法治疗无效，且已可预见无其他疗法能达到持久反应之复发(Relapsed)或难治(Refractory)的1~21岁急 性淋巴母细胞白血病(Acute lymphoblastic leukemia)病人。
Evoltra 1mg/ml (Clofarabine)Evoltra 1mg/ml Description, Presentation and DosageEvoltra 1mg/ml DescriptionEvoltra 1mg/ml Drug Class DescriptionAntineoplastic agents, antimetabolites, ATC code: L01BB06Evoltra 1mg/ml Drug DescriptionEach ml of concentrate contains 1 mg of clofarabine. Each 20 ml vial contains 20 mg of clofarabine.Excipient:Each 20 ml vial contains 180 mg of sodium chloride.Evoltra 1mg/ml Generic NameClofarabineEvoltra 1mg/ml PresentationEvoltra 1mg/ml PresentationConcentrate for solution for infusion .Clear, practically colourless solution with a pH of 4.5 to 7.5 and an osmolarity of 270 to 310 mOsm/l.Updated23 October 2012Evoltra 1mg/ml DosageEvoltra 1mg/ml Adult DosageTherapy must be initiated and supervised by a physician experienced in the management of patients with acute leukaemias.PosologyAdult population (including the elderly)There are currently insufficient data to establish the safety and efficacy of clofarabine in adult patients.Paediatric populationThe recommended dose is 52 mg/m2 of body surface area administered by intravenous infusion over 2 hours daily for 5 consecutive days. Body surface area must be calculated using the actual height and weight of the patient before the start of each cycle. Treatment cycles should be repeated every 2 to 6 weeks (from the starting day of the previous cycle) following recovery of normal haematopoiesis (i.e. ANC ≥ 0.75 × 109/l) and return to baseline organ function. A 25% dose reduction may be warranted in patients experiencing significant toxicities (see below). There is currently limited experience of patients receiving more than 3 treatment cycles.The majority of patients who respond to clofarabine achieve a response after 1 or 2 treatment cycles. Therefore, the potential benefit and risks associated with continued therapy in patients who do not show haematological and/or clinical improvement after 2 treatment cycles should be assessed by the treating physician.Children (weighing < 20 kg): An infusion time of > 2 hours should be considered to help reduce symptoms of anxiety and irritability, and to avoid unduly high maximum concentrations of clofarabine.Children (< 1 year old): There are no data on the pharmacokinetics, safety or efficacy of clofarabine in infants. Therefore, a safe and effective dosage recommendation for patients (< 1 year old) has yet to be established.Patients with renal insufficiency: The limited data available indicate that clofarabine may accumulate in patients with decreased creatinine clearance. Clofarabine is contraindicated in patients with severe renal insufficiency and should be used with caution in patients with mild to moderate renal insufficiency.Patients with moderate renal impairment (creatinine clearance 30 — <60 ml/min) require a 50% dose reduction.Patients with hepatic impairment: There is no experience in patients with hepatic impairment (serum bilirubin > 1.5 x ULN plus AST and ALT > 5 x ULN) and the liver is a potential target organ for toxicity. Therefore, clofarabine is contraindicated in patients with severe hepatic impairment (see section 4.3) and should be used with caution in patients with mild to moderate hepatic impairment.Dose reduction for patients experiencing haematological toxicities: If the ANC does not recover by 6 weeks from the start of a treatment cycle, a bone marrow aspirate / biopsy should be performed to determine possible refractory disease. If persistent leukaemia is not evident, it is recommended that the dose for the next cycle be reduced by 25% of the previous dose following recovery of ANC to ≥ 0.75 × 109/l. Should patients experience an ANC < 0.5 × 109/l for more than 4 weeks from the start of the last cycle, it is recommended that the dose for the next cycle be reduced by 25%.Dose reduction for patients experiencing non-haematological toxicitiesInfectious events: If a patient develops a clinically significant infection, clofarabine treatment may be withheld until the infection is clinically controlled. At this time, treatment may be reinitiated at the full dose. In the event of a second clinically significant infection, clofarabine treatment should be withheld until the infection is clinically controlled and may be reinitiated at a 25% dose reduction.Non-infectious events: If a patient experiences one or more severe toxicities (US National Cancer Institute (NCI) Common Toxicity Criteria (CTC) Grade 3 toxicities excluding nausea and vomiting), treatment should be delayed until the toxicities resolve to baseline parameters or to the point where they are no longer severe and the potential benefit of continued treatment with clofarabine outweighs the risk of such continuation. It is then recommended that clofarabine be administered at a 25% dose reduction.Should a patient experience the same severe toxicity on a second occasion, treatment should be delayed until the toxicity resolves to baseline parameters or to the point where it is no longer severe and the potential benefit of continued treatment with clofarabine outweighs the risk of such continuation. It is then recommended that clofarabine be administered at a further 25% dose reduction.Any patient who experiences a severe toxicity on a third occasion, a severe toxicity that does not recover within 14 days (see above for exclusions), or a life-threatening or disabling toxicity (US NCI CTC Grade 4 toxicity) should be withdrawn from treatment with clofarabine.Method of administrationThe recommended dosage should be administered by intravenous infusion although it has been administered via a central venous catheter in ongoing clinical trials. Evoltra must not be mixed with or concomitantly administered using the same intravenous line as other medicinal products.Drug Information SecondaryEvoltra 1mg/ml Precautions, Reactions and ContraindicationsEvoltra 1mg/ml Special PrecautionsEvoltra 1mg/ml Special PrecautionsEvoltra is a potent antineoplastic agent with potentially significant haematological and non-haematological adverse reactions.The following parameters should be closely monitored in patients undergoing treatment with clofarabine:• Complete blood and platelet counts should be obtained at regular intervals, more frequently in patients who develop cytopenias.• Renal and hepatic function prior to, during active treatment and following therapy. Clofarabine should be discontinued immediately if substantial increases in creatinine or bilirubin are observed.• Respiratory status, blood pressure, fluid balance and weight throughout and immediately after the 5 day clofarabine administration period.Suppression of bone marrow should be anticipated. This is usually reversible and appears to be dose-dependent. Severe bone marrow suppression, including neutropaenia, anaemia and thrombocytopenia have been observed in patients treated with clofarabine. In addition, at initiation of treatment, most patients in the clinical studies had haematological impairment as a manifestation of leukaemia. Because of the pre-existing immuno-compromised condition of these patients and prolonged neutropaenia that can result from treatment with clofarabine, patients are at increased risk for severe opportunistic infections, including severe sepsis, with potentially fatal outcomes. Patients should be monitored for signs and symptoms of infection and treated promptly.Occurrences of enterocolitis, including neutropaenic colitis and C. difficile colitis, have been reported during treatment with clofarabine. This has occurred more frequently within 30 days of treatment, and in the setting of combination chemotherapy.Administration of clofarabine results in a rapid reduction in peripheral leukaemia cells. Patients undergoing treatment with clofarabine should be eva luated and monitored for signs and symptoms of tumour lysis syndrome and cytokine release (e.g. tachypnoea, tachycardia, hypotension, pulmonary oedema) that could develop into Systemic Inflammatory Response Syndrome (SIRS), capillary leak syndrome and/or organ dysfunction.• Prophylactic administration of allopurinol should be considered if hyperuricemia (tumour lysis) is expected.• Patients should receive intravenous fluids throughout the 5 day clofarabine administration period to reduce the effects of tumour lysis and other events.• The use of prophylactic steroids (e.g., 100 mg/m2 hydrocortisone on Days 1 through 3) may be of benefit in preventing signs or symptoms of SIRS or capillary leak.Clofarabine should be discontinued immediately if patients show early signs or symptoms of SIRS, capillary leak syndrome or substantial organ dysfunction and appropriate supportive measures instituted. In addition, clofarabine treatment should be discontinued if the patient develops hypotension for any reason during the 5 days of administration. Further treatment with clofarabine, generally at a lower dose, can be considered when patients are stabilised and organ function has returned to baseline.The majority of patients who respond to clofarabine achieve a response after 1 or 2 treatment cycles. Therefore, the potential benefit and risks associated with continued therapy in patients who do not show haematological and/or clinical improvement after 2 treatment cycles should be assessed by the treating physician.Patients with cardiac disease and those taking medicinal products known to affect blood pressure or cardiac function should be closely monitored during treatment with clofarabine.There is no clinical study experience in paediatric patients with renal insufficiency (defined in clinical studies as serum creatinine ≥ 2 x ULN for age) and clofarabine is predominately excreted via the kidneys. Pharmacokinetic data indicate that clofarabine may accumulate in patients with decreased creatinine clearance. Therefore, clofarabine should be used with caution in patients with mild to moderate renal insufficiency. The safety profile of clofarabine has not been established in patients with severe renal impairment or patients receiving renal replacement therapy. The concomitant use of medicinal products that have been associated with renal toxicity and those eliminated by tubular secretion such as NSAIDs, amphotericin B, methotrexate, aminosides, organoplatines, foscarnet, pentamidine, cyclosporin, tacrolimus, acyclovir and valganciclovir, should be avoided particularly during the 5 day clofarabine administration period; preference should be given to those medicinal products that are not known to be nephrotoxic.Patients receiving clofarabine may experience vomiting and diarrhoea; they should, therefore, be advised regarding appropriate measures to avoid dehydration. Patients should be instructed to seek medical advice if they experience symptoms of dizziness, fainting spells, or decreased urine output. Prophylactic anti-emetic medicinal products should be considered.There is no experience in patients with hepatic impairment (serum bilirubin > 1.5 x ULN plus AST and ALT > 5 x ULN) and the liver is a potential target organ for toxicity. Therefore, clofarabine should be used with caution in patients with mild to moderate hepatic impairment. The concomitant use of medicinal products that have been associated with hepatic toxicity should be avoided wherever possible.If a patient experiences a hematologic toxicity of Grade 4 neutropaenia (ANC <0.5 x 109/l) lasting ≥4 weeks, then the dose should be reduced by 25% for the next cycle.Any patient who experiences a severe non-hematologic toxicity (US NCI CTC Grade 3 toxicity) on a third occasion, a severe toxicity that does not recover within 14 days (excluding nausea/vomiting) or a life-threatening or disabling non-infectious non-hematologic toxicity (US NCI CTC Grade 4 toxicity) should be withdrawn from treatment with clofarabine.Patients who have previously received a hematopoietic stem cell transplant (HSCT) may be at higher risk for hepatotoxicity suggestive of veno-occlusive disease (VOD) following treatment with clofarabine (40 mg/m2) when used in combination with etoposide (100 mg/m2) and cyclophosphamide (440 mg/m2). Severe hepatotoxic events have been reported in an ongoing Phase 1/2 combination study of clofarabine in paediatric patients with relapsed or refractory acute leukaemia.There are currently limited data on the safety and efficacy of clofarabine when administered for more than 3 treatment cycles.Each vial of Evoltra contains 180 mg of sodium chloride. This is equivalent to 3.08 mmol (or 70.77 mg) of sodium and should be taken into consideration for patients on a controlled sodium diet.Evoltra 1mg/ml Adverse ReactionsEvoltra 1mg/ml Adverse ReactionsThe information provided is based on data generated from clinical trials in which 115 patients (> 1 and ≤ 21 years old) with either ALL or acute myeloid leukaemia (AML) received at least one dose of clofarabine at the recommended dose of 52 mg/m2 daily x 5. Adverse reactions are listed by system organ class and frequency (very common (≥1/10); common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100; rare (≥1/10,000 to <1/1,000) and very rare (<1/10,000)) in the table below. Adverse reactions reported during the post-marketing period are also included in the table under the frequency category “not known” (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.Patients with advanced stages of ALL or AML may have confounding medical conditions that make causality of adverse events difficult to assess due to the variety of symptoms related to the underlying disease, its progression and the co-administration of numerous medicinal products.Nearly all patients (98%) experienced at least one adverse event considered by the study investigator to be related to clofarabine. Those most frequently reported were nausea (61% of patients), vomiting (59%), febrile neutropaenia (35%), headache (24%), rash (21%), diarrhoea (20%), pruritus (20%) , pyrexia (19%), palmar-plantar erythrodysaesthesia syndrome (15%), fatigue (14%), anxiety (12%), mucosal inflammation (11%), and flushing (11%). Sixty-eight patients (59%) experienced at least one serious clofarabine-related adverse event. One patient discontinued treatment due to grade 4 hyperbilirubinaemia considered as related to clofarabine after receiving 52 mg/m2/day clofarabine. Three patients died of adverse events considered by the study investigator to be related to treatment with clofarabine: one patient died from respiratory distress, hepatocellular damage, and capillary leak syndrome; one patient from VRE sepsis and multi-organ failure; and one patient from septic shock and multi-organ failure.Adverse reactions considered to be related to clofarabine reported at frequencies ≥ 1/100 (i.e. in > 1/115 patients) in clinical trials and post-marketingInfections and infestationsCommon: Septic shock*, sepsis, bacteraemia, pneumonia, herpes zoster, herpes simplex, oral candidiasisFrequency not known: C. difficile colitisNeoplasms benign and malignant (including cysts and polyps)Common: Tumour lysis syndrome*Blood and lymphatic system disordersVery common: Febrile neutropaeniaCommon: NeutropaeniaImmune system disordersCommon: HypersensitivityMetabolism and nutrition disordersCommon: Anorexia, decreased appetite, dehydrationPsychiatric disordersVery common: AnxietyCommon: Agitation, restlessness, mental status changeNervous system disordersVery common: HeadacheCommon: Somnolence, peripheral neuropathy, paraesthesia, dizziness, tremorEar and labyrinth disordersCommon: HypoacusisCardiac disordersCommon: Pericardial effusion*, tachycardia*Vascular disordersVery common: Flushing*Common: Hypotension*, capillary leak syndrome, haematomaRespiratory, thoracic and mediastinal disordersCommon: Respiratory distress, epistaxis, dyspnoea, tachypnoea, coughGastrointestinal disordersVery common: Vomiting, nausea, diarrhoeaCommon: Mouth haemorrhage, gingival bleeding, haematemesis, abdominal pain, stomatitis, upper abdominal pain, proctalgia, mouth ulcerationFrequency not known: Pancreatitis elevations in serum amylase and lipase, enterocolitis, neutropaenic colitisHepato-biliary disordersCommon: Hyperbilirubinaemia, jaundice, veno-occlusive disease, increases in alanine (ALT)* and aspartate (AST)* aminotransferasesGeneral disorders and administration site conditionsVery common: Fatigue, pyrexia, mucosal inflammationCommon: Multi-organ failure, systemic inflammatory response syndrome*, pain, chills, irritability, oedema, peripheral oedema, feeling hot, feeling abnormalSkin and subcutaneous tissue disordersVery common: Palmar-plantar erythrodysaesthesia syndrome, pruritusCommon: Maculo-papular rash, petechiae, erythema, pruritic rash, skin exfoliation, generalised rash, alopecia, skin hyperpigmentation, generalised erythema, erythematous rash, dry skin, hyperhidrosisFrequency not known: Stevens Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN)Musculoskeletal, connective tissue and bone disordersCommon: Pain in extremity, myalgia, bone pain, chest wall pain, arthralgia, neck and back painRenal and urinary disordersCommon: Haematuria*InvestigationsCommon: Weight decreasedInjury, poisoning and procedural complicationsCommon: Contusion* = see belowAll adverse reactions occurring at least twice (i.e., 2 or more events (1.7%)) are included in this tableBlood and lymphatic system disorders: the most frequent haematological laboratory abnormalities observed in patients treated with clofarabine were anaemia (83.3%; 95/114); leucopaenia (87.7%; 100/114); lymphopaenia (82.3%; 93/113), neutropaenia (63.7%; 72/113), and thrombocytopaenia (80.7%; 92/114).The majority of these events were of grade ≥3.Vascular disorders: Sixty-four patients of 115 (55.7%) experienced at least one vascular disorders adverse event. Twenty-three patients out of 115 experienced a vascular disorder considered to be related to clofarabine, the most frequently reported being flushing (13 events; not serious) and hypotension (5 events; all of which were considered to be serious). However, the majority of these hypotensive events were reported in patients who had confounding severe infections.Cardiac disorders: Fifty percent of patients experienced at least one cardiac disorders adverse event. Eleven events in 115 patients were considered to be related to clofarabine, none of which were serious and the most frequently reported cardiac disorder was tachycardia (35%); 6.1% (7/115) patient’s tachycardia were considered to be related to clofarabine. Most of the cardiac adverse events were reported in the first 2 cycles.Pericardial effusion and pericarditis were reported as an adverse event in 9% (10/115) of patients. Three of these events were subsequently assessed as being related to clofarabine: pericardial effusion (2 events; 1 of which was serious) and pericarditis (1 event; not serious). In the majority of patients (8/10), the pericardial effusion and pericarditis were deemed to be asymptomatic and of little or no clinical significance on echocardiographic assessment. However, the pericardial effusion was clinically significant in 2 patients with some associated haemodynamic compromise.Infections and infestations: Forty-eight percent of patients had one or more ongoing infections prior to receiving treatment with clofarabine. A total of 83% of patients experienced at least 1 infection after clofarabine treatment, including fungal, viral and bacterial infections. Twenty-one (18.3%) events were considered to be related to clofarabine of which catheter related infection (1 event), sepsis (2 events) and septic shock (2 events; 1 patient died (see above)) were considered to be serious.Renal and urinary disorders: Forty-one patients of 115 (35.7%) experienced at least one renal and urinary disorders adverse event. The most preva lent renal toxicity in paediatric patients was elevated creatinine. Grade 3 or 4 elevated creatinine occurred in 8% of patients. Nephrotoxic medicinal products, tumour lysis, and tumour lysis with hyperuricemia may contribute to renal toxicity. Haematuria was observed in 13% of patients overall. Four renal adverse events in 115 patients were considered to be related to clofarabine, none of which were serious; haematuria (3 events) and acute renal failure (1 event).Hepato-biliary disorders: The liver is a potential target organ for clofarabine toxicity and 25.2% of patients experienced at least one hepato-biliary disorders adverse event. Six events were considered to be related to clofarabine of which acute cholecystitis (1 event), cholelithiasis (1 event), hepatocellular damage (1 event; patient died (see above)) and hyperbilirubinaemia (1 event; the patient discontinued therapy (see above)) were considered to be serious. Two paediatric reports (1.7%) of veno-occlusive disease (VOD) were considered related to study drug.In addition, 50/113 patients receiving clofarabine had at least severely (at least US NCI CTC Grade 3) elevated ALT, 36/100 elevated AST and 15/114 elevated bilirubin levels. The majority of elevations in ALT and AST occurred within 10 days of clofarabine administration and returned to ≤ grade 2 within 15 days. Where follow-up data are available, the majority of bilirubin elevations returned to ≤ grade 2 within 10 days.Systemic Inflammatory Response Syndrome (SIRS) or capillary leak syndrome: SIRS, capillary leak syndrome (signs and symptoms of cytokine release, e.g., tachypnea, tachycardia, hypotension, pulmonary oedema) were reported as an adverse event in 5% (6/115) of paediatric patients (5 ALL, 1 AML). Thirteen events of tumour lysis syndrome, capillary leak syndrome or SIRS have been reported; SIRS (2 events; both were considered to be serious), capillary leak syndrome (4 events; 3 of which were considered serious and related) and tumour lysis syndrome (7 events; 6 of which were considered related and 3 of which were serious).Evoltra 1mg/ml ContraindicationsEvoltra 1mg/ml ContraindicationsHypersensitivity to clofarabine or to any of the excipients.Use in patients with severe renal insufficiency or severe hepatic impairment.Breast-feeding should be discontinued prior to, during and following treatment with Evoltra.