地尼白介素-2注射剂(ONTAK for intravenous infusion)

产地国家：美国

处方药：是

所属类别： 300微克/毫升 2毫升/瓶 6瓶/盒

包装规格： 300微克/毫升 2毫升/瓶 6瓶/盒

计价单位：盒

生产厂家英文名：Eisai Inc

原产地英文商品名：ONTAK 300MCG/ML 2ML/VIAL 6VIAL/BOX

原产地英文药品名：DENILEUKIN DIFTITOX

中文参考商品译名：ONTAK静脉滴注注射剂 300微克/毫升 2毫升/瓶 6瓶/盒

中文参考药品译名：地尼白介素2

简介

部分中文Ontak处方资料（仅供参考）

地尼白介素-2注射剂（Denileukin Diftitox，Dd，ONTAK）：Dd为包含白喉毒素活性域和IL-2蛋白序列的基因工程融合蛋白。这种蛋白中的IL-2部分与细胞表面的IL-2受体结合，使白喉毒素进入细胞，导致细胞死亡。50%～60%的皮肤T细胞淋巴瘤（CTCL）表达IL-2受体。

1999年2月美国食品和药物管理局FDA快速通道批准Dd用于治疗表达CD25（IL-2受体α亚基）的皮肤T细胞淋巴瘤（CTCL）。Dd的主要不良反应为输液反应和毛细血管渗漏综合征，加用皮质激素能提高疗效和降低毒性。ONTAK(NSC 697979 DENILEUKIN DIFTITOX)其他名:Ontak。

来源：利用基因重组把白喉毒素A和B段基因与白介素-2基因连接，转染大肠杆菌产生白介素-2和免疫毒素复合物。

作用机制：本品是白介素-2和免疫毒素的融合剂，可以介导白喉毒素的细胞毒作用，杀伤表达IL-2受体的细胞。人类IL-2受体有三种形式，低亲和力（CD25），和亲和力（CD122/CD132),高亲和力于活化T细胞，活化B细胞，活化巨噬细胞。包括皮肤T细胞淋巴瘤在内的某些白血病和淋巴瘤细胞表达一种以上IL-2受体亚单位。体外实验发现本品与细胞表面高亲和性IL-2受体结合，通过白喉毒素作用，抑制细胞蛋白合成，导致细胞几小时内死亡。

药代动力学：在小鼠体内进了放射性标记药物48小时内生物分布与排泄的研究。肝、肾是血管外药物分布与聚集的首要部位。本品通过蛋白降解代谢。淋巴瘤患者静脉输入本品3～31mg/ml(kg/d)。首次给药后，本品呈两室分布相（半衰期2～5分钟）和终末相（半衰期70～80分钟）。清除率为1.5～2ml/(min.kg),分布容积相当于循环血（0.06～0.08L/kg).第一次和第五次用药之间没有明显药物聚集。

相互作用：尚无相关研究。

适应症：表达CD25（白细胞介素2受体，IL-2R）的难治性、复发性皮肤T细胞淋巴瘤。单药有效率：治疗皮肤T细胞淋巴瘤单药有效率为30%～38%，完全缓解率为10%～16%。

剂型：针剂，每支300mg/2ml冷冻溶液。

剂量：推荐方案：9mg/(kg.d)或18mg(kg.d)，静脉用药，连用5天，21天为一个疗程。输液时间15分钟以上。对于输液时间过长，如超过80分钟，尚无相关研究，尚未确定最佳疗程数，但是研究表明治疗4个疗程后，只有2%（1/51）的患者肿瘤负荷降低∠25%。

给药途径：静脉给药。配伍：不能与其他药品混合使用。

禁忌症：对本品和白喉毒素、IL-2过敏的患者禁用。老年患者、孕妇慎用，哺乳期妇女治疗期间应停止哺乳。

不良反应

1.全身症状：发热、寒战、感染、头痛。

2.呼吸系统：呼吸急促、咳嗽、声音嘶哑。

3.循环系统：心率加快、心律失常。

4.消化系统：吞咽困难、腹痛、消化不良、在老年患者更易于发生。

5.皮肤病变：皮疹、皮肤发热、潮红、皮肤红斑、注射部位肿瘤。

6.肌肉骨骼：背痛、胸痛、肘部疼痛、腹股沟疼痛、腿痛、足部或下肢肿胀、面部肿胀。

7.神经精神：睡眠障碍、眩晕、晕厥、共济失调、视力突然改变、手足无力、指（趾）尖麻木。

8.泌尿系统：絮状尿、血尿、尿痛、排尿困难、尿少。

临床应用规程

1.用药前检测血常规、心电图、血压。

2.用药后定期检测血常规、心电图、血压、神经系统检查。

3.稀释和配制时需要无菌操作，用塑料注射器和配液袋，不能使用玻璃容器，因为药品会吸附在玻璃上，影响药品浓度。

4.配掖过程中药物浓度至少15mg/ml，最好吸出所需要的药品，注入空的静脉输液袋内。每1ml药品加入不超过9ml的不含防腐剂的无菌盐水。

5.输液前30分钟给予抗组胺药、解热镇痛药、密切观察输液反应和过敏反应，并予相应处理。

6.输液时间不短于15分钟。

7.本品不能一次冲式给药。应该使用输液泵或者静脉输液袋。

英文版说明书

ONTAK® (denileukin diftitox) Injection for intravenous infusionontak(denileukin diftitox)solution[Eisai Inc.]WARNING: Only physicians experienced in the use of antineoplastic therapy and management of patients with cancer should use ONTAK (denileukin diftitox). Patients treated with denileukin diftitox must be managed in a facility equipped and staffed for cardiopulmonary resuscitation and where the patient can be closely monitored for an appropriate period based on his or her health status.DESCRIPTIONONTAK®(denileukin diftitox), a recombinant DNA-derived cytotoxic protein composed of the amino acid sequences for diphtheria toxin fragments A and B (Met1-Thr387)-His followed by the sequences for interleukin-2 (IL-2; Ala1-Thr133), is produced in an E. coli expression system. ONTAK has a molecular weight of 58 kD. Neomycin is used in the fermentation process but is undetectable in the final product. The product is purified using reverse phase chromatography followed by a multistep diafiltration process.ONTAK is supplied in single use vials as a sterile, frozen solution intended for intravenous (IV) administration. Each 2 mL vial of ONTAK contains 300 mcg of recombinant denileukin diftitox in a sterile solution of citric acid (20 mM), EDTA (0.05 mM) and polysorbate 20 (<1%) in Water for Injection, USP. The solution has a pH of 6.9 to 7.2.CLINICAL PHARMACOLOGYGeneralDenileukin diftitox is a fusion protein designed to direct the cytocidal action of diphtheria toxin to cells which express the IL-2 receptor. The human IL-2 receptor exists in three forms, low (CD25), intermediate (CD122/CD132) and high (CD25/CD122/CD132) affinity. The high affinity form of this receptor is usually found only on activated T lymphocytes, activated B lymphocytes and activated macrophages. Malignant cells expressing one or more of the subunits of the IL-2 receptor are found in certain leukemias and lymphomas including cutaneous T-cell lymphoma (CTCL)1. Ex vivo studies suggest that denileukin diftitox interacts with the high affinity IL-2 receptor on the cell surface and inhibits cellular protein synthesis, resulting in cell death within hours.The biodistribution and excretion of radiolabeled denileukin diftitox were eva luated over 48 hours in rats. The liver and kidneys were the primary sites of distribution and accumulation of radiolabeled material outside of the vasculature. Denileukin diftitox was metabolized by proteolytic degradation. Excreted material was less than 25% of the total injected dose and consisted of low molecular weight breakdown products.PharmacokineticsPharmacokinetic parameters associated with denileukin diftitox were determined over a range of doses (3 to 31 mcg/kg/day) in patients with lymphoma. Denileukin diftitox was administered as an IV infusion following the schedule used in the clinical trials. Following the first dose, denileukin diftitox displayed 2-compartment behavior with a distribution phase (half-life approximately 2 to 5 minutes) and a terminal phase (half-life approximately 70 to 80 minutes). Systemic exposure was variable but proportional to dose. Clearance was approximately 1.5 to 2.0 mL/min/kg and the volume of distribution was similar to that of circulating blood (0.06 to 0.08 L/kg). No accumulation was evident between the first and fifth doses. Development of antibodies to denileukin diftitox has been shown to significantly impact clearance rates (see PRECAUTIONS, Immunogenicity). Gender, age, and race were introduced into a multivariate analysis with various pharmacokinetic parameters. The limited available data revealed no statistical relationships between these variables.CLINICAL STUDIESA randomized, double-blind study was conducted to eva luate doses of 9 or 18 mcg/kg/day in 71 patients with recurrent or persistent, Stage Ib to IVa CTCL. Entry to this study required demonstration of CD25 expression on at least 20% of the cells in any relevant tumor tissue sample (skin biopsy) or circulating cells. Tumor biopsies were not eva luated for expression of other IL-2 receptor subunit components (CD122/CD132). ONTAK was administered as an IV infusion daily for 5 days every 3 weeks. Patients received a median of 6 courses of ONTAK therapy (range 1 to 11). The study population had received a median of 5 prior therapies (range 1 to 12) with 63% of patients entering the trial with Stage IIb or more advanced stage disease. Overall, 30% (95% CI: 18-41%) of patients treated with ONTAK experienced an objective tumor response (50% reduction in tumor burden which was sustained for ≥6 weeks; Table 1). Seven patients (10%) achieved a complete response and 14 patients (20%) achieved a partial response. The overall median duration of response, measured from first day of response, was 4 months with a median duration for complete response of 9 months and for partial response of 4 months. In a Phase I/II dose-escalation study, 35 patients with Stage Ia to IVb CTCL were treated. ONTAK was administered as an IV infusion at doses ranging from 3 to 31 mcg/kg/day, daily for 5 days every 3 weeks. The overall response rate in patients with CTCL who expressed CD25 was 38% (12 of 32 patients); the complete response rate was 16% and the partial response rate was 22%. There were no responses in 21 patients with Hodgkin's disease.Table 1 Response in the Phase III Double-Blind Study Patients withINDICATIONSONTAK is indicated for the treatment of patients with persistent or recurrent cutaneous T-cell lymphoma whose malignant cells express the CD25 component of the IL-2 receptor ( see PRECAUTIONS, Laboratory Tests, for CD25 expression testing). The safety and efficacy of denileukin diftitox in patients with CTCL whose malignant cells do not express the CD25 component of the IL-2 receptor have not been examined.CONTRAINDICATIONSONTAK is contraindicated for use in patients with a known hypersensitivity to denileukin diftitox or any of its components: diphtheria toxin, interleukin-2, or excipients.WARNINGSAcute Hypersensitivity-type ReactionsAcute hypersensitivity reactions were reported in 98 of 143 patients (69%) during or within 24 hours of ONTAK infusion; approximately half of the events occurred on the first day of dosing regardless of the treatment cycle. The constellation of symptoms included one or more of the following, defined as the incidence (%) in these 98 patients: hypotension (50%), back pain (30%), dyspnea (28%), vasodilation (28%), rash (25%), chest pain or tightness (24%), tachycardia (12%), dysphagia or laryngismus (5%), syncope (3%), allergic reaction (1%) or anaphylaxis (1%). These events were severe in 2% of patients. Death during infusion has been reported. Management consists of interruption or a decrease in the rate of infusion (depending on the severity of the reaction); 3% of infusions were terminated prematurely and reduction in rate occurred in 4% of the infusions during the clinical trials. The administration of IV antihistamines, corticosteroids, and epinephrine may also be required; two subjects received epinephrine and 18 (13%) received systemic corticosteroids in the clinical studies. These drugs and resuscitative equipment should be readily available during ONTAK administration.Vascular Leak SyndromeThis syndrome, characterized by 2 or more of the following 3 symptoms (hypotension, edema, hypoalbuminemia) was reported in 27% (38/143) of patients in the clinical studies. Six percent (8/143) of patients were hospitalized for the management of these symptoms. The onset of symptoms in patients with vascular leak syndrome was delayed, usually occurring within the first two weeks of infusion; symptoms may persist or worsen after the cessation of denileukin diftitox. Cases of vascular (capillary) leak with a fatal outcome have been reported. Special caution should be taken in patients with preexisting cardiovascular disease ( See ADVERSE REACTIONS, Cardiovascular System).Weight, edema, blood pressure and serum albumin levels should be carefully monitored on an outpatient basis. This syndrome is usually self-limited and treatment should be used only if clinically indicated. The type of treatment will depend on whether edema or hypotension is the primary clinical problem. Pre-existing low serum albumin levels appear to predict and may predispose patients to the syndrome ( see PRECAUTIONS, Laboratory Tests).Visual LossLoss of visual acuity, usually with loss of color vision, with or without retinal pigment mottling has been reported following administration of ONTAK. Recovery was reported in some of the affected patients; however, most patients reported persistent visual impairment.PRECAUTIONSGeneralPatients should be monitored carefully for infection since patients with CTCL have a predisposition to cutaneous infection. Also, the binding of denileukin diftitox to activated lymphocytes and macrophages can lead to cell death and may impair immune function in patients.ImmunogenicityThe immunogenicity data reflect the percentage of patients whose test results were considered positive for antibody to denileukin diftitox in ELISA assays and in a functional cellular assay. These results are highly dependent on the sensitivity and the specificity of the assays. Additionally, the observed incidence of the antibody positivity may be influenced by several factors including sample handling, concomitant medication, and underlying disease. For these reasons, the comparison of the incidence of antibodies to denileukin diftitox with the incidence of antibodies to other products may be misleading. Patients who develop a hypersensitivity to denileukin diftitox may have allergic or hypersensitivity reactions to other products produced in E. coli expression systems and to vaccines against diphtheria.An immune response to denileukin diftitox was assessed using two enzyme-linked immunoassays (ELISA), one measuring reactivity directed against the intact DAB389IL-2 and the other against the IL-2 portion of the protein. An additional in vitro cell-based assay that measured the ability of antibodies in serum to protect a human IL-2R-expressing cell line from toxicity by DAB389IL-2, was used to detect the presence of antibodies which inhibited functional activity. A total of 131 patients were assessed for an immune response by ELISA prior to treatment. Of these, 51 patients (39%) had antibodies to the intact fusion protein and 24 (18%) had antibodies that were directed against the IL-2 portion of the molecule. Among the 60 patients assessed prior to treatment, 27 (45%) had evidence of an immune response inhibiting activity in the cellular assay. After one cycle of treatment, 76% of the patients tested had an antibody response against DAB389IL-2 and 35% against the IL-2 portion by ELISA; 73% of patients had a positive immune response in the cellular assay. After 3 cycles of treatment, 97% of patients tested had an immune response to DAB389IL-2 in both the ELISA and the cellular assay.The development of antibodies was correlated with a significant increase (two- to three-fold) in clearance. The increased clearance resulted in a decrease in mean systemic exposure of approximately 75%. The presence of antibodies did not correlate with risk of immediate hypersensitivity-type infusional adverse events.Laboratory TestsPrior to administration of this product, the patient's malignant cells should be tested for CD25 expression. A testing service for the assay of CD25 on skin biopsy samples is available. For information on this service call 800-964-5836.A complete blood count and a blood chemistry panel, including liver and renal function and serum albumin levels, should be performed prior to initiation of ONTAK treatment and weekly during therapy.Eighty-three percent (118/143) of patients with lymphoma experienced hypoalbuminemia, which was considered moderate or severe in 17% (20/118) of the affected patients. For most patients, the nadir for hypoalbuminemia occurs one to two weeks after ONTAK administration. Serum albumin levels should be monitored prior to the initiation of each treatment course. Administration of ONTAK should be delayed until serum albumin levels are at least 3.0 g/dL ( see WARNINGS).Drug InteractionsNo clinical drug interaction studies have been conducted. However, in a single in vivo rodent study denileukin diftitox had no effect on P450 levels.Carcinogenesis, Mutagenesis, Impairment of FertilityThere have been no studies to assess the carcinogenic potential of denileukin diftitox. Denileukin diftitox showed no evidence of mutagenicity in the Ames test and the chromosomal aberration assay. There have been no studies to assess the effect of denileukin diftitox on fertility.Pregnancy Category CAnimal reproduction studies have not been conducted with ONTAK. It is also not known whether ONTAK can cause fetal harm when administered to a pregnant woman or affect reproductive capacity. ONTAK should be given to a pregnant woman only if clearly needed.Nursing MothersIt is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants, patients receiving ONTAK should discontinue nursing.Pediatric UseSafety and effectiveness in pediatric patients have not been established.Geriatric UseForty-nine percent (35/71) of the patients enrolled in the randomized two dose study were 65 years of age or older, and those patients had response rates similar to those seen in younger patients. The following adverse events (regardless of causality) tended to be more frequent and/or more severe in lymphoma patients who were 65 years of age or older: anorexia, hypotension, anemia, confusion, rash, nausea and/or vomiting.ADVERSE REACTIONSAdverse reactions are presented in Table 2. These data are based on adverse reactions observed in two clinical studies of 143 patients with lymphoma, including 105 patients with CTCL, treated at doses ranging from 3 to 31 mcg/kg/day.All patients experienced one or more adverse events. Twenty-one percent (30/143) of patients required hospitalization for drug-related adverse events; the most common reasons were eva luation of fever, management of vascular leak syndrome or dehydration secondary to gastrointestinal toxicity. Five percent of clinical adverse reactions were severe or life-threatening. The occurrence of adverse events tended to diminish in frequency after the first two courses, possibly related to antibody development.Table 2 Adverse Reactions Occurring in Lymphoma Patients (Frequency ≥5% of Patients) N = 143 patientsHypersensitivity(see WARNINGS)Vascular Leak Syndrome(see WARNINGS)Hypoalbuminemia( see PRECAUTIONS, Laboratory Tests)Infectious ComplicationsInfections of various types were reported by 48% (69/143) of the study population, of which 23% (16/69) were considered severe.Six of the 143 patients (4%) discontinued ONTAK therapy because of infections.Decreased lymphocyte counts (<900 cells/μL) occurred in 34% of lymphoma patients. In general, lymphocyte counts dropped during the dosing period (Days 1 to 5) and then returned to normal by Day 15. Smaller changes and more rapid recoveries were observed with subsequent courses.Infusion-associated Reactions( see WARNINGS) There are two distinct clinical syndromes associated with ONTAK infusion, an acute hypersensitivity-type symptom complex and a flu-like symptom complex. Overall, 69% of patients had infusion-related, hypersensitivity-type symptoms; for additional information, see WARNINGS. A flu-like syndrome was experienced by 91% of patients within several hours to days after ONTAK infusion. The symptom complex consists of one or more of the following: fever and/or chills (81%), asthenia (66%), digestive (64%), myalgia (17%) and arthralgia (8%). In the majority of patients, these symptoms were mild to moderate and responded to treatment with antipyretics and/or anti-emetics. Antipyretics and/or anti-emetics were used to relieve flu-like symptoms; however, the usefulness of these agents in ameliorating these toxicities or as prophylactic agents to decrease the incidence of the acute, flu-like toxicities has not been prospectively studied.GastrointestinalDiarrhea was reported in 29% (42/143) of the study population. The onset of diarrhea may be delayed and the duration can be prolonged. Dehydration, usually concurrent with vomiting or anorexia, occurred in 9% (13/143) of the patients. The majority of transient hepatic transaminase elevations occurred during the first course of ONTAK, were self-limited and resolved within two weeks.RashGeneralized maculopapular, petechial, vesicular bullous, urticarial and/or eczematous rashes, with both acute and delayed onset, have been reported in 34% (48/143) of patients. Antihistamines may be effective in relieving the symptoms, but more severe rashes may require the use of topical and/or oral corticosteroids.Cardiovascular SystemTwo patients, both of whom had known or suspected pre-existing coronary artery disease, sustained acute myocardial infarctions while on study. Ten additional patients (7%) experienced thrombotic events. Two patients with progressive disease and multiple medical problems experienced deep vein thrombosis. Another patient sustained a deep vein thrombosis and pulmonary embolus during hospitalization for management of congestive heart failure and vascular leak syndrome. One patient with a history of severe peripheral vascular disease sustained an arterial thrombosis. Six patients experienced less severe superficial thrombophlebitis. Thrombotic events were also observed in preclinical animal studies.Infrequent Serious Adverse EventsThe following serious adverse events occurred at an incidence of less than 5%: pancreatitis, acute renal insufficiency, microscopic hematuria, oral ulcer, hyperthyroidism including thyroiditis and thyrotoxicosis, and hypothyroidism.Post-MarketingThe following adverse reactions have been identified during post approval use of ONTAK. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.Special SensesSee WARNINGS: Visual LossOVERDOSAGEThere is no clinical experience with accidental ONTAK overdosage and no known antidote. At a dose of 31 mcg/kg/day, the dose-limiting toxicities were moderate-to-severe nausea, vomiting, fever, chills and/or persistent asthenia. Doses greater than 31 mcg/kg/day have not been eva luated in humans. If overdose occurs, hepatic and renal function and overall fluid balance should be closely monitored.DOSAGE AND ADMINISTRATIONONTAK is for intravenous (IV) use only. The recommended treatment regimen (one treatment cycle) is 9 or 18 mcg/kg/day administered intravenously for five consecutive days every 21 days. ONTAK should be infused over at least 15 minutes. If infusional adverse reactions occur ( see ADVERSE REACTIONS), the infusion should be discontinued or the rate should be reduced depending on the severity of the reaction. There is no clinical experience with prolonged infusion times (> 80 minutes).The optimal duration of therapy has not been determined; however, only 2% (1/51) of patients who did not demonstrate at least a 25% decrease in tumor burden prior to the fourth course of treatment subsequently responded.Special HandlingONTAK must be brought to room temperature, up to 25°C (77°F), before preparing the dose. The vials may be thawed in the refrigerator at 2 to 8°C (36 to 46°F) for not more than 24 hours or at room temperature for 1 to 2 hours. ONTAK must not be heated.The solution in the vial may be mixed by gentle swirling; do not vigorously shake ONTAK solution.After thawing, a haze may be visible. This haze should clear when the solution is at room temperature.ONTAK solution must not be used unless the solution is clear, colorless and without visible particulate matter.ONTAK must not be refrozen.Preparation and AdministrationUse appropriate aseptic technique in dilution and administration of ONTAK.Prepare and hold diluted ONTAK in plastic syringes or soft plastic IV bags. Do not use a glass container because adsorption to glass may occur in the dilute state.The concentration of ONTAK must be at least 15 mcg/mL during all steps in the preparation of the solution for IV infusion. This is best accomplished by withdrawing the calculated dose from the vial(s) and injecting it into an empty IV infusion bag. For each 1 mL of ONTAK from the vial(s), no more than 9 mL of sterile saline without preservative should then be added to the IV bag.The ONTAK dose should be infused over at least 15 minutes.ONTAK should not be administered as a bolus injection.Do not physically mix ONTAK with other drugs.Do not administer ONTAK through an in-line filter.Prepared solutions of ONTAK should be administered within 6 hours, using a syringe pump or IV infusion bag.Unused portions of ONTAK should be discarded immediately.How SuppliedONTAK is supplied as:150 mcg/mL sterile, frozen solution (300 mcg in 2 mL) in a sterile, single-use vialNDC 62856-603-01, 6 vials in a package.Store frozen at or below -10°C (14°F).1）