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注射用维多珠单抗Entyvio(vedolizumab)使用说明

 

-溃疡性结肠炎或克罗恩病的最新治疗药
2014年5月20日FDA批准了Takeda制药公司Entyvio (vedolizumab，靶向α4β7整合素的人源单克隆抗体)注射液，用于既往接受过至少1种标准疗法（皮质激素、免疫调节剂、anti-TNF-α）但响应不足的中重度溃疡性结肠炎和克罗恩病患者。对于这两个适应症，FDA咨询委员会曾在2013年12月9日分别给出了21:0和21:1的投票结果。
溃疡性结肠炎是一种慢性疾病，会导致腹部不适、胃肠道出血及腹泻，美国大约有62万例患者。2项涉及约900例对标准疗法响应不足患者的临床研究评估了Entyvio对溃疡性结肠炎的疗效和安全性，考察指标包括排便频率、直肠出血、内窥镜检查结果和总体评分等。结果显示，Entyvio组实现并维持临床应答、临床缓解的患者比例均显著高于安慰剂组，结肠内窥镜检查结果也有明显改善。
克罗恩病也是一种慢性炎性肠病，会引起炎症、腹部隆肿、消化道刺激，美国确诊的克罗恩病患者超过50万人。3项涉及1500例对标准疗法响应不足患者的临床研究证实了Entyvio对克罗恩病的疗效和安全性，Entyvio组实现临床响应、临床缓解以及无皮质激素临床缓解的患者比例明显高于安慰剂组。
Entyvio最常见的治疗相关不良反应包括头痛、关节痛、恶心及发热，最严重的治疗相关风险包括重度感染、超敏反应和肝毒性。
注射用ENTYVIO(维多珠单抗[vedolizumab])，为静脉使用
美国初次批准：2014
适应证和用途
ENTYVIO是一种整合素受体拮抗剂适用为：
成年溃疡性结肠炎(UC)
⑴ 成年有中度至严重活动性UC患者，对一种肿瘤坏死因子(TNF)阻滞剂或免疫调节剂已反应不足，失去反应，或不能耐受；或对皮质激素已反应不足，不能耐受，或显示依赖性：
⒈ 诱导和维持临床反应
⒉ 诱导和维持临床缓解
⒊ 改善内窥镜粘膜外观
⒋ 实现无皮质激素缓解
成年克罗恩病[ Crohn's Disease](CD)
⑵有中度至严重活动性CD成年患者，对一种TNF阻滞剂或免疫调节剂已反应不足，失去反应，或不能耐受；或对皮质激素已反应不足，不能耐受，或显示对依赖性：
⒈ 实现临床反应
⒉ 实现临床缓解
⒊ 实现无皮质激素缓解
剂量和给药方法
⑴ 在UC和CD中推荐剂量：在零，2和6周时，历时约30分钟静脉输注300mg而其后每8周。
⑵ 在第14周时没有显示治疗获益的患者终止ENTYVIO。
⑶ 必须用无菌注射用水重建ENTYVIO冻干粉和给药前必须稀释在250mL无菌0.9%氯化钠。
⑷ 在重建和稀释4个小时内给予输注溶液。
⑸ 在开始用ENTYVIO治疗前(按照当前免疫接种指导原则)给予患者所有最新免疫接种。
剂型和规格
注射用：300mg冻干维多珠单抗在一个单次使用20mL小瓶。
禁忌证
对ENTYVIO或其任何赋形剂曾有已知严重或严重程度超敏性反应患者。
警告和注意事项
⑴ 超敏性反应(包括过敏性反应)：如发生过敏反应或其他严重过敏反应终止ENTYVIO。
⑵ 感染：有活动性，严重感染患者建议不用ENTYVIO治疗直至感染被控制。当用ENTYVIO治疗发生严重感染患者中考虑不给ENTYVIO。
⑶ 进行性多灶性脑白质病：尽管在ENTYVIO临床试验没有观察到病例，用另一种整合素受体拮抗剂治疗患者中曾导致JCV[乳头多瘤空泡病毒]感染导致进行性多灶性脑白质病(PML)和死亡。不能除外PML的风险。监视患者任何新神经学体征和症状或恶化。
不良反应
最常见不良反应(发生率≥3%和≥1%较高于安慰剂)：鼻咽炎，头痛，关节炎，恶心，发热，上呼吸道感染，疲乏，咳嗽，支气管炎，流感，背痛，皮疹，瘙痒，窦炎，口咽痛，和肢体疼痛 

 

Entyvio

Generic Name: Vedolizumab
Class: GI Drugs, Miscellaneous
Chemical Name: Anti-(human integrin LPAM-1 (lymphocyte Peyer's patch adhesion molecule 1)) (human-Mus musculus heavy chain) immunoglobulin G1 disulfide with human-Mus musculus κ-chain dimer
Molecular Formula: C6528H10072N1732O2042S42
CAS Number: 943609-66-3

 

(ve doe LIZ ue mab)

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous [preservative free]:

Entyvio: 300 mg (1 ea) [contains mouse (murine) and/or hamster protein, polysorbate 80]

 

Entyvio Gastrointestinal Agent, MiscellaneousMonoclonal AntibodyMonoclonal Antibody, Selective Adhesion-Molecule Inhibitor

Vedolizumab is a humanized monoclonal antibody that binds to the alpha4beta7 integrin and blocks the interaction of alpha4beta7 integrin with mucosal addressin cell adhesion molecule-1 (MAdCAM-1) and inhibits the migration of memory T-lymphocytes across the endothelium into inflamed gastrointestinal parenchymal tissue. The interaction of the alpha4beta7 integrin with MAdCAM-1 has been implicated as an important contributor to the chronic inflammation that is a hallmark of ulcerative colitis and Crohn disease.

Vd: 5 L

25 days (serum, at 300 mg dosage)

Crohn disease: Treatment of moderately to severely active Crohn disease in patients who have had an inadequate response with, lost response to, or were intolerant to inhibitors of tumor necrosis factor-alpha (TNF-alpha) blocker or immunomodulator; or had an inadequate response with, were intolerant to, or demonstrated dependence on corticosteroids.

Ulcerative colitis Treatment of moderately to severely active ulcerative colitis in patients who have had an inadequate response with, were intolerant to inhibitors of tumor necrosis factor-alpha (TNF-alpha) blocker or immunomodulator; or had an inadequate response with, were intolerant to, or demonstrated dependence on corticosteroids.

Serious or severe hypersensitivity to vedolizumab or any component of the formulation

Canadian labeling: Additional contraindications (not in US labeling): Patients with active severe infections or opportunistic infections.

Note: Prior to initiating treatment, all patients should be brought up to date with all immunizations according to current immunization guidelines.

Crohn disease or ulcerative colitis: IV: 300 mg at 0, 2, and 6 weeks and then every 8 weeks thereafter. Discontinue therapy in patients who show no evidence of therapeutic benefit by week 14.

Refer to adult dosing.

There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

There are no dosage adjustments provided in the manufacturer's labeling (has not been studied). Discontinue use with jaundice or signs/symptoms of hepatic injury.

Reconstitute at room temperature with 4.8 mL of sterile water for injection. Gently swirl vial for at least 15 seconds; do not vigorously shake or invert. Allow the solution to sit for up to 20 minutes at room temperature to allow for reconstitution and for any foam to settle; the vial can be swirled and inspected for dissolution during this time. If not fully dissolved after 20 minutes, allow another 10 minutes for dissolution. Do not use the vial if the drug product is not dissolved within 30 minutes. Solution should be clear or opalescent, colorless to light brownish yellow and free of visible particulates. Do not administer reconstituted solution showing uncharacteristic color or containing particulates.

Prior to withdrawing the reconstituted vedolizumab solution from the vial for dilution, gently invert vial 3 times. Add the 5 mL (300 mg) of reconstituted vedolizumab solution to 250 mL of sterile sodium chloride 0.9% and gently mix the infusion bag. Once reconstituted and diluted, use the infusion solution as soon as possible.

IV: Infuse over 30 minutes. Do not administer by IV push or bolus. Following infusion , flush with 30 mL of sterile 0.9% sodium chloride injection. Observe patients during infusion (until complete) and monitor for hypersensitivity reactions; discontinue if a reaction occurs.

Refrigerate unopened vials at 2°C to 8°C (36ºF to 46ºF). Retain in original package to protect from light. Following reconstitution and dilution, the infusion solution may be stored for up to 4 hours at 2°C to 8°C (36ºF to 46ºF). Do not freeze. Discard any unused portion.

Anti-TNF Agents: May enhance the adverse/toxic effect of Vedolizumab. Avoid combination

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Belimumab: Monoclonal Antibodies may enhance the adverse/toxic effect of Belimumab. Avoid combination

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Natalizumab: Vedolizumab may enhance the adverse/toxic effect of Natalizumab. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Travelers' Diarrhea and Cholera Vaccine: Vedolizumab may diminish the therapeutic effect of Travelers' Diarrhea and Cholera Vaccine. Management: Administer travelers' diarrhea andl cholera vaccine prior to initiation of therapy with vedolizumab. Consider therapy modification

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation.Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

>10%:

Central nervous system: Headache (12%)

Immunologic: Antibody development (4% to 13%; neutralizing: 2%)

Neuromuscular & skeletal: Arthralgia (12%)

Respiratory: Nasopharyngitis (13%)

1% to 10%:

Central nervous system: Fatigue (6%)

Dermatologic: Pruritus (3%), skin rash (3%)

Gastrointestinal: Nausea (9%)

Hepatic: Increased serum ALT (≥3 x ULN: <2%), increased serum AST (≥3 x ULN: <2%)

Infection: Influenza (4%)

Neuromuscular & skeletal: Back pain (4%), limb pain (3%)

Respiratory: Upper respiratory tract infection (7%), cough (5%), bronchitis (4%), oropharyngeal pain (3%), sinusitis (3%)

Miscellaneous: Fever (9%), infusion related reaction (4%)

<1% (Limited to important or life-threatening): Hepatitis, hypersensitivity reaction, infection (including anal abscess, sepsis, tuberculosis, salmonella sepsis, listeria meningitis, giardiasis, cytomegaloviral colitis), malignant neoplasm (excluding dysplasia and basal cell carcinoma)

Concerns related to adverse effects:

• Hypersensitivity reactions: Hypersensitivity reactions have been reported including anaphylaxis. Allergic reactions including dyspnea, bronchospasm, urticaria, flushing, rash, and increased blood pressure and heart rate have also been observed. Symptom onset may vary from during the infusion, immediately post-infusion, to several hours post-infusion. If serious reactions occur, discontinue administration immediately.

• Infections: Use may be associated with an increased risk for developing infections; most commonly reported infections included upper respiratory and nasal mucosa. Serious infections have also been reported in patients treated, including anal abscess, sepsis (some fatal), tuberculosis, salmonella sepsis, Listeria meningitis, giardiasis, and cytomegaloviral colitis. Therapy is not recommended in patients with uncontrolled, active, severe infections. If a patient develops a serious infection, consider discontinuing therapy. Use with caution in patients with a history of recurring severe infections. Screening for tuberculosis should be considered.

• Liver injury: Elevations of transaminase and/or bilirubin have been reported in patients receiving vedolizumab. Discontinue therapy in patients with jaundice or other evidence of significant liver injury such as fatigue, anorexia, right upper abdominal discomfort, or dark urine.

• Progressive multifocal leukoencephalopathy: Integrin receptor antagonists have been associated with progressive multifocal leukoencephalopathy (PML), a rare and often fatal opportunistic infection of the central nervous system caused by the John Cunningham (JC) virus. Monitor patients for any new onset or worsening of neurological signs and symptoms including progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. Symptoms may progress over days to weeks and can lead to death or severe disability in weeks to months. If PML is suspected withhold therapy and refer to a neurologist; if confirmed, discontinue therapy permanently.

Other warnings/precautions:

• Immunizations: Patients should be brought up to date with all immunizations according to immunization guidelines before initiating therapy. Live vaccines should not be given concurrently unless the benefits outweigh the risks; there are no data on the secondary transmission of infection by live vaccines with vedolizumab. Non-live vaccines may be given concurrently.

Observe patients during infusion (until complete) and monitor for hypersensitivity reactions; LFTs; tuberculosis screening according to local practice; signs/symptoms of infection; any new onset or worsening of neurological signs and symptoms

B

Adverse events have not been observed in animal reproduction studies. Monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester. Any adverse pregnancy effect would likely be greater during the second and third trimesters of pregnancy.

Health care providers are encouraged to enroll women exposed to vedolizumab during pregnancy in a pregnancy exposure registry. Information about the registry can be obtained by calling 1-877-825-3327.

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience back pain, common cold symptoms, joint pain, nausea, rhinitis, pharyngitis, extremity pain, or loss of strength and energy. Have patient report immediately to prescriber signs of infection, signs of infusion reaction, signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), shortness of breath, wheezing, coughing, dizziness, flushing, tachycardia, arrhythmia, severe headache, or signs of progressive multifocal leukoencephalopathy (confusion, depression, trouble with memory, behavioral changes, change in strength on one side, trouble speaking, change in balance, or vision changes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.