英文药名: Revlimid(Lenalidomide)

中文药名: 雷利米得（来那度胺胶囊）

品牌药生产商：Celgene公司（美国细胞基因公司）

药品介绍

FDA批准Revlimid用于治疗骨髓增生异常综合征美国食品药品管理局批准了美国细胞基因公司的来那度胺（lenalidomide/revlimid）。
Revlimid是一种具备抗血管增生和抗肿瘤活性的新一代免疫调节剂。它是目前治疗复发和难治性多发性骨髓瘤效果最佳的药品，临床试验的有效率超过50％（而对照组的有效率低于20％）。Revlimid(雷利度胺)也证明可以有效治疗5q染色体缺失的骨髓增生异常综合症（患此疾患的病人有严重的贫血并且需要输注红细胞来治疗）。67％的这种骨髓增生异常综合症病人用revlimid(雷利度胺)治疗后可以不再需要输血来治疗。 瑞法纳是一种具备抗血管增生和抗肿瘤活性的新一代免疫抑制剂。在两个三期临床试验中，雷利度胺被证明可以有效地治疗多发性骨髓瘤，治疗组的有效率超过50%，而对照组的有效率低于20%，用雷利度胺治疗的骨髓瘤病人的开始出现疾病进展的时间比对照组可以推迟一倍。

适应症

1．多发性骨髓瘤（Multiple Myeloma, MM)： 合用地塞米松(Dexamethasone)治疗已经接受过至少一种疗法的多发性骨髓瘤患者。
2．骨髓异常综合症(Myelodysplastic syndrome, MDS)：用于具有５ｑ缺失细胞遗传学异常的骨髓增生异常综合征所致的输血依赖性再生障碍性贫血患者的治疗。
 
用法用量

1．多发性骨髓瘤
每28天为一个周期，第1－21天，每天服用25mg瑞法纳。前4个周期的第1－4、9－12、17－20天，每天服用40mg的地塞米松，以后每个周期的第1－4天，每天服用40mg地塞米松。
 
2．骨髓异常综合症

推荐起始剂量为每天10mg。

用温开水一次口服，并在服药同时喝一大杯温开水。
不良反应

血小板减少, 中性粒细胞减少, 腹泻, 瘙痒, 皮疹.

警告
1、雷利度胺是沙利度胺的化学结构类似物，因此它可能会引起致命性的胎儿毒性作用。
2、中心粒细胞减少和血小板减少是用雷利度胺治疗的常见毒副作用。
3、多发性骨髓瘤病人用雷利度胺治疗伴随着深静脉血栓和肺动脉栓塞发病率增加的危险。

主要毒副作用
除上述三类毒副作用以外，其它常见的副作用包括胃肠道的反应和淋巴系统的障碍。

Revlimid为口服制剂，且毒性较低，该品获批后将成为骨髓增生异常综合征患者的治疗选择之一

品牌药生产商：Celgene公司（美国细胞基因公司）包装规格为：5mg  10mg.15mg.20mg的4个规格，该产品同时在香港，韩国，美国，欧盟上市。

MEDICATION GUIDE
REVLIMID® (lenalidomide)
Read the Medication Guide that comes with REVLIMID® before you start taking it and each time you get a new prescription. There may be new information. This Medication Guide does not take the place of talking to your healthcare professional about your medical condition or your treatment.
What is the most important information I should know about REVLIMID®?
• REVLIMID® is only for patients who understand and agree to all of the instructions in the REVASSIST® program.
• REVLIMID® may cause serious side effects including:
  1. birth defects
  2. low white blood cells and platelets
  3. blood clots in veins and in the lungs
1. Possible birth defects (deformed babies) or death of an unborn baby. Female patients who are pregnant or who plan to become pregnant must not take REVLIMID®.
REVLIMID® is similar to the medicine thalidomide (THALOMID®). We know thalidomide causes life-threatening birth defects. REVLIMID® has not been tested in pregnant women. REVLIMID® has harmed unborn animals in animal testing.
Female patients must not get pregnant:
  • for 4 weeks before starting REVLIMID®
  • while taking REVLIMID®
  • during dose interruptions of REVLIMID®
  • for 4 weeks after stopping REVLIMID®
  It is not known if REVLIMID® passes into semen, so:
  • Male patients, including those who have had a vasectomy, must use a latex condom during any sexual contact with a pregnant female or a female that can become pregnant while taking REVLIMID® and for 4 weeks after stopping REVLIMID®.
 If you get pregnant while taking REVLIMID®, stop taking it right away and call your healthcare professional. Female partners of males taking REVLIMID® should call their healthcare professional right away if they get pregnant. Healthcare professionals and patients should report all cases of pregnancy to:
  • FDA MedWatch at 1-800-FDA-1088, and
  • Celgene Corporation at 1-888-423-5436
2. Low white blood cells (neutropenia) and low platelets (thrombocytopenia). REVLIMID® causes low white blood cells and low platelets in most patients. You may need a blood transfusion or certain medicines if your blood counts drop too low. If you are being treated for del 5q myelodysplastic syndromes (MDS) your blood counts should be checked weekly during the first 8 weeks of treatment with REVLIMID®, and at least monthly thereafter. If you are being treated for multiple myeloma, your blood counts should be checked every 2 weeks for the first 12 weeks and then at least monthly thereafter.
3. An increased chance for blood clots in veins and in the lungs. Call your healthcare professional or get emergency medical care right away if you get the following signs or symptoms:
  • shortness of breath
  • chest pain
  • arm or leg swelling
What is REVLIMID® and what is it used for?
REVLIMID® is a medicine taken by mouth to treat certain patients who have myelodysplastic syndromes (MDS). Patients with MDS have bone marrow that does not produce enough mature blood cells. This causes a lack of healthy blood cells that can function properly in the body. There are different types of MDS. REVLIMID® is for the type of MDS with a chromosome problem where part of chromosome 5 is missing. This type of MDS is known as deletion 5q MDS. Patients with this type of MDS may have low red blood cell counts that require treatment with blood transfusions.
REVLIMID® is also used with dexamethasone to treat patients with multiple myeloma who have already had another treatment. Multiple myeloma is a cancer of plasma cells. Plasma cells are found in the bone marrow. Plasma cells produce a protein called antibodies. Some antibodies can attack and kill disease causing germs. Patients with this type of cancer may have low blood cell counts and immune problems giving them a higher chance for getting infections such as pneumonia. The bones can be affected leading to bone pain and breaks (fractures).
REVLIMID® can only be:
• prescribed by healthcare professionals who are registered in the RevAssist® program
• dispensed by a pharmacy that is registered in the RevAssist® program
• given to patients who are registered in the RevAssist® program and who agree to do everything required in the program
REVLIMID® has not been studied in children under 18 years of age.
Who should not take REVLIMID®?
• Do not take REVLIMID® if you are pregnant, plan to become pregnant, or become pregnant during REVLIMID® treatment. REVLIMID® may cause birth defects. See "What is the most important information I should know about REVLIMID®?"
• Do not take REVLIMID® if you are allergic to anything in it. See the end of this Medication Guide for a complete list of ingredients in REVLIMID®.
What should I tell my healthcare professional before taking REVLIMID®?
Tell your healthcare professional about all of your medical conditions, including if you:
• are pregnant or breastfeeding. REVLIMID® must not be used by women who are pregnant or breastfeeding.
Tell your healthcare professional about all the medicines you take including prescription and non-prescription medicines, vitamins and herbal supplements. It is possible that REVLIMID® and other medicines may affect each other causing serious side effects.
Know the medicines you take. Keep a list of them to show your healthcare professional and pharmacist.
How should I take REVLIMID®?
• Take REVLIMID® exactly as prescribed. You must also follow all the instructions of the RevAssist® program. Before prescribing REVLIMID®, your healthcare professional will:
 
  • explain the RevAssist® program to you
  • have you sign the Patient-Physician Agreement Form
 
You will not be prescribed REVLIMID® if you cannot agree to or follow all of the instructions of the RevAssist® program.

You will get no more than a 28-day supply of REVLIMID® at one time. This is to make sure you follow the RevAssist® program.
 
• Swallow REVLIMID® capsules whole with water once a day. Do not break, chew, or open your capsules.
 
• If you miss a dose of REVLIMID®, take it as soon as you remember that day. If you miss taking your dose for the entire day, go back to taking your regular dose the next day. Do not take 2 doses at the same time.
 
• If you take too much REVLIMID® or overdose, call your healthcare professional or poison control center right away.
 
• You will have regular blood tests during your treatment with REVLIMID®. If you are being treated for del 5q myelodysplastic syndromes (MDS) you should have your blood tested every week during your first 8 weeks of treatment, and at least monthly after that. If you are being treated for multiple myeloma, your blood counts should be checked every two weeks for the first 12 weeks and then at least monthly after that. Your healthcare professional may adjust your dose of REVLIMID® or interrupt your treatment based on the results of your blood tests and on your general condition.
 
• Female patients who can get pregnant will get regular pregnancy testing. 
 
• get a pregnancy test weekly for 4 weeks.
 
• Female patients who can become pregnant must agree to use 2 separate forms of effective birth control at the same time, 4 weeks before, while taking, and for 4 weeks after stopping REVLIMID®.
 
• Male patients, even those who have had a vasectomy, must agree to use a latex condom during sexual contact with a pregnant female or a female who can become pregnant.
 
What should I avoid while taking REVLIMID®?
 
• Do not get pregnant while taking REVLIMID® and for 4 weeks after stopping REVLIMID®. See "What is the most important information I should know about REVLIMID®?"
 
• Do not breastfeed while taking REVLIMID®. We do not know if REVLIMID® passes into your milk and harms your baby.
 
• Do not share REVLIMID® with other people. It may cause birth defects and other serious problems.
 
• Do not give blood while you take REVLIMID® and for 4 weeks after stopping REVLIMID®. If someone who is pregnant gets your donated blood, her baby may be exposed to REVLIMID® and may be born with birth defects.
 
• Male patients should not donate sperm while taking REVLIMID® and for 4 weeks after stopping REVLIMID®. If a female who is trying to become pregnant gets your sperm, her baby may be exposed to REVLIMID® and may be born with birth defects.
 
What are the possible side effects of REVLIMID®?
 
• REVLIMID® may cause serious side effects including:
 
  • birth defects
  • low white blood cells and platelets
  • blood clots in veins and in the lungs
 
See "What is the most important information I should know about REVLIMID®?"

Other common side effects of REVLIMID® are:
 
  • diarrhea
  • itching
  • rash
  • tiredness
 
Tell your healthcare professional about any side effect that bothers you or that does not go away.

These are not all the side effects with REVLIMID®. Ask your healthcare professional or pharmacist for more information.

How should I store REVLIMID®?

Store REVLIMID® at room temperature, 59° to 86°F (15° to 30° C).

Keep REVLIMID® and all medicines out of the reach of children.

General information about the safe and effective use of REVLIMID®

Medicines are sometimes prescribed for conditions that are not mentioned in Medication Guides. Do not take REVLIMID® for conditions for which it was not prescribed. Do not give REVLIMID® to other people, even if they have the same symptoms you have. It may harm them.

This Medication Guide provides a summary of the most important information about REVLIMID®. If you would like more information, talk with your healthcare professional. You can ask your healthcare professional or pharmacist for information about REVLIMID® that is written for health professionals. You can also call 1-888-423-5436 or visit www.REVLIMID.com.

What are the ingredients in REVLIMID®?

REVLIMID® (lenalidomide) capsules contain 5 mg, 10 mg, 15 mg or 25 mg of lenalidomide and are available as gelatin capsules for oral administration.

The inactive ingredients of REVLIMID® capsules are: lactose anhydrous, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate.

The 5 mg and 25 mg capsule shells contain gelatin, titanium dioxide and black ink. The 10 mg capsule shell contains gelatin, FD&C blue #2, yellow iron oxide, titanium dioxide and black ink. The 15 mg capsule shell contains gelatin, FD&C blue #2, titanium dioxide and black ink.
REVLIMID® (lenalidomide) in combination with dexamethasone is indicated for the treatment of multiple myeloma patients who have received at least one prior therapy.

REVLIMID® (lenalidomide) is indicated for patients with transfusion-dependent anemia due to Low- or Intermediate-1–risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities. 

Important Safety Information

WARNINGS:

1. POTENTIAL FOR HUMAN BIRTH DEFECTS.
Lenalidomide is an analogue of thalidomide. Thalidomide is a known human teratogen that causes severe life-threatening human birth defects. If lenalidomide is taken during pregnancy, it may cause birth defects or death to an unborn baby. Females should be advised to avoid pregnancy while taking REVLIMID® (lenalidomide).
Male Patients: It is not known whether lenalidomide is present in the semen of patients receiving the drug. Therefore, males receiving REVLIMID® (lenalidomide) must always use a latex condom during any sexual contact with females of childbearing potential even if they have undergone a successful vasectomy.
 
Special Prescribing Requirements 
Because of this potential toxicity and to avoid fetal exposure to REVLIMID® (lenalidomide), REVLIMID® (lenalidomide) is only available under a special restricted distribution program. This program is called “RevAssist®”. Under this program, only prescribers and pharmacists registered with the program can prescribe and dispense the product. In addition, REVLIMID® (lenalidomide) must only be dispensed to patients who are registered and meet all the conditions of the RevAssist® program.

2. HEMATOLOGIC TOXICITY (NEUTROPENIA AND THROMBOCYTOPENIA).
This drug is associated with significant neutropenia and thrombocytopenia. Eighty percent of patients with del 5q myelodysplastic syndromes had to have a dose delay/reduction during the major study. Thirty-four percent of patients had to have a second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study. Patients on therapy for del 5q myelodysplastic syndromes should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors. (see DOSAGE and ADMINISTRATION)

3. DEEP VENOUS THROMBOSIS AND PULMONARY EMBOLISM.
This drug has demonstrated a significantly increased risk of deep venous thrombosis (DVT) and pulmonary embolism (PE) in patients with multiple myeloma who were treated with REVLIMID® (lenalidomide) combination therapy. Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Patients should be instructed to seek medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. It is not known whether prophylactic anticoagulation or antiplatelet therapy prescribed in conjunction with REVLIMID® (lenalidomide) may lessen the potential for venous thromboembolic events. The decision to take prophylactic measures should be done carefully after an assessment of an individual patient’s underlying risk factors.

ADDITIONAL WARNINGS: HEMATOLOGIC TOXICITY

Multiple Myeloma

In the pooled multiple myeloma studies, Grade 3 and 4 hematologic toxicities were more frequent in patients treated with the combination of REVLIMID® (lenalidomide) and dexamethasone than in patients treated with dexamethasone alone

Patients on therapy should have their complete blood counts monitored every 2 weeks for the first 12 weeks and then monthly thereafter

Patients may require dose interruption and/or dose reduction

CONTRAINDICATIONS:

Pregnancy Category X:

Lenalidomide is contraindicated in pregnant women and women capable of becoming pregnant. When there is no alternative, females of childbearing potential may be treated with lenalidomide provided adequate precautions are taken to avoid pregnancy

Hypersensitivity:

REVLIMID® (lenalidomide) is contraindicated in any patients who have demonstrated hypersensitivity to the drug or its components

PRECAUTIONS:

Angioedema, Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis:

Angioedema and serious dermatologic reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive REVLIMID® (lenalidomide). REVLIMID® (lenalidomide) interruption or discontinuation should be considered for Grade 2-3 skin rash. REVLIMID® (lenalidomide) must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS or TEN is suspected, and should not be resumed following discontinuation for these reactions

Tumor Lysis Syndrome:

Lenalidomide has antineoplastic activity and therefore the complications of tumor lysis syndrome may occur. The patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken

Renal impairment:

Since lenalidomide is primarily excreted unchanged by the kidney, adjustments to the starting dose of REVLIMID® (lenalidomide) are recommended to provide appropriate drug exposure in patients with moderate or severe (CLcr < 60 mL/min) renal impairment and in patients on dialysis

Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it would be prudent to monitor renal function

Nursing mothers: It is not known whether REVLIMID® (lenalidomide) is excreted in human milk.
Because of the potential for adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the mother

ADVERSE REACTIONS:

Multiple Myeloma

In the REVLIMID® (lenalidomide)/dexamethasone treatment group, 151 patients (45%) underwent at least one dose interruption with or without a dose reduction of REVLIMID® (lenalidomide) compared to 21% in the placebo/dexamethasone treatment group

Of these patients who had one dose interruption with or without a dose reduction, 50% in the REVLIMID® (lenalidomide)/dexamethasone treatment group underwent at least one additional dose interruption with or without a dose reduction compared to 21% in the placebo/dexamethasone treatment group

Most adverse events and Grade 3/4 adverse events were more frequent in MM patients who received the combination of REVLIMID® (lenalidomide)/dexamethasone compared to placebo/dexamethasone

Other adverse events reported in multiple myeloma patients (REVLIMID® (lenalidomide)/dexamethasone vs dexamethasone/placebo): constipation (39% vs 19%), fatigue (38% vs 37%), insomnia (32% vs 37%), muscle cramp (30% vs 21%), diarrhea (29% vs 25%), neutropenia (28% vs 5%), anemia (24% vs 17%), asthenia (23% vs 25%), pyrexia (23% vs 19%), nausea (22% vs 19%), headache (21% vs 21%), peripheral edema (21% vs 19%), dizziness (21% vs 15%), dyspnea (20% vs 15%), tremor (20% vs 7%), decreased weight (18% vs 14%), thrombocytopenia (17% vs 10%), rash (16% vs 8%), back pain (15% vs 14%), hyperglycemia (15% vs 14%), and muscle weakness (15% vs 15%).

Myelodysplastic Syndromes

Thrombocytopenia (61.5%; 91/148) and neutropenia (58.8%; 87/148) were the most frequently reported adverse events observed in the del 5q MDS population

Other adverse reactions reported in del 5q MDS patients (REVLIMID® (lenalidomide)): diarrhea (49%), pruritus (42%), rash (36%), fatigue (31%), constipation (24%), nausea (24%), nasopharyngitis (23%), arthralgia (22%), pyrexia (21%), back pain (21%), peripheral edema (20%), cough (20%), dizziness (20%), headache (20%), muscle cramp (18%), dyspnea (17%), and pharyngitis (16%).

DOSAGE AND ADMINISTRATION:

Dosing is continued or modified based upon clinical and laboratory findings. Dosing modifications are recommended to manage Grade 3 or 4 neutropenia or thrombocytopenia or other Grade 3 or 4 toxicity judged to be related to REVLIMID® (lenalidomide)

For other Grade 3 or 4 toxicities judged to be related to REVLIMID® (lenalidomide), hold treatment and restart at next lower dose level when toxicity has resolved to less than or equal to Grade 2

Please see full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, PRECAUTIONS, and ADVERSE REACTIONS.

Revlimid(Lenalidomide)治疗MM的新药问世

Celgene公司用于治疗由骨髓异常综合症（MDS）导致的贫血药物Revlimid。
MDS患者体内的骨髓未产生足够的正常血细胞时，会导致身体多方面出现异常。MDS患者可以通过输血或输注血小板进行治疗，同时使用抗生素以防感染。在临床试验中，患者使用Revlimid进行平均44周的治疗之后，不再需要输血或输注血小板。
该药与会导致胎儿畸形的Thalidomide相似。FDA称，这种药在销售时应在标签中应加入警示信息，女性患者在使用这种药之前应进行怀孕检测并征得医生同意，开这种药的医生应进行相应登记。目前，相关人员正在通过动物试验确定怀孕期间服用Revlimid是否会导致胎儿畸形。
Celgene公司近日宣布，revlimid（曾用名：revimid）已被欧洲药品评审局(EMEA)定义为罕用药。Revlimid是新型的免疫调节剂，适应证范围广泛，包括多发性骨髓瘤、恶性血液疾病（譬如：骨髓增生异常综合征和转移性黑色素瘤）。
Revlimid作为罕用药享有EMEA授予的优惠措施。一旦revlimid获批上市，将在多发性骨髓瘤治疗领域享有10年市场独占期。EMEA将为revlimid在欧洲的集中申请程序提供便利，减少申请费用。
多发性骨髓瘤在常见的血癌中排名第二位，全球影响到15万人，每年新增患者大约7.4万。2002年5.7万人死于该病。2003年，revlimid被FDA认定为罕用药，进入快速审批通道，用于治疗骨髓瘤和骨髓增生异常综合征。骨髓增生异常综合征是一种血细胞生成障碍性疾病，最终将导致急性白血病，全球大约30万人患有该病。

Revlimid的Ⅱ期临床纳入70例患者。患者平均年龄为62岁，有23例已经接受骨髓干细胞移植，23例接受了沙利度胺治疗。研究中有57例患者参加了药物毒性评估，46例患者参加了对疗效的评估。Lenalidomide通过了FDA的批准。Celgene公司计划将该药商品名定为Revlimid.

——美国FDA批准Revlimid(lenalidomide)用于治疗骨髓增生异常综合症
FDA已批准药物Revlimid(通用名：lenalidomide)用于治疗患亚型骨髓增生异常综合症（Myelodysplastic Syndrome，MDS）的病人。该亚型是5q缺失染色体异常（deletion 5q cytogenetic abnormality）的MDS病人。
MDS是一种异常的集合，包括骨髓不能正常发挥功能，并且身体不能制造足够的正常血细胞。患MDS的病人可能需要血液和血小板输注及抗生素疗法以抗感染。在临床试验中，接受Revlimid治疗的病人不再需要输血，多数病人3个月内不需要输血。输血免除期平均持续44星期。
“该新产品将为遭受这种罕见病的病人提供非常需要的治疗选择，在一些病例中，这种罕见病被发现已发展成致命型白血病。”FDA的CDER主任Steven Galson医学博士称。
MDS可以在其他疾病的药物疗法或放射疗法后生成，或者在无已知起因的情况下生成。一些类型的MDS可以发展成急性骨髓白血病（AML），一种生成太多白细胞的癌症类型。
估计美国每年诊断出7000到12000个MDS新病例。尽管MDS在所有年龄群发生，但在60岁以上的人群中发病率最高。典型症状包括体虚、疲劳、感染、易瘀伤、出血及发烧。
Revlimid结构上类似于反应停（thalidomide），一种已知导致严重出生缺陷的药物。更多研究正在动物中进行，以解决当怀孕期间服用Revlimid是否也有导致出生缺陷的风险。尽管这些研究还在进行中，该公司正在一个称为RevAssist的旨在预防胎儿暴露的风险管理计划下销售Revlimid。
根据RevAssist，只有在该计划中登记的药剂师和处方者能处方和分发Revlimid。该计划要求病人，包括女性病人进行强制性孕期检测，以在开始服用Revlimid前提供知情同意。医生将检查孕期测试，限制处方为一个月的邮寄供应，并将任何孕期服用报给FDA。当进一步关于出生缺陷的动物测试结果完成时，FDA和生产商将再评价该风险管理计划。
Revlimid的标签将包括一个黑框警告（Black Box Warning）和一个关于胎儿暴露预防的药物指南（Medication Guide）。另外的黑框警告包括因血球计数抑制和血栓风险增加而可能需要降低剂量。常见的报道与Revlimid有关的副作用包括血小板减少（低血小板计数）、嗜中性白血球减少症（低白细胞记数）、腹泻、搔痒（痒）、皮疹和疲劳。
Revlimid由位于新泽西州Summit市的Celgene公司分销。