Contraindications for TARGRETIN
Pregnancy (Cat.X).

Warnings/Precautions for TARGRETIN
Be fully familiar with this drug's toxicity before use. Pancreatitis or risk of pancreatitis (eg, history of pancreatitis, uncontrolled hyperlipidemia, excess alcohol consumption, uncontrolled diabetes, biliary tract disease, drugs that can cause pancreatitis). Counsel patients monthly about need for contraception. Women of childbearing potential: obtain reliable negative pregnancy test within 1 week of start; repeat monthly. Start therapy on 2nd or 3rd day of normal menstrual period. Use two effective forms of contraception 1 month prior to, during, and for 1 month after therapy. Max 1 month/℞. Men with partners who are or may become pregnant: use condoms during and for at least 1 month after therapy. Monitor lipids before treatment, weekly until stable, then every 8 weeks; try to keep triglycerides <400mg/dL; treat hyperlipidemia, or reduce or suspend bexarotene if needed. Hepatic or renal insufficiency. Monitor liver function at baseline, 1, 2, and 4 weeks after start, then (if stable) at least every 8 weeks during therapy; consider suspending or discontinuing treatment if SGOT/AST, SGPT/ALT, or bilirubin >3xULN occurs. Monitor WBC with differential and thyroid function at baseline and during treatment; treat hypothyroidism if needed. Avoid sun and UV light. Nursing mothers: not recommended.

Interactions for TARGRETIN
Concomitant gemfibrozil: not recommended. Levels may be increased by CYP3A4 inhibitors (eg, ketoconazole, itraconazole, erythromycin, grapefruit juice). Levels may be reduced by CYP3A4 inducers (eg, rifampin, phenobarbital, phenytoin). May potentiate antihyperglycemics (eg, insulin, sulfonylureas, thiazolidinediones); monitor. May potentiate or be potentiated by protein-bound drugs. May antagonize tamoxifen, hormonal contraceptives, other CYP3A4 substrates. Limit Vit. A supplements to avoid toxicity. May increase CA125 assay values.

Adverse Reactions for TARGRETIN
Lipid abnormalities, headache, hypothyroidism, asthenia, leukopenia, anemia, rash, GI disturbances, peripheral edema, dry skin, exfoliative dermatitis, alopecia, insomnia, fatigue, abnormal liver function tests, pancreatitis, pruritus, photosensitivity.

How is TARGRETIN supplied?
Caps—100

Related Disease:
Lymphoma, cutaneous T-cell

---------------------------------------------------------------

Targretin® (bexarotene) gel 1%

Targretin^® (bexarotene) gel 1% is a prescription medicine used to treat the skin problems arising from a disease called cutaneous T-cell lymphoma (CTCL). Targretin gel is used for the topical treatment of skin lesions in patients with CTCL (Stage IA and IB) when other therapies have not worked or were not tolerated. A doctor must advise on the proper use of Targretin gel.

CTCL is a rare disease. In CTCL, T-cells become cancerous and affect the skin and the blood. Normally T-cells are used by the body to fight infections. CTCL symptoms are often mistaken for a rash, eczema or psoriasis.

In the United States, there are nearly 2,000 new cases annually and the annual incidence continues to rise and its cause is unknown.

Important Safety Information

• Do not use Targretin gel if you are pregnant or if you plan to become pregnant. Targretin gel may harm your fetus (unborn baby). You should contact your doctor immediately if you believe or suspect you are pregnant while you are using Targretin gel and until one month after you stop using Targretin gel.
  
• Do not use Targretin gel if you are allergic to this medicine.
  
• Tell your doctor if you are breastfeeding or are allergic to retinoid medications (for example: Accutane^® [isotretinoin], Soriatane^® [acitretin], Tegison [etretinate], Vesinoid^® [tretinoin].
  
• Because vitamin A in large doses may cause some side effects which are similar to those seen in patients applying Targretin gel, do not take more than the recommended daily dietary allowance of vitamin A (4000 to 5000 International Units). If you are not sure, ask your doctor or pharmacist.
  
• Your skin may become more sensitive to sunlight while using this medicine. Minimize exposure to sunlight and do not use a sunlamp.
  
• Do not apply Targretin gel to the healthy skin around the lesion and avoid application of the gel on or near mucosal surfaces of the body such as eyes, nostrils, mouth, lips, vagina, tip of the penis, rectum, or anus.
  
• Do not use insect repellents or other products containing DEET while using Targretin gel.
  
• Store Targretin gel at room temperature. Keep away from heat or flame.
  
• The most common side effects include redness, itching, burning, irritation and scaling at the area of application.

TARGRETIN GEL  软膏

Generic Name for TARGRETIN GEL
Bexarotene 1%; gel.

Legal Classification:
Rx

Pharmacological Class for TARGRETIN GEL
Retinoid.

Manufacturer of TARGRETIN GEL
Eisai Pharmaceuticals
 

Indications for TARGRETIN GEL
Cutaneous lesions in patients with CTCL (Stage IA and IB) who have refractory or persistent disease after other therapies or who have not tolerated other therapies.

Adult dose for TARGRETIN GEL
Apply once every other day for the 1st week; then increase frequency at weekly intervals to once daily, then twice daily, then 3 times daily, then 4 times daily based on lesion tolerance. Usual dosing frequency: 2–4 times daily; may reduce if application site toxicity occurs. Allow gel to dry. Do not occlude.

Children's dosing for TARGRETIN GEL
Not recommended.

Contraindications for TARGRETIN GEL
Pregnancy (Cat.X).

Warnings/Precautions for TARGRETIN GEL
Be fully familiar with this drug's toxicity before use. Counsel patients monthly about need for contraception. Women of childbearing potential: obtain reliable negative pregnancy test within 1 week of start; repeat monthly. Start therapy on 2nd or 3rd day of normal menstrual period. Use two effective forms of contraception 1 month prior to, during, and for 1 month after therapy. Max 1 month/℞. Men with partners who are or may become pregnant: use condoms during and for at least 1 month after therapy. Hepatic or renal insufficiency. Discontinue temporarily if severe irritation occurs. Avoid sun, UV light, and mucosal membranes. Nursing mothers: not recommended.

Interactions for TARGRETIN GEL
Avoid concomitant products that contain DEET. May be potentiated by CYP3A4 inhibitors (eg, ketoconazole, itraconazole, erythromycin, grapefruit juice). Caution with gemfibrozil. Limit Vit. A supplements to avoid toxicity.

Adverse Reactions for TARGRETIN GEL
Application site reactions (eg, rash, pruritus, skin disorders, pain, contact dermatitis).

How is TARGRETIN GEL supplied?
Gel—60g

Related Disease:
Lymphoma, cutaneous T-cell

DESCRIPTION

Targretin® (bexarotene) is a member of a subclass of retinoids that selectively activate retinoid X receptors (RXRs). These retinoid receptors have biologic activity distinct from that of retinoic acid receptors (RARs). Each soft gelatin capsule for oral administration contains 75 mg of bexarotene.

The chemical name is 4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) ethenyl] benzoic acid, and the structural formula is as follows:

Bexarotene is an off-white to white powder with a molecular weight of 348.48 and a molecular formula of C24H28O2. It is insoluble in water and slightly soluble in vegetable oils and ethanol, USP.

药品名称：贝沙罗汀
英文名：Bexarotene
商品名：Targretin&reg; （美国Ligand制药公司）
药理作用及作用机制：
贝沙罗汀是一种新型的合成维甲酸类似物，它可以选择性地与维甲酸类X受体（RXR）亚单位（RXRa，RXRb，RXRg）结合，因而可以选择性地发挥其功能并可降低临床用药的毒性；它可以抑制造血系统及鳞细胞恶性肿瘤细胞系的生长；它可以诱导一些恶性肿瘤细胞系的程序化死亡；它可以抑制人鳞细胞肿瘤的异种移植物；在鼠皮肤癌模型中它可以明显地抑制乳突淋瘤的生长；对于碳水化合物和脂质代谢研究有应用前景。
制剂的剂型和规格：
软胶囊：75毫克/粒；凝胶剂：10g：0.1g(含贝沙罗汀1%)
适应证及用法、用量：
用于治疗顽固性皮肤T-细胞淋巴瘤。
软胶囊剂： 300-400毫克/m2/日
凝胶剂用法：1次-4次/日
贝沙罗汀（Bexarotene）是由美国Ligand制药公司研制的新型抗癌药，其口服软胶囊和外用凝胶剂获FDA批准于2000年在美国上市，用于治疗皮肤T-细胞淋巴瘤。2001年在欧洲市场获准上市。该药未载入药典，我国也未进口，按新药审批办法，属于3.1类新药。
背景
贝沙罗汀是一种新型的RXR受体选择性的合成维甲酸类似物，它可以选择性地与维甲酸类X受体（RXR）亚单位（RXRa，RXRb，RXRg）结合，因而可以选择性地发挥其功能并可降低临床用药的毒性；它可以抑制造血系统及鳞细胞恶性肿瘤细胞系的生长；它可以诱导一些恶性肿瘤细胞系的程序化死亡；它可以抑制人鳞细胞肿瘤的异种移植物；在鼠皮肤癌模型中，它可以明显地抑制乳突淋瘤的生长；对于碳水化合物和脂质代谢研究有应用前景。目前贝沙罗汀用于治疗皮肤T-细胞淋巴瘤。口服制剂国外现正在开展治疗乳腺癌、牛皮癣、卡波氏肉瘤、肺癌的三期临床试验；凝胶剂现正开展治疗牛皮癣、顽固性手癣的三期临床试验，市场前景颇为广阔。
国外临床研究和使用情况
①．贝沙罗汀软胶囊的临床疗效
在第一项研究中，对至少两种治疗方法无反应或不能耐受的早期皮肤T-细胞淋巴瘤病人服用本品一日300mg/m2后，28例病人中有15例（54%）获得全部或部分反应（改善至少达50%以上），而更高剂量组反应率为10例/15例（67%），此外，一日300mg/m2组中有2例病人在25周内复发。
在第二项研究中，94例至少一种全身性治疗方法无效的晚期皮肤T-细胞淋巴瘤病人中，56例接受本品一日300mg/m2后有25例（45%）获得反应，另外35例接受较高剂量本品，有21例（55%）获得反应；低剂量组有反应的病人中有9例经中位时间19周复发。

在研究中，共有84例病人接受本品一日300mg/m2，其中3例（4%）获得完全反应，40例（48%）获得部分反应；在高剂量组中，完全反应率为9例/53例（17%）。

贝沙罗汀软胶囊作为生物活性制剂与化疗药物联合应用前景看好。目前，美国Ligand制药公司正在进行试验评价贝沙罗汀与传统化疗药在非小细胞肺癌中的疗效。另外，贝沙罗汀对恶性细胞株有诱导凋亡作用，在化学预防中起作用，目前正在验证贝沙罗汀在肺癌中的预防和治疗作用。
43例Ⅳ期肺癌病人联合服用贝沙罗汀、顺铂、长春瑞宾合计400mg/m2/day，18.6%d的病人获得反应。
该药对乳腺癌、牛皮癣等症状的Ⅱ、Ⅲ期临床试验。该药已被列为正在开发中的治疗牛皮癣的新药。
148例晚期乳腺癌病人（多中心研究）服用本品200mg/m2/day，经8-10周所有病人均获得反应。
50例中-重度牛皮癣病人（多中心研究）服用本品35-240mg/m2/day，经12-24周治疗，有46%的病人有>50%的改善。

②．贝沙罗汀凝胶的临床疗效：

贝沙罗汀凝胶用于治疗早期的或对其他治疗方法无反应或不能耐受的皮肤T-细胞淋巴瘤病人：在一项67名CTCL病人参加的Ⅰ/Ⅱ期临床研究中，局部应用贝沙罗汀凝胶至少4周，63％（42名）的病人显示有效，50％病人临床症状得到改善。21％病人（13名）完全显效。局部皮肤损害得到中等程度的改善一般在给药开始后24周，包括红斑、斑块隆起、脱屑以及搔痒。给药起效的中位时间为20周（范围为4-86周）。平均治疗时间为315天，接受治疗的最长时间为4.25年且尚在治疗中。疗效持续的中位时间为428天，最短的为2个月，范围为57-428天。给予病人治疗浓度的1％贝沙罗汀凝胶，87％的病人（58名）显示出对其有良好的局部耐受性。副作用主要发生在使用部位，而且轻微。包括皮疹（73%），搔痒（33%），疼（在应用部位的烧灼感24%），没有严重的副作用产生。

一项Ⅲ期临床试验（多中心），美国50例难治性早期皮肤T-细胞淋巴瘤患者，贝沙罗汀凝胶的有效率是44%（8%获完全有效）。中期治疗时间165天，最长治疗687天。副作用包括皮疹（72%），搔痒（32%），在应用部位疼（22%），皮肤失调（16%），接触性皮（12%）。

贝沙罗汀凝胶应用于患皮肤T-细胞淋巴瘤合并蕈样霉菌病患者的Ⅰ/Ⅱ临床试验，11/27（41%）获得疗效，病人对该品有很好的耐受性。
在美国，贝沙罗汀凝胶应用于卡波氏肉瘤或蕈样霉菌病病人的Ⅱ期临床试验，15%的病人获得反应。

贝沙罗汀凝胶应用于顽固性手癣：手部皮炎正在受到制药业越来越多的注意。目前，还没有专门批准用于这种适应症的治疗药，现有的治疗选择仅限于润肤剂和局部应用类固醇或口服皮质类固醇、环孢素、光治疗或用于严重病例的放射治疗。然而，这种病相当普遍，如北欧的普遍性达到6%至11%。Ligand公司正计划对贝沙罗汀(1%)凝胶局部用于顽固性手癣的Ⅱ/Ⅲ期临床试验。它的Ⅰ/Ⅱ期临床试验观察了55例严重长期手部皮炎病人单独局部用贝沙罗汀(1%)凝胶、局部用贝沙罗汀(1%)凝胶加莫米松(mometasone furoate)和局部用贝沙罗汀(1%)凝胶加氢化可的松(hydrocortisone)的疗效比较。结果表明，贝沙罗汀(1%)凝胶加莫米松效果最好，医生固定评价(PSA)反应率(至少90％改进)，PGA反应率(至少50％改进)分别为46％和77％。单独用贝沙罗汀(1%)凝胶效果次之(PSA和PGA分别为39％和79％)。而与可的松联用(分别为21％和50％)。据认为，贝沙罗汀凝胶对严重手部皮炎有明显改善作用。
贝沙罗汀凝胶应用于牛皮癣病人：UVB光线疗法是经FDA批准治疗牛皮癣的方法，而该方法对厚的鳞屑效果不好，贝沙罗汀(1%)凝胶能使厚鳞屑变薄，使紫外线能够很好的穿过起抑制效果，UBV与贝沙罗汀(1%)凝胶合并治疗有望提高疗效。贝沙罗汀凝胶是FDA批准用于治疗T-细胞淋巴瘤的局部治疗药，并且正在进行治疗牛皮癣的临床。1％贝沙罗汀凝胶加NBUBV治疗损伤部位，有意义的临床改善率是67.6%；空白凝胶加NBUBV治疗损伤部位，改善率是48.2%。因为所用病历损伤面积小，使用非统计参数的Wilcoxon rank-sum test来分析两个组得分差异。1％贝沙罗汀凝胶加NBUBV疗效的评分大于空白凝胶对照组，有统计意义(P=0.04)，通过治疗，病灶的斑块隆起、红斑、硬化大幅减少，副作用轻微，仅仅是皮疹和皮肤刺激。进一步的临床研究已被批准。
贝沙罗汀的药物半衰期很短，避免了药物在体内积蓄。口服软胶囊具有生物利用度高，密封安全，含量精确，外型美观等特点。其凝胶剂直接作用于患病皮肤，具有不油腻，易于涂布、使用安全，用药方便的特点。