简介：

部分中文日达仙处方资料（仅供参考）
日达仙注射用粉针 Zadaxin 　　
商品名:
日达仙注射用粉针 Zadaxin 　　
通用名:
注射用胸腺肽а1 　　
英文名:Thymosin Alpha for Injection 　　
贮藏/有效期　　
储存于2-8°C，配备后马上注射。
日达仙是一种精制的、化学合成的胸腺肽α1消毒干粉制剂，用来治疗那些18岁以上的慢性乙型肝炎患者，治疗后可产生病毒性缓解并使转氨酶水平恢复正常。
性状
本药是一种精制的、化学合成的胸腺肽α1消毒干粉制剂，每一瓶含1.6 mg胸腺肽α1及50 mg甘露醇和用磷酸钠缓冲剂调整到pH=6.8。本药是一个乙酰化的多酞，有如下的氨基酸组合：Ac-Ser-Asp-Ala-Ala-Val-Asp-Thr-Ser-Ser-Glu-Ile-Thr-Thr-Lys-Asp-Leu- Lys-Glu-Lys-Lys-Glu-Val-Val-Glu-Val-Val-Glu-Glu-Ala-Glu-Asn-OH，其分子量是3108，PI是3.8。
药理作用
本药治疗慢性乙型肝炎或在增进免疫系统反应性方面的作用机理尚未完全查明。在多个不同的活体外试验中，本药促使致有丝分裂原激活后的外周血淋巴细胞的T细胞成熟作用，增加T细胞在各种抗原或致有丝分裂原激活后产生各种淋巴因子例如α、γ干扰素、白介素2和白介素3的分泌和增加T细胞上的淋巴因子受体的水平。它同时通过对T4辅助细胞的激活作用来增强异体和自体的人类混合的淋巴细胞反应。胸腺肽α1可能影响NK前体细胞的募集，该前体细胞在暴露于干扰素后变得更有细胞毒性。在活体内，胸腺肽α1能增强经刀豆球蛋白A激活后的小鼠淋巴细胞增加分泌白介素2，和增加白介素2受体的表达作用。

药代动力学
在900ug/m2剂量下，胸腺肽α1皮下注射约1小时后血浓度峰值是25-30 ug/mL。峰水平持续6小时而在随后18小时内回复到基础水平。连续每周两次注射15周后，胸腺肽α1的血浆基础值作很轻微地增加。

适应症
慢性乙型肝炎本药是用来治疗那些18岁以上的慢性乙型肝炎患者，且患者的肝病有代偿性和有乙肝病毒复制(血清HBV-DNA阳性)，在那些血清乙肝表面抗原阳性最少6个月，且有血清转氨酶升高的患者所做的研究显示，本药治疗后可产生病毒性缓解并使转氨酶水平恢复正常。在一些作出应答的患者，本药治疗可除去血清表面抗原。临床试验提示当本药与α干扰素联用时可能比单用本药或单用干扰素具有更高的应答率。作为免疫损害病者的免疫增强剂 免疫系统功能受到抑制者，包括接受慢性血液透析者和老年病患，本药可增强病者对病毒性疫苗，例如流感疫苗或乙肝疫苗的免疫应答。对血液透析患者所作研究显示，在接种流感疫苗后，应用本药作为佐剂者有65%病人产生抗流感病毒抗体滴度水平增高4倍以上，安慰剂组只有24%患者作出此反应。
用法用量
本药不应作肌注或静注。应使用随盒的1.0 mL注射用水溶解后马上皮注。
慢性乙型肝炎 本药治疗慢性乙肝的推荐量是每针1.6 mg，皮下注射，每周二次，两剂量大约相隔3-4日。治疗应连续6个月(52针)期间不得中断。假如本药是与α干扰素联合使用，应参考α干扰素处方资料内的剂量和注意事项，在联合应用的临床经验上，当两药物在同一日使用时，一般上在早上给予本药而在晚上给予干扰素。作为免疫损害病者的疫苗增强剂本药作为病毒性疫苗增强剂使用，推荐剂量是1.6 mg皮下注射，每周二次，每次相隔3-4日，疗程应持续4周(共8针) ，第一针应在疫苗后马上给予。
不良反应
一般来说，本药的耐受性良好。在超过990例各种年龄患者的临床试验，没有任何由于本药引起副作用的报告，在一早期试验使用与目前配方不同的Tα1制剂，3例出现注射处有灼热感和1例作短暂性失去肌质。所有4病例都是使用同一批号药物和当转用另一新批号时所有症状均消失。在一单剂量范围试验 ；一例接受2.4 mg/m2剂量后出现高热，2例接受4.8和9.6 mg/m2剂量后有恶心。这些剂量都是超过推荐剂量900 ug/m2。正如其它新药一样，某些极稀少发生的副作用可能在大量商业销售使用后被发现。而这些副作用在小规模临床试验下均未能观察出。慢乙肝病人接受本药治疗时，可能ALT水平短暂上升到基础值的两倍(ALT波动)以上，当ALT波动发生时本药通常继续使用，除非有肝衰竭的症状和预兆出现。
禁忌症
禁用于那些有对Tα1或注射液内其它成份有过敏历史的患者。因为本药治疗是通过增强患者的免疫功能，因此在那些行免疫抑制疗法的病人(例如器官移植受者)是禁用的，除非治疗带来的好处明显地大于危险。
注意事项
当用来治疗慢性乙肝时，治疗期间定期评估肝功能，包括血清ALT、白蛋白和胆红素。治疗完毕后应检测HBeAg、HBsAg、HBV-DNA和ALT酶，且应在治疗完毕后2、4和6个月检测，因为病人可能在治疗完毕后随访期内出现应答。
致癌、诱变作用及对生育力的损害 目前还没有长期的研究来说明其是否有致癌作用。诱变作用的研究显示本药无此副作用。
用药说明
孕妇及哺乳期妇女用药
动物生育研究显示在对照组及本药治疗组，其胚胎异常方面没有任何差异。目前还不知道本药是否对胚胎有伤害，或是能影响生育能力。故本药只能在十分必要时才给予孕妇使用。目前还未知道本药是否经由人乳排泄，因为很多药物均经人乳排出，因此本药使用在哺乳妇人时应特别注意。
儿童用药
在18岁以下患者，本药的安全性和有效性尚未确立。
药物过量
目前还没有任何关于在人体过量(治疗或意外)的报告。动物毒性试验显示在10 mg/kg剂量下(目前研究所用之最高量)没有任何副反应发生。
用药须知
与其它免疫调节药物同时给药时应谨慎。不应与任何其它药物混合作注射用。
妊娠分级
C级 ：动物研究证明药物对胎儿有危害性（致畸或胚胎死亡等），或尚无设对照的妊娠妇女研究，或尚未对妊娠妇女及动物进行研究。本类药物只有在权衡对孕妇的益处大于对胎儿的危害之后，方可使用。
规格与价格:1.6mg*2/合
制造商:赛生
日达仙是一种精制的、化学合成的胸腺肽α1消毒干粉制剂。具有治疗慢性乙型肝炎或在增进免疫系统反应性方面的作用。在多个不同的活体外试验中，本药促使致有丝分裂原激活后的外周血淋巴细胞的T细胞成熟作用，增加T细胞在各种抗原或致有丝分裂原激活后产生各种淋巴因子例如α、γ干扰素、白介素2和白介素3的分泌和增加T细胞上的淋巴因子受体的水平。它同时通过对T4辅助细胞的激活作用来增强异体和自体的人类混合的淋巴细胞反应。胸腺肽α1可能影响NK前体细胞的募集，该前体细胞在暴露于干扰素后变得更有细胞毒性。在活体内，胸腺肽α1能增强经刀豆球蛋白A激活后的小鼠淋巴细胞增加分泌白介素2，和增加白介素2受体的表达作用。
日达仙治疗慢性乙肝的情况
单用胸腺肽α1治疗慢性乙肝中内外有研究表明，单用日达仙治疗慢性乙肝，持续应答率（ALT复常+DNA转阴+HBeAg转阴）在37%左右，与单用干扰素相近，不过没有干扰素的毒副作用。
在中国台湾应用胸腺肽α1治疗慢性乙肝的临床研究表明，胸腺肽α1具有延迟的治疗效应。当胸腺肽α1治疗结束后，ALT有一过性升高，同时伴有HBeAg的血清转换，HBV DNA消失。
HBV DNA转阴率及血清转换优越性的研究结果表明：单用胸腺肽α1治疗慢性乙肝有长期疗效，而没有明显不良反应。对于晚期肝纤维化患者，高剂量的日达仙治疗效果较好

Drug Description

ZADAXIN®
Thymosin Alpha 1, Injection (thymalfasin)

ZADAXIN™ thymosin alpha 1 (thymalfasin) for subcutaneous injection is a purified sterile lyophilized preparation of chemically synthesized thymosin alpha 1 identical to human thymosin alpha 1. Thymosin alpha 1 is an acetylated polypeptide with the following sequence: Ac-Ser-Asp-Ala-Ala-Val-Asp-Thr-Ser-Ser-Glu-Ile-Thr-Thr-Lys-Asp-Leu-Lys-Glu-Lys-Lys-Glu-Val-Val-Glu-Glu-Ala-Glu-Asn-OH,and having a molecular weight of 3,108 daltons. The lyophilized preparation contains 1.6 mg thymosin alpha 1, 50 mg mannitol, and sodium phosphate buffer to adjust the pH to 6.8.

Product for Injection: Prior to administration, the lyophilized powder is to be reconstituted with 1 ml of the provided diluent (sterile water for injection). After reconstitution, the final concentration of ZADAXIN (thymalfasin) is 1.6 mg/ml.

Indications & Dosage

ZADAXIN thymosin alpha 1 (thymalfasin) is indicated as a monotherapy or combination therapy with interferon for the treatment of chronic hepatitis B. Pooled analysis of 3 randomized controlled trials comprising 223 patients was performed. Thymosin alpha 1 was administered twice weekly for 6 months. Follow-up assessments were performed at 12 months after completion of treatment (see table). In multiple studies, ZADAXIN (thymalfasin) was shown to have a delayed therapeutic response 12 months or longer after completion of therapy. A transient increase in ALT to more than twice baseline value (flare) can occur during ZADAXIN (thymalfasin) therapy. When ALT flare occurs, ZADAXIN (thymalfasin) should generally be continued unless signs and symptoms of liver failure are observed.

Efficacy of Thymosin Alpha 1 Monotherapy for Chronic Hepatitis B

ZADAXIN thymosin alpha 1 (thymalfasin) is indicated as a combination therapy with interferon for the treatment of chronic hepatitis C. Pooled analysis of 2 randomized controlled trials and 1 historical controlled trial comprising 121 ZADAXIN (thymalfasin) plus interferon, or interferon treated patients, was performed. Thymosin alpha 1 was administered at least twice weekly for 6 to 12 months and interferon was administered up to three times weekly for 6 to 12 months. Follow-up assessments were performed upon completion of treatment and at 6 months after completion of treatment (see table).

Pooled intent-to-treat analysis demonstrated sustained bio-chemical (ALT) response, defined as normal ALT 6 to 12 months after completion of treatment, observed in 22.4% of patients treated with combination therapy compared to 9.3% with interferon alone.

Efficacy of Thymosin Alpha 1 Combination Therapy with Interferon for Chronic Hepatitis C

ZADAXIN thymosin alpha 1 (thymalfasin) is indicated as a adjuvant therapy for chemotherapy-induced immune depression, immune insufficiency and immune suppression in patients with non-small cell lung carcinoma (NSCLC), malignant melanoma, hepatocellular carcinoma (HCC), breast cancer, non-Hodgkin's lymphoma (CHOP program), colorectal cancer, head and neck cancer, leukemia's, pancreatic carcinoma, and renal cell carcinoma. Clinical studies in over 1,000 patients with various types of cancer demonstrated that thymosin alpha 1 improved immunological parameters increased tumor response rates, and improved survival and quality of life (see table for some of these studies) Thymosin alpha 1 was either administered for 6 months or given between chemotherapy cycles for the duration of treatment.

Efficacy of Thymosin Alpha 1 as Adjuvant Therapy for Some Types of Cancer

ZADAXIN (thymalfasin) is intended for subcutaneous injection and should not be given intravenously. It should be reconstituted with 1.0 ml of the diluent provided, which consists of 1.0 ml Sterile Water for Injection, immediately prior to use. At the discretion of the physician, the patient may be taught to self-administer the medication.

The recommend-ed dose of ZADAXIN (thymalfasin) for chronic hepatitis B when used as a monotherapy or in combination with interferon (at the labeled dose and schedule for interferon) is 1.6 mg (900 µg/m2) administered subcutaneously twice a week for 6 to 12 months. Patients weighing less than 40 kg should receive a ZADAXIN (thymalfasin) dose of 40 µg/kg.

The recommended dose of ZADAXIN (thymalfasin) for cancer is 1.6 mg (900 µg/m2) administered subcuta neous-ly using various schedules for 6 months or given between chemotherapy cycles for the duration of treat-ment.

ZADAXIN (thymalfasin) is supplied in single use vials containing 1.6 mg of lyophilized thymosin alpha 1 per vial. Each carton contains two vials of ZADAXIN (thymalfasin) . Each carton also contains two ampoules of diluent for ZADAXIN (thymalfasin) , each containing 1.0 ml of Sterile Water for Injection, which are to be used for reconstituting the ZADAXIN (thymalfasin) .

Store ZADAXIN (thymalfasin) between 2° and 8°C (36° to 46° F). Reconstituted ZADAXIN (thymalfasin) should be used immediately.

REFERENCES

1. Mutchnick, M.G., Cummings, G.D., Hoofnagle, J.H., and D.A. Shafritz (1992) Thymosin: An innovative approach to the treatment of chronic hepatitis B, in Combination therapies Biological Response Modifiers in the Treatment of Cancer and Infectious Diseases, A.L Goldstein and E. Garaci, Editors. Plenum Publishing Corp: New York. p. 149-156

2. Mutchnick, M.G., Lindsay, K.L., Schiff, E.R., Cummings, G.D., and H.D. Appelman (1995) Thymosin alpha 1 treatment of chronic hepatitis B: a multicenter, randomized, placebo-controlled double blind study Gastroenterology 108(4): p. A1127

3. Lee, S.-D., D.-S. Chen, and Y.-F. Liaw (1997) Multicenter Study of Thymosin Alpha 1 in the Treatment of Chronic Hepatitis B. Data on file.

4. Chien, R.-N., Liaw Y.-F., Chen, T.-C, Yeh, C.-T., and I.-S. Sheen (1998) Efficacy of Thymosin α1 in Patients with Chronic Hepatitis B: A Randomized, Controlled TrialHepatology 27 (5) May 1998: p.1383-1387.

5. Niedzwiecki, D., Luo, D., Finn, D.S., Whiting, G.W., Connelly, J.E., Kumashiro, M., Allen, I.E. and S.D. Ross (1997) The efficacy of thymosin alpha 1 in chronic hepatitis B: a meta-analysis, Data on file.

6. Sherman, K.E., Sjogren, M., Greager, R.L. Damiano, M.A., Freeman, S., Lewey, S. Davis, D., Root, S., Weber, F.L., Ishak K.G., and Z.D. Goodman (1998) Combination Therapy with Thymosin alpha 1 and Interferon for the Treatment of Chronic Hepatitis C Infection: A Randomized, Placebo-Controlled Double-Blind Trial, Hepatology 27 (4): p. 1128-1135

7. Rasi, G., DiVirgilio, D., Mutchnick, M.G., Colella, F, Sinibaldi-Vallebona, P., Pierimarchi, P. Balli, B., and E. Garaci (1996) Combination thymosin α1 and lymphoblastoid interferon treatment in chronic hepatitis C, Gut 39: p. 679-683.

8. Moscarella, S ., Buzzelli, G., Monti M., Giannini, C, Careccia, G. Marrochi, E.M., Romanelli, R.G. and A.L. Zignego (1997) Treatment with interferon-alpha and thymosin alpha 1 of naive patients affected by chronic hepatitis C, in 4th International meeting on Hepatitis C Virus and Related Viruses. Kyoto, Japan

9. Sherman, K.E., and S.N. Sherman (1997) Pooled analysis of interferon + thymosin alpha-1 efficacy for the treatment of chronic hepatitis C. Second International Conference on Therapies for Viral Hepatitis, Kona, Big Island Hawaii, December 15-19: abstract #P50

10. Stefanini, G.F., et al., Alpha-1 thymosin and transcatheter arterial chemoembolization in hepatocellular carcinoma patients: a preliminary experience Hepatogastroenterology, 1988. 45 (19): p.209-215

11. Schulof, R.S., et al., A randomized trial to evaluate the immunorestorative properties of synthetic thymosin alpha 1 in patients with lung cancer. Journal of Biological Response Modifiers 1985 4: p. 147-158

12. Salvati, F, et al., Combined treatment with thymosin alpha 1 and low dose interferon-alpha after ifosfamide in non-small cell lung cancer: a phase II controlled trial. Anticancer Research 1996 16: p. 1001-1004

13. Rasi, G., Terzoli, E., lzzo, F., et al., Combined treatment with thymosin alpha 1 and low dose nterferon alpha after dacarbazine in advanced melanoma. Melanoma Research 2000 10: p 189-192

14. Lopez, M, et al., Biochemotherapy with thymosin alpha 1, inteluken-2 and dacarbazine in patients with metastatic melanoma: clinical and immunological effects. Annals of Oncology 1994 5: p. 741-746.

ZADAXIN thymosin alpha 1 (thymalfasin) for injection is manufactured for SciClone Pharmaceuticals International Ltd., by PATHEON Italia S.p.A., Monza, Italy. For further information contact SciClone Pharmaceuticals International Ltd. in Hong Kong at +852-2-510-0118, or in San Mateo, California, USA at +650-358-3456.

Side Effects & Drug Interactions

ZADAXIN (thymalfasin) is well tolerated. During clinical experience involving over 2000 individuals with various diseases distributed over all age groups, no clinically significant adverse reactions attributable to thymosin alpha 1 administration were reported (see table below).

Adverse experiences have been infrequent and mild, consisting primarily of local discomfort at the injection site, and rare instances of erythema, transient muscle atrophy, polyarthralgia combined with hand edema, and rash.

Interactions between ZADAXIN (thymalfasin) and other drugs have not been fully evaluated. Caution should be exercised when administering ZADAXIN (thymalfasin) therapy in combination with other immunomodulating drugs ZADAXIN (thymalfasin) should not be mixed with any other drug

Warnings & Precautions

None

Long term studies with thymosin alpha 1 have not been done to determine carcinogenicity. Mutagenicity studies with thymosin alpha 1 showed no adverse findings.

Teratology studies in mice and rabbits have shown no difference in fetal abnormalities in control animals and animals given thymosin alpha 1. It is not known whether ZADAXIN (thymalfasin) can cause fetal harm when administered to a pregnant woman or affect reproduction capacity. ZADAXIN (thymalfasin) should be given to a pregnant woman only if the benefits clearly outweigh the risks

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ZADAXIN (thymalfasin) is administered to a nursing woman.

Safety and effectiveness have not been established in patients below the age of 18 years.

Overdosage & Contraindications

There are no reported instances of deliberate or accidental overdosage in humans. Animal toxicology studies have shown no adverse reactions in single doses up to 20 mg/kg and in repeated doses up to 6 mg/kg/day for 13 weeks, which were the highest doses studied. The highest single dose tested in animals represents 800-times the clinical dose. Human studies have shown no adverse reactions at doses up to 16 mg biw for 4 weeks.

ZADAXIN (thymalfasin) is contraindicated in patients with a history of hypersensitivity to thymosin alpha 1 or any component of the injection. Because ZADAXIN (thymalfasin) therapy appears to work by enhancing the immune system, it should be considered contraindicated in patients who are being deliberately immunosuppressed, such as organ transplant patients, unless the potential benefits of the therapy clearly outweigh the potential risks

Clinical Pharmacology

Preclinical Pharmacology : The mechanism of action of ZADAXIN (thymalfasin) is not completely understood but is thought to be related to its immunomodulating activities, centered primarily around augmentation of T-cell function. In various in vitro assays, thymosin alpha 1 has been shown to promote T-cell differentiation and maturation; for example, CD4+, CD8+, and CD3+ cells have all been shown to be increased. Thymosin alpha 1 has also been shown to increase production of IFN-γ, IL-2, IL-3, and expression of IL-2 receptor following activation by mitogens or antigens, increase NK cell activity, increase production of migratory inhibitory factor (MIF), and increase antibody response to T-cell dependent antigens. Thymosin alpha 1 has also been shown to antagonize dexamethasone-induced apoptosis of thymocytes in vitro. In vivo administration of thymosin alpha 1 to animals immunosuppressed by chemotherapy, tumor burden, or irradiation showed that thymosin alpha 1 protects against cytotoxic damage to bone marrow, tumor progression and opportunistic infections, thereby increasing survival time and number of survivors. Many of the in vitro and in vivo effects of thymosin alpha 1 have been interpreted as influences on either differentiation of pluripotent stem cells to thymocytes or activation of thymocytes into activated T-cells.

The pharmacokinetics of thymosin alpha 1 were studied in adult volunteers at single subcutaneous doses ranging from 0.8 to 6.4 mg and in multiple dose studies of 5 to 7 days duration at subcutaneous doses ranging from 1.6 to 16 mg. Thymosin alpha 1 was rapidly absorbed with peak serum levels achieved at approximately 2 hours. A dose proportional increase was seen in serum levels for C max and AUC, and serum levels returned to basal levels by 24 hours after administration. The serum half-life was approximately 2 hours and there was no evidence of accumulation following multiple subcutaneous doses. Urine excretion ranged from 31% to 60% of the administered dose following single and multiple doses.

Medication Guide

Patients receiving ZADAXIN (thymalfasin) treatment should be directed in its use and informed of the benefits and risks associated with treatment. If home use is prescribed, a puncture-resistant container for the disposal of used syringes and needles should be supplied to the patient. Patients should be thoroughly instructed in the importance of proper disposal and cautioned against any reuse of syringes or needles. Patients should be instructed to store ZADAXIN (thymalfasin) refrigerated between 2°and 8°C (36° to 46° F). Reconstituted ZADAXIN (thymalfasin) should be used immediately