英文药名: Tasigna(Nilotinib Capsules)

中文药名: 达希纳(尼洛替尼胶囊)

生产厂家: Novartis

药品介绍；

2010年6月17日，FDA批准了尼洛替尼（达希纳胶囊，诺华公司生产），一种口服的激酶抑制剂，用于Ph染色体阳性的慢性期慢性粒细胞白血病成年人患者一线治疗，推荐剂量是300mg bid。Tasigna最早是在2007年10月被批准用于对于前期治疗（包括伊马替尼）耐药的慢性期和加速期慢性粒细胞的白血病成年患者的治疗。

【药品名称】 达希纳
【药品名称】尼洛替尼胶囊
【产品规格】200mg*112粒
【生产企业】Novartis诺华公司

【适应症】
用于对既往治疗（包括伊马替尼）耐药或不耐受的费城染色体阳性的慢性髓性白血病（Ph+ CML）慢性期或加速期成人患者。

【用法用量】
本品的初始治疗应该在对CML患者有治疗经验的医师指导下进行。
对伊马替尼耐药的定义是：伊马替尼治疗3个月未能达到完全血液学缓解、治疗6个月未能达到细胞遗传学缓解或治疗12个月未能达到主要细胞遗传学缓解，失去已经获得的完全血液学缓解或细胞遗传学缓解、疾病进展或出现耐药的Bcr-Abl激酶突变。
对伊马替尼不耐受的定义是：尽管采用了最佳支持治疗，在任何剂量和/或治疗期间，患者仍由于3或4级不良事件的持续存在而中止伊马替尼治疗 ；或者，尽管采用了最佳支持治疗，与伊马替尼治疗相关的2级不良事件仍持续时间≥1个月，或反复发生超过3次，不论是否剂量减少或中止治疗。
推荐剂量为每日2次，每次400 mg，间隔约12小时，饭前至少1小时之前或饭后至少2小时之后服用。
只要患者持续受益，本品治疗应持续进行。
胶囊应用水完整吞服，不应咀嚼或吮吸，不应打开胶囊。手接触胶囊后应立即清洗。小心不要吸入胶囊中的任何粉末（比如胶囊损坏），也不要让药粉接触皮肤或粘膜。如果发生皮肤接触，用肥皂和水清洗局部。如果眼睛接触了药粉，用水冲洗。如果胶囊中的药粉撒出，应该用手套和可弃去的湿毛巾擦去，置于密封的容器中正确丢弃。
剂量调整 ：如果心电图显示QTc>480毫秒，则应停止服用本品，及时检测血清钾和镁，如果血清钾和镁低于正常值低限，则应补液使之达到正常范围，并必须检查合并用药的情况；如果QTcF恢复到<450毫秒，并与基线值相差不超过20毫秒，则可在2周内恢复本品先前的剂量 ；如果2周后，QTcF在450-480毫秒之间，则应降低本品剂量至每日1次400 mg；如果降低剂量至每日400 mg后，QTcF仍>480毫秒，则应停止使用本品。任何1次的剂量调整，均应在7天后复查心电图。
如果出现血液学毒性（加速期：ANC<0.5×109/升或血小板<10×109/升；慢性期 ：ANC<1.0×109/升或血小板<50×109/升），应暂停本品的使用，如果2周内加速期患者血象恢复至ANC>1.0×109/升或血小板>20×109/升以上，或者慢性期患者血象恢复至ANC>1.0×109/升或血小板>50×109/升，则可以重新按照初始剂量服用。如果血象仍然低，可考虑减低本品剂量，每日服用1次，每次400 mg。
如果出现有显著临床意义的中度或严重的非血液学毒性，应该中止服药 ；一旦毒性缓解，可以恢复每日1次，每次400 mg的剂量。如果临床上适合，可考虑将剂量重新增加至每日2次，每次400 mg。
血清脂肪酶升高：如果出现3-4级血清脂肪酶升高，剂量应降低至每日1次，每次400 mg或中止服药。应每月监测血清脂肪酶。
胆红素和肝转氨酶升高：如果出现3-4级胆红素升高，剂量应降低至每日1次，每次400 mg或中止服药。应每月监测胆红素和转氨酶。
*特殊剂量推荐
儿童和青少年：尚无在儿童或青少年中进行的临床研究。所以不推荐用于治疗小于18岁的患者。
老年患者：对超过65岁的患者，不需要进行特殊的剂量调整。
肾功能不全的患者：尚无在肾功能不全的患者中进行的临床研究。
本品及其代谢产物只有少部分经肾排泄，所以预计肾功能不全的患者并不会出现总体清除率的降低。对肾功能不全的患者，不需要进行剂量调整。
肝功能不全的患者：没有在肝功能不全的患者中对本品进行过研究。所以对转氨酶超过正常值2.5倍或胆红素升高超过正常值1.5倍的肝功能不全患者，不推荐本品治疗。

【药物过量】
尚无药物过量的病例报告。当过量发生时，应密切观察患者并给予适当的支持治疗。
*服药与进食
空腹服用 (饭前至少1小时之前或饭后至少2小时之后用水完整吞服。).

【禁忌】
对本品活性物质或任何赋形剂成份过敏者 ；伴有低钾血症、低镁血症或长QT综合征的患者禁用。

【注意事项
骨髓抑制：本品能引起3/4级血小板减少、中性粒细胞减少和贫血。在最初的2个月，应每隔2周做一次全血细胞计数，之后可每个月检测一次，或者在有临床指征时进行。骨髓抑制一般是可逆的，可以通过暂时停用本品或降低剂量来控制。
QT间期延长：已经显示本品能延长心室复极，可通过心电图上的QT间期检测出来，呈剂量依赖性。QT间期延长能够引起尖端扭转型室性心动过速，可能引起昏厥、惊厥和/或死亡。
本品禁用于低钾血症和低镁血症或长QT综合征的患者。在使用本品之前，应纠正低钾血症和低镁血症，并在治疗期间定期监测电解质。避免使用已知延长QT间期的药物和强CYP 3A4抑制剂。在基线时、服药开始7天后、有临床指征时定期做心电图，在剂量调整之后也需要做心电图。
猝死：在一项正在进行的临床研究中，接受本品治疗的867例患者中有5例猝死的报道（0.6%）。在扩展用药项目中观察到了相似的发生率。与尼洛替尼相关的早发猝死提示这可能与心室复极化的异常有关。
血清脂肪酶升高：使用本品会引起血清脂肪酶升高。建议慎用于有胰腺炎病史的患者。应该定期监测血清脂肪酶水平。
肝功能异常：使用本品可能引起胆红素、ALT/AST和碱性磷酸酶升高，应定期进行肝功能检测。
电解质异常：使用本品可能引起低磷、低钾、高钾、低钙和低钠血症。在开始使用本品之前必须纠正电解质异常，治疗过程中应定期监测电解质。

【药物相互作用】
避免使用CYP 3A4强诱导剂或延长QT间期的药物。如果患者必须使用这样的药物治疗，应该考虑停止本品的服用 ；如果不能停止本品的治疗，并需要同时服用上述药物时，应密切监测QT间期。见[药物相互作用]。
食物的作用：进食会使本品的生物利用度增加。本品不应与食物一起服用。服药前2小时之内和服药后1小时之内避免进食。应该避免进食葡萄柚汁和其它已知的有抑制CYP 3A4作用的食物。
肝损害：在肝损害的患者中尚未进行过对本品的研究。临床研究已经排除了ALT和/或AST>2.5（或> 5，如果与疾病相关的话）倍正常值上限和/或总胆红素>1.5倍正常值上限的患者。本品主要经肝代谢，因此，肝损害患者的本品暴露量可能增加，推荐在肝损害的患者中谨慎使用，并且应该密切监测这些患者的QT间期延长。
乳糖：本品含有乳糖，所以对于有遗传性半乳糖不耐受问题、严重的乳糖缺陷或葡萄糖-半乳糖吸收障碍的患者，不推荐使用本品。
实验室检查：在最初的2个月，应每隔2周做一次全血细胞计数，之后可每个月检测一次。应定期检查生化。在基线时、服药开始7天后、有临床指征时应定期做心电图，在剂量调整之后也应该做心电图。对接受本品的患者，应该根据医生的判断进行一定频率的实验室检查。
对驾驶能力和操作机器能力的影响 ：尚未进行过本品对驾驶能力和操作机器能力的影响的研究。不良反应中如头昏、恶心和呕吐，在本品治疗期间是有可能出现的，所以驾驶或操作机器时应该谨慎。

【儿童用药】
尚无在儿童或青少年中进行的临床研究，所以不推荐用于治疗小于18岁的患者。

【老年患者用药】
对超过65岁的患者，不需要进行特殊的剂量调整。

【孕妇及哺乳期妇女用药】
妊娠：在妊娠妇女中，没有使用本品的数据。动物研究没有证据显示致畸性，但是在引起母体毒性的剂量下，也观察到胚胎毒性和胎儿毒性。在妊娠期间，不应该服用本品，如果有必要在妊娠期间使用，必须告知患者对胎儿的潜在毒性。在服用本品期间，男性患者和有妊娠可能的女性患者必须采用有效的避孕措施。
哺乳：尚不清楚本品是否通过人乳汁排泄。动物研究显示，本品会进入乳汁中。服用本品的妇女不应该哺乳。
【不良反应】
在一项开放的、多中心研究中，暴露于本品的438位患者的安全性研究结果显示，平均治疗时间为5-8个月，13%的患者因为不良反应而终止治疗。
本品的主要毒性是骨髓抑制，包括血小板减少症（27%）、中性粒细胞减少症（15%）和贫血（13%）。最常见的药物相关的非血液学不良反应是皮疹、瘙痒、恶心、头痛、疲劳、便秘和腹泻。这些不良反应多数是轻度到中度。
观察到骨痛、关节炎、肌肉痉挛和外周水肿的频率较低。
也观察到胸膜和心包积液、水潴留和心衰（各<1%）、胃肠道出血（1%）、中枢神经系统出血（<1%）和QTcF间期>500毫秒（<1%）。没有尖端扭转型室性心动过速的病例报告。
发生频率：分为很常见（≥1/10）、常见（≥1/100到<1/10）、不常见（≥1/1000到<1/100）、罕见（≥1/10000到<1/1000）和非常罕见（<1/10000以及单发病例）。
感染和传染病
不常见 ：肺炎、尿路感染、胃肠炎、咽炎 ；非常罕见 ：脓血症、支气管炎、单纯疱疹、念珠菌病。
血液和淋巴系统异常
很常见：血小板减少（慢性期28%，加速期37%）、中性粒细胞减少（28%，37%）、贫血（8%，23%）；常见：发热性中性粒细胞减少、全血细胞减少。
内分泌异常
不常见：甲状腺机能亢进；非常罕见：甲状腺机能减退、甲状腺炎。
代谢和营养失衡
常见：低镁血症、高钾血症、高血糖、食欲不振、体重增加 ；不常见 ：低钾血症、低钠血症、低钙血症、低磷血症、脱水、食欲减低、食欲增加；非常罕见：糖尿病、高钙血症、高磷血症。
精神异常
常见：失眠 ；不常见 ：抑郁、焦虑 ；非常罕见：方向感丧失、混乱。
神经系统异常
很常见：头痛（15%） ；常见：头昏、感觉异常；不常见：颅内出血、偏头痛、震颤、感觉减退、感觉过敏；非常罕见：脑水肿、意识丧失、视觉神经炎、外周神经炎。
眼异常
常见：眼睛出血、视觉敏锐度受损、眼窝外周水肿、结膜炎、眼刺激症状、眼干；非常罕见：视神经乳头水肿、复视、视力模糊、畏光、眼睛肿胀、眼睑炎、眼痛。
耳和迷路异常
常见：眩晕；非常罕见：听觉损伤、耳痛。
心血管异常
常见：心悸、QT间期延长；不常见：心衰、心绞痛、房颤、心包积液、冠状动脉疾病、心脏扩大症、心杂音、心动过缓 ；非常罕见 ：心肌梗塞、心室功能异常、心包炎、心脏扑动、期外收缩。
血管异常
常见：高血压、潮红；不常见：高血压危象、血肿；非常罕见：出血性休克、低血压、静脉栓塞。
呼吸道异常
常见：呼吸困难、运动性呼吸困难、咳嗽、发声困难；不常见：肺水肿、胸膜积液、间质性肺病、胸膜疼痛、胸膜炎、鼻衄、咽喉疼痛、咽喉炎；非常罕见：肺动脉高压。
消化系统异常
很常见：恶心（19%）、便秘（11%）、腹泻（10%）；常见：呕吐、腹痛、腹部不适、消化不良、胃肠胀气 ；不常见：胰腺炎、胃肠道出血、黑便、腹胀、口腔溃疡、胃食管返流、口腔炎、口干 ；非常罕见 ：溃疡穿孔、腹膜后出血、呕血、胃溃疡、溃疡性食管炎、不完全肠梗阻。
肝胆系统异常
常见：转氨酶水平升高、胆红素水平升高；不常见：肝炎；非常罕见 ：肝毒性、肝肿大、黄疸。
皮肤和皮下组织异常
很常见：皮疹（26%）、瘙痒（22%）；常见 ：脱发、盗汗、湿疹、红斑、多汗、皮肤干燥；不常见：剥脱性皮疹、瘀癍、面部水肿 ；非常罕见 ：结节性红斑、皮肤溃疡、瘀点、光过敏。
肌肉骨骼系统
常见：肌痛、关节痛、肌肉痉挛、骨痛、肌肉骨骼性胸痛、肌肉骨骼疼痛；不常见：肌无力 ；非常罕见：关节炎、关节肿胀。
肾和泌尿系统异常
不常见：排尿困难、尿急、遗尿、尿频、肌酐水平升高；非常罕见：肾衰、血尿、尿失禁。
生殖系统和乳腺异常
不常见：乳腺疼痛、男子女性型乳房、勃起障碍。
全身性异常
很常见：疲劳（16%） ；常见：虚弱、外周水肿、发热 ；不常见：胸痛、面部水肿、下肢水肿、感冒样症状、寒战、不适。
检查（3/4级实验室检查异常）
很常见：脂肪酶升高 ；常见：血淀粉酶升高、丙氨酸转氨酶升高、天冬氨酸氨基转移酶升高、血胆红素升高、血碱性磷酸酶升高、γ-谷氨酰转移酶升高、肌酸磷酸激酶升高、血糖升高、体重降低、体重增加；不常见：乳酸脱氢酶升高、血糖降低、血肌酐增加、血尿素增加 ；发生频率未知 ：肌钙蛋白增加、血钾降低、血未结合胆红素增加。

Pharmaco-therapeutic Group
Antineoplastic agents

Pharmacologic class
Kinase inhibitors

Chemical Structure

Chemical designation (IUPAC)

4-methyl-N-[3-(4-methyl-1-H-imidazol-1-yl)- 5-(trifluoromethyl)phenyl]-3- [(4-pyridin-3-ylpyrimidin-2-yl) amino]benzamide

Molecular formula

C28H22F3N7O

White to slightly yellowish to slightly greenish yellow powder

Europe: Summary of Product Characteristics

USA: Nilotinib (Tasigna®) for USA Residents
Europe: Nilotinib (Tasigna®) for non-USA Residents

First Approved:
US FDA: August 2007
Europe (EMEA): 19 November 2007

Orphan designation
On 22 May 2006, orphan designation (EU/3/06/375) was granted by the European Commission to Novartis Europharm Limited, United Kingdom, for nilotinib for the treatment of chronic myeloid leukemia CML).

Approved Indication
FDA (USA): Nilotinib, second generation oral kinase inhibitor indicated for the treatment of chronic phase and accelerated phase Philadelphia chromosome positive Chronic Myelogenous Leukemia (CML) in adult patients.

Europe (EMEA): Nilotinib is authorised in the European Union for the treatment of Philadelphia-chromosome-positive chronic myelogenous leukaemia.

Marketing Authorization
Europe (EMEA): EU/1/07/422/001-004

Recommended Dosing
FDA (USA): 400 mg orally twice daily, approximately 12 hours apart and should not be taken with food. The capsules should be swallowed whole with water. No food should be consumed for at least 2 hours before the dose is taken and no food should be consumed for at least one hour after. Dose adjustment may be required for hematologic and non-hematologic toxicities, and drug interactions.

Europe (EMEA): The recommended dose of nilotinib is 400 mg twice daily. Treatment should be continued as long as the patient continues to benefit. Nilotinib should be taken twice daily approximately 12 hours apart and must not be taken with food. The capsules should be swallowed whole with water. No food should be consumed for 2 hours before the dose is taken and no food should be consumed for at least one hour after the dose is taken. Nilotinib may be given in combination with haematopoietic growth factors such as erythropoietin or granulocyte colony-stimulating factor (G-CSF) if clinically indicated. Nilotinib may be given with hydroxyurea or anagrelide if clinically indicated.

Black Box Warning (USA)
Nilotinib prolongs the QT interval. Sudden deaths have been reported in patients receiving nilotinib. Nilotinib should not be used in patients with hypokalemia, hypomagnesemia, or long QT syndrome. Hypokalemia or hypomagnesemia must be corrected prior to nilotinib administration and should be periodically monitored. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided. Patients should avoid food 2 hours before and 1 hour after taking dose. A dose reduction is recommended in patients with hepatic impairment. ECGs should be obtained to monitor the QTc at baseline, seven days after initiation, and periodically thereafter, as well as following any dose adjustments.

Drug Availability

Nilotinib capsules are light yellow opaque hard gelatin capsules, size 0 with the red axial imprint ‘NVR/TKI’. Nilotinib capsules are supplied in blister packs as cartons of 4 blister pack or blisters of 28 capsules. Each blister pack contains one folded blister card of 28 capsules each, for dosing two in the morning and two in the evening at 12 hour intervals over a 7 day period.

General background
Pharmacology Disease Overview
Nilotinib possesses an in vitro Bcr-Abl binding potency 30 times greater than imatinib in imatinib-resistant cells, and 5-7 times greater than imatinib in imatinib-susceptible leukemic cells. The clinical importance of nilotinib’s greater binding affinity is not established in patients with imatinib-susceptible disease. Nilotinib absorption greatly decreases with increasing dose above 400 mg. Absorption increases significantly in the presence of food. The clinical course of CML begins with an indolent chronic phase, but can quickly progress to the more aggressive accelerated, then blast phases if left untreated. Disease classification is based on the degree of cell abnormality in the blood and bone marrow. Nearly 85% of patients are diagnosed during the chronic stage, when treatment is most effective. Diagnosis is often made from a routine blood test wherein leukocytosis (up to 1000 × 109/L) is found. Disease staging is primarily based on percent of blasts in the blood and bone marrow. Staging criteria vary between guidelines. Most CML studies follow criteria established at M.D. Anderson Cancer Center. The World Health Organization (WHO) guidelines propose a lower threshold for the acute and blastic phases of CML. Other criteria such as clonal evolution and platelet abnormalities also contribute to disease staging. Patients in the blastic phase with symptoms of malaise, fever, and worsening splenomegaly are considered to be in blast crisis.

How is nilotinib expected to act?
Enzymes are proteins produced by the human body that speed up the transformation of certain substances into other substances. Nilotinib inhibits a certain class of enzymes called tyrosine kinases. These enzymes play a role in a cascade of molecular reactions that bring a certain signal from outside the cell into the cell thereby controlling the growth of cells. In chronic myeloid leukaemia, the function of these enzymes is disturbed causing uncontrolled growth and multiplication of the cancer cells. Nilotinib might, by inhibition of one or more of these enzymes activity, at certain levels in the cascade, help in slowing down or stopping the further growth of the cancer cells.

Drug interaction
Nilotinib, and certain other medicines, including over the counter medications or herbal supplements (such as St. John’s Wort) can interact with each other. Nilotinib should not be taken within two hours before and one hour after eating.

Food interaction
Nilotinib is metabolised by CYP3A4 and strong inhibitors or inducers of this enzyme may significantly affect exposure to nilotinib. Patients taking nilotinib should avoid foods such as grapefruit juice which inhibit CYP3A4.

Pregnancy
Pregnancy Category: D (USA)
The use of nilotinib during pregnancy may cause serious harm to the fetus. Unless strictly necessary, nilotinib should not be taken during pregnancy. Women of childbearing potential should use effective contraceptives if taking nilotinib. Sexually active female patients taking nilotinib should use adequate contraception.

Pediatric Use
Nilotinib is not recommended for use in children and adolescents below 18 years of age due to a lack of data on safety and efficacy data.

Guidelines
USA (NCCN): The National Comprehensive Cancer Network (NCCN) recommends nilotinib for CML (grade 2A) as follows: Follow-up therapy after primary treatment with imatinib in patients with the following indications: no hematologic remission or in hematologic relapse at 3 months, no cytogenetic response at 6 months, minor or no cytogenetic response or in cytogenetic relapse at 12 months, partial, minor, or no cytogenetic response or in cytogentic relapse at 18 months; post-transplant follow-up treatment in patients with the following indications: molecular relapse (polymerase chain reaction positive) following cytogenetic remission, cytogenetic relapse or those who are not in cytogenetic remission; for the treatment of CML in accelerated phase in patients with disease progression on imatinib therapy; alternative treatment for patients with the following indications: severe hepatotoxicity due to imatinib therapy, severe nonhematologic toxicity due to imatinib or dasatinib therapy. The NCCN also recommends nilotinib for the treatment of GIST (grade 2A) for progressive disease when patient is no longer receiving benefit from imatinib or sunitinib.

Europe (NICE): A National Institute for Health and Clinical Excellence (NICE) assessment for nilotinib is pending.

Clinical Efficacy
Efficacy data for nilotinib are limited to 3 case series in patients with CML with resistance or intolerance to imatinib. One of these trials included 13 patients with ALL, but they were excluded from efficacy analyses. The majority of data from these trials was from patients with chronic phase or accelerated phase CML. A major cytogenetic response was observed in 18% - 48% of patients, and a complete hematologic response in 26 - 92% of patients. There are no published trials comparing nilotinib to other agents. Patients diagnosed with advanced gastrointestinal stromal tumors (GISTs) who are resistant or intolerant to both imatinib and second-line sunitinib have a poor prognosis and few therapeutic options. An evaluation tested the efficacy of nilotinib, a novel tyrosine kinase inhibitor (TKI) in patients pretreated with imatinib and sunitinib. Fifty-two consecutive patients treated with oral nilotinib, 400mg twice daily, within the nilotinib compassionate use program in 12 European cancer centers were included in this retrospective analysis. Median age was 59 years (range 24-80), and all patients had WHO performance score better than 3. All patients had failed both imatinib and sunitinib pretreatment, either due to progressing GIST (96%) or intolerance (4%). Five patients (10%; 95% confidence interval (CI) 2-18) responded to nilotinib and 19 patients (37%; 95% CI 24-50) achieved a disease stabilization. Nilotinib was generally well tolerated, but six patients (12%) discontinued treatment due to intolerance. Median progression-free survival of nilotinib treatment was 12 weeks (95% CI 9-15; range 0-104) and median overall survival was 34 weeks (95% CI 3-65; range 2-135). Nilotinib is active in GIST resistant to both imatinib and sunitinib.

Adverse Reactions

The most common drug related adverse effects include rash, pruritus, constipation, nausea, vomiting, diarrhea, thrombocytopenia, and neutropenia. Other serious adverse events with nilotinib include elevated lipase and liver function tests, and electrolyte abnormalities. Nilotinib is a competitive inhibitor of CYP3A4, CYP2C8, CYP2C9, and CYP2D6. Nilotinib is also metabolized by the hepatic enzyme CYP3A4 and is transported through the P-glycoprotein efflux system. Drugs that are substrates, inducers, or inhibitors of these enzymes may have significantly interacted with nilotinib.
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原产地英文商品名:
TASIGNA 150mg/cap 28caps/box
原产地英文药品名:
NILOTINIB HYDROCHLORIDE
中文参考商品译名:
达希纳 150毫克/胶囊 28胶囊/盒
中文参考药品译名:
盐酸尼洛替尼
产地国家: 美国
所属类别: 抗癌药物->治疗白血病药物
处方药:处方药
包装规格: 150毫克/胶囊 28胶囊/盒
销售单价(美元 US$): 2,986 美元
销售单价(人民币 RMB): 19,709 元
计价单位: 盒
生产厂家中文参考译名:
诺华公司

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原产地英文商品名:
TASIGNA 200mg/cap 112caps/box
原产地英文药品名:
NILOTINIB HYDROCHLORIDE
中文参考商品译名:
达希纳 200毫克/胶囊 112胶囊/盒
中文参考药品译名:
盐酸尼洛替尼
产地国家: 美国
所属类别: 抗癌药物->治疗白血病药物
处方药:处方药
包装规格: 200mg毫克/胶囊 112胶囊/盒
销售单价(人民币 RMB): 79,709 元
计价单位: 盒
生产厂家中文参考译名:
诺华公司