【通用名】去羟肌苷肠溶胶囊

【商品名】惠妥滋

【英文名】Videx EC

【汉语拼音】：Quqianjigan Changrongjiaonang

【成分】去羟肌苷。

【性状】本品为肠溶胶囊剂，内容物为白色或类白色颗粒或粉末。

【药理毒理】去羟肌苷是核苷类药物，与人体内的腺苷相比，后者的3'-羟基为氢。去羟肌苷被细胞激酶磷酸化后，生成有活性的代谢物5'-三磷酸双脱氧腺苷。5'-三磷酸双脱氧腺苷抑制HIV逆转录酶。其机制包括与体内三磷酸脱氧腺苷竞争，从而掺入至病毒DNA中，终止DNA链的延长，起到抑制HIV的生长。

体外HIV敏感性：用HIV-1感染的淋巴细胞系和单核细胞/巨噬细胞培养，测定去羟肌苷体外抗病毒活性。在淋巴细胞系，50%抑制病毒复制的药物浓度(IC50)范围在2.5到10μM之间(1μM=0.24μg/ml)。同样，对于单核细胞/巨噬细胞培养，IC50范围在0.01到0.1μM之间。尽管体外HIV对去羟肌苷的敏感性已确定，去羟肌苷对人体内HIV复制的抑制作用尚不明确。

耐药性：从体外和经去羟肌苷治疗的病人中都分离出了对去羟肌苷敏感性减弱的HIV-1。对去羟肌苷治疗的病人中分离出的HIV进行遗传分析，发现其逆转录酶中有三个氨基酸发生了突变，即K65R、L74V和M184V。临床分离株L74V的突变发生率最高。对接受去羟肌苷单药治疗6-24个月的60例病人(其中有些患者先前曾接受过齐多夫定治疗)中分离出HIV-1进行表型分析发现，60个患者中有10个患者，其病毒对去羟肌苷的体外敏感性减弱了10倍。临床上分离出的敏感性降低的病毒，或多或少都发生了与去羟肌苷相关的突变，至于遗传型与表型的改变与临床的相关性，目前尚未确定。

交叉耐药：经齐多夫定和去羟肌苷联合治疗后，39例病人中分离出HIV-1，其中有2例在体外对齐多夫定、去羟肌苷、扎西他滨和拉米夫定的敏感性降低。这些分离出的病毒在逆转录酶中有五个突变，即A62V、V751、F77L、F116Y和Q151M，这些发现的临床意义尚不明确。

【动物毒理学】

小鼠和大鼠的大于90天的长期毒性实验中发现，当去羟肌苷剂量相当于人的吸收剂量的1.2至12倍时，引起剂量限制性骨骼肌肉毒性，而在狗的长期毒性实验中，未发现此毒性，此发现与人服用去羟肌苷是否会发生肌肉病变的相关性，目前尚不明确。然而，已有报道服用其他核苷类药物会发生肌肉病变。

遗传毒性：去羟肌苷在下列遗传毒性实验中呈阳性：1)大肠杆菌测试株WP2uvrA细菌突变实验；2)L5178Y/TK±小鼠淋巴瘤哺乳类细胞基因突变实验；3)人类淋巴细胞培养的体外染色体畸变实验；4)中国仓鼠肺细胞的体外染色体畸变实验；5)BALB/c3T3体外转型实验。在Ames沙门氏菌突变实验和大鼠、小鼠体内微核实验试验中，未发现突变。

生殖毒性：怀孕、生殖和生育力：属生殖试验B类。按临床剂量形成的血浆浓度折算，12倍的去羟肌苷对大鼠的生育力和胎儿无影响；14.2倍的去羟肌苷对家兔的生育力和胎儿也无影响。12倍的去羟肌苷对雌性大鼠和幼仔在哺乳中期和晚期有轻度毒性；这些大鼠进食量和体重减少，而后代的体格和功能发育均不受影响。第二代无明显变化。有实验显示，去羟肌苷能通过大鼠胎盘转运给胎儿。在怀孕妇女，尚未有充分核实的研究。动物生殖实验不能完全预言人类对药物的反应，因此，怀孕期间，一般不应使用去羟肌苷。已经有报导，怀孕妇女同时服用去羟肌苷、司他夫定和其他抗HIV药可引起致命性、乳酸性酸中毒。尚未清楚怀孕妇女服用核苷类药物引起乳酸性酸中毒与胰腺炎是否比非怀孕妇女更危险。怀孕妇女患者在服用去羟肌苷时应警惕乳酸性酸中毒及胰腺炎的发生，并早期诊断。

致癌作用和致突变作用：一项去羟肌苷对小鼠和大鼠的终身致癌作用的研究，为期分别为22和24个月，在小鼠实验中，去羟肌苷的初始剂量为120、800和1200mg/公斤/日，雌雄两性同样剂量。8个月后，雌性的剂量减少为120、210和210mg/公斤/日，雄性的剂量减少为120、300和600mg/公斤/日。雌性小鼠不能耐受两个较高剂量；雄性小鼠不能耐受高剂量；按相对AUC比较，雌性小鼠所用的小剂量，相当于人用最高剂量的0.68倍，雄性小鼠所用的中剂量相当于人用的最高剂量的1.7倍。在大鼠实验中，去羟肌苷的初始剂量为100、250和1100mg/公斤/日，18个月后，高剂量减少为500mg/公斤/日，雌雄两性大鼠所用的高剂量相当于人用最高剂量的3倍。最大耐受剂量时，去羟肌苷用在小鼠和大鼠均不增加肿瘤的发生率。

【药代动力学】去羟肌苷吸收迅速，口服给药一般在0.25至1.5hr内达血药峰浓度。在50到400mg剂量范围内，去羟肌苷血浆浓度与剂量成正比。稳态药物代谢动力学参数与一次给药的数据无明显差异。体外试验表明，去羟肌苷与血清蛋白的结合微弱(<5%)。体外和动物实验表明，去羟肌苷在人体内的代谢与内源性的嘌呤的代谢一样。用餐后服用去羟肌苷肠溶胶囊，去羟肌苷血浆浓度(Cmax)与血浆药物浓度-时间曲线下面积(AUC)分别降低46%与19%。因此本品应空腹服用。

【适应症】适用于与其他抗逆转录酶病毒药物合用，以治疗HIV-1(人类免疫缺陷病毒)感染患者。

【用法用量】本品应空腹、不破碎完整吞服。口服剂量按体重服用，每日一次。≥60kg，400mg，一次/日；＜60kg，250mg，一次/日。
剂量调整：一旦出现胰腺炎的临床征兆和实验室检查异常，患者应即刻暂缓用药并确定是否发生胰腺炎。胰腺炎被确诊后，停止使用本品。若患者出现外周神经病变的症状，待此症状消退后，患者仍能耐受减量的本品治疗。重复使用本品后，若再出现外周神经病变，应考虑完全停止本品治疗。肾功能损害的患者服用本品，因消除速率降低，剂量需作调整。不适用于肌酐清除率<10ml/分钟，体重低于60kg的患者，应另外制定剂量。连续腹膜透析或血液透析的患者—建议使用常规剂量给药(参阅表3：肌酐清除率小于10ml/分钟患者的推荐剂量)。血液透析后，不需要再补充给药。肝功能损害—参阅注意事项。

【不良反应】约9%的用药患者在推荐剂量或低于推荐剂量时发生胰腺炎。约34%的治疗病人在正常推荐剂量或低于推荐剂量情况下出现外周神经病变，有神经痛或神经毒性药物治疗史的病人发生率较高，表现为麻刺感、灼烧感或疼痛、手脚麻木等。已报道有4名儿童因应用高于推荐剂量而出现视网膜失色素症。此外，约1/3用药者有头痛和腹泻；20%~25%病人出现恶心、呕吐、腹痛、失眠、药疹、瘙痒等；10%~20%病人可呈现忧郁、疼痛、便秘、口炎、味觉障碍、肌痛、关节炎、肝酶异常。

【禁忌】对本品过敏者禁用。

【注意事项】
1.已经在单独或联合用药的患者中出现致命的胰腺炎，应注意免疫抑制的程度。有胰腺炎征兆的患者需暂时终止用药，已确诊胰腺炎者须立即停药。用去羟肌苷/司他夫定治疗的患者也许会增加胰腺炎发生的危险。因延长生命所需，使用有胰腺毒性的药物时，需停止去羟肌苷治疗。患者有患胰腺炎的危险因素时，使用去羟肌苷须密切注意且明确无危险才可用药。患有严重的HIV感染者有增加胰腺炎的危险须密切随访。如果不调整剂量，肾损伤患者有增大胰腺炎的危险。发生胰腺炎的几率与剂量无关。在小儿用药研究中，胰腺炎发生几率为3%(初始剂量)和13%(较高剂量)。有胰腺炎体征或已确证胰腺炎的患者须终止去羟肌苷治疗。
2.单独或联用核苷类似物已有乳酸性酸中毒/脂肪变性肝肿大报道，甚至是致命的，包括去羟肌苷及其他抗病毒药。这些情况在女性患者中同样常见。肥胖和长期的核苷类治疗也许是危险因素。对于已知有肝病危险的患者，服用去羟肌苷须特别注意；但没有肝病危险的患者，也有此严重并发症的报道。用去羟肌苷治疗时，在临床或实验室研究中证明有乳酸中毒征兆或者发现肝脏毒性(肝肿大、脂肪变性，即使未发现转氨酶升高)。
3.视网膜病变和视神经炎：在小儿与成人患者中均有报道。接收去羟肌苷治疗的患者建议定期检查视网膜。
4.警惕外周神经病变：外周神经病变表现为手或脚麻木、麻刺感或疼痛，在接受去羟肌苷疗法的患者中已有报导。外周神经病变在下述患者中较常见：晚期艾滋病患者、曾有神经病变史者或曾服用过神经毒性药物者(包括司他夫定等)。
5.去羟肌苷应空腹、餐前30分钟或餐后2小时服用。
6.避免饮用酒精类饮料，因可能增加去羟肌苷毒性。
.患者须知：去羟肌苷不能治愈艾滋病，患者可能继续出现艾滋病并发症包括机会性感染，因此，患者仍需在医生监护下治疗。治疗期间，并不能减少艾滋病病毒通过性接触及血液污染传播。长期使用去羟肌苷对人体影响目前仍然未知。

【孕妇及哺乳期妇女用药】禁用

【儿童用药】尚未确证本品在儿童中使用安全及有效性。

【老年患者用药】以本品治疗高于65岁老年HIV患者时引起胰腺炎发病率约10%，而一般患者发病率为5%，高龄老年人服用本品临床人数不足，因此难以确定老年人胰腺炎发病率与一般患者发病率之间的差别，去羟肌苷影响患者肾功能并引起毒性反应，尤其对肾功能不全患者。因此，老年人更容易引起肾功能进一步损害，必须制定合适剂量。

【规格】0.4g*30粒/瓶

【贮藏】遮光、密封保存。

【有效期】暂定18个月

【批准文号】注册证号 H20100469

【生产企业】美国Bristol-Myers Squibb Company

【原产地英文商品名】VIDEX EC 400mg/cap 30caps/bottle
【原产地英文药品名】DIDANOSINE
【中文参考商品译名】
注：以下产品不同规格和不同价格，购买时请以电话咨询为准！
·惠妥滋肠溶胶囊 125毫克/胶囊 30胶囊/瓶
·惠妥滋肠溶胶囊 250毫克/胶囊 30胶囊/瓶
·惠妥滋肠溶胶囊 400毫克/胶囊 30胶囊/瓶
【中文参考药品译名】去羟肌苷
【生产厂家中文参考译名】百时美施贵宝
【生产厂家英文名】BRISTOL MYERS SQUIBB

Videx EC (didanosine, or ddI)

en español
Pronunciation(s): VY-dex-EE-SEE; dye-DAH-no-seen

What is Videx EC?
Videx EC is an HIV medications. It is in a category of HIV medications called nucleoside reverse transcriptase inhibitors (NRTIs). NRTIs prevent HIV from altering the genetic material of healthy CD4 cells. This prevents the cells from producing new virus and decreases the amount of virus in the body.
 
Videx, manufactured by Bristol-Myers Squibb, was the second drug approved for the treatment of HIV, and was originally approved as a chewable or desolvable tablet by the U.S. Food and Drug Administration in 1991. Videx EC capsules were approved by the FDA in 2000 and have since replaced Videx tablets.
 
Generic versions of delayed-release didanosine (similar to Videx EC), manufactured by Barr Laboratories, are now available. It was approved by the FDA in December 2004.
 
Videx EC must be used in combination with at least two other HIV drugs.

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What is known about Videx EC?
Enteric coated (delayed release) didanosine is available as Videx EC, the brand-name version of the drug, and as a generic formulation. A pharmacy may automatically dispense the generic version of delayed release didanosine in order to reduce the cost of treatment.
 
The correct dose of Videx EC is one 400mg capsule once a day (for people who weigh 132 pounds or more) or one 250mg capsule (for people who weigh less than 132 pounds). It is also possible to take Videx EC capsules twice a day: one 200mg capsule twice a day (for people who weigh 132 pounds or more) or one 125mg capsule twice a day (for people who weigh less than 132 pounds).
 
Videx EC should not be used by babies or children. Didanosine powder, sold as Videx, is necessary for pediatric patients. To learn about treatment options for children, click here.
 
Videx EC must be taken on an empty stomach (not eating within two hours before or one hour after taking Videx EC). Food and many liquids can prevent Videx EC from being properly absorbed into the bloodstream. Videx EC should be taken with water. It should not be taken with acidic juices, soda, or milk.
 
Videx EC can be taken with other medications.

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How effective is Videx EC? And what about resistance?
Numerous studies have demonstrated that Videx EC is effective for the treatment of HIV when combined with other HIV drugs, usually at least one other nucleoside reverse transcriptase inhibitor (NRTI) and either a protease inhibitor or non-nucleoside reverse transcriptase inhibitor (NNRTI). Videx EC should not be taken alone (as monotherapy).
 
The generic version of didanosine has been shown to be pharmacologically equivalent to the brand-name version of the drug, meaning that it achieves the same drug levels in the body as Videx EC. The generic version is also regulated by the FDA, meaning that the manufacturer must adhere to strict quality control measures.
 
For HIV-positive adults beginning HIV drug therapy for the first time, Videx EC is listed as an "alternative" NRTI options by the United States Department of Health and Human Services in its treatment guidelines. Truvada (tenofovir plus emtricitabine) is listed as the "preferred" NRTI option. To learn more about these recommendations and options, click here.
 
 The DHHS recommends against using Videx EC and Zerit (stavudine) in the same drug combination. The risk of side effects, which are similar for Zerit and Videx EC, are increased when these drugs are used at the same time.
 
Therapy with Videx EC can cause certain changes (mutations) in HIV's structure to occur. Some mutations will prevent Videx EC from working against HIV. Some studies suggest that HIV is much more likely to become resistant to Videx EC if it is already resistant to Retrovir (zidovudine), another NRTI. If HIV is not resistant to Retrovir, resistance to Videx EC may develop much more slowly. If your viral load does not go undetectable or becomes detectable (and increases) while you are taking an HIV drug regimen, your doctor can order a drug-resistance test to determine if your HIV has mutations that are causing resistance to Videx EC and to help you figure out which NRTIs your HIV is still sensitive to.

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What about drug interactions?
HIV-positive people must be very careful about using Videx EC in combination with Viread (tenofovir). There are two important warnings to know about:
 
Drug regimens consisting of Sustiva (efavirenz) or Viramune (nevirapine) plus Viread and Videx EC have been associated with premature drug failure. If you are receiving Videx EC with either Sustiva or Viramune, you may want to discuss alternative options with your doctor.
 
Viread increases the amount of Videx EC in the body. This can increase the risk of experiencing side effects that can be caused by Videx EC, such as pancreatitis, peripheral neuropathy, and lactic acidosis. In turn, if Viread and Videx EC are used together, Videx EC should be taken at a dose of 250mg once a day (reduced from the usual daily dose of 400mg a day).
 
Because there are now a number of concerns regarding the use of Viread in combination with Videx EC, many experts recommend avoiding this combination altogether.
 
Ribavirin (Rebetol; Copegus), one of the two drugs that are often prescribed to treat hepatitis C, can increase Videx EC levels inside cells. Researchers have not yet determined the correct dose of Videx EC for HIV-positive people who are also taking ribavirin to treat their hepatitis C infection. In turn, it is probably best to avoid combining these drugs.
 
Because Videx EC can cause pancreatitis, it should be used carefully in combination with other drugs that can also cause pancreatitis. These include intravenous pentamidine and TMP/SMX (Bactrim; Septra). It is also possible that combining Videx EC with hydroxyurea, a cancer drug that has been studied as a treatment for HIV, increases the risk of pancreatitis.
 
The oral form of Cytovene (ganciclovir), a treatment used to prevent CMV from recurring in people who have had this disease, can decrease Videx EC levels in the bloodstream. Videx EC can increase Cytovene levels in the bloodstream. No dosing recommendations have been made.
 
Methadone, a drug frequently used to help people recovering from heroin addiction, can decrease the amount of Videx EC in the bloodstream. This can result in an HIV drug regimen being less effective against HIV, which can cause drug resistance.
 
Combining Videx EC with Zerit, another nucleoside reverse transcriptase inhibitor (NRTI), may increase the risk of developing lactic acidosis. This is especially true in HIV-positive pregnant women who take both of these drugs together. In turn, the U.S. Food and Drug Administration (FDA) has recommended that HIV-positive women not take these two drugs together while they are pregnant.

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What about side effects?
Lactic acidosis, which can be fatal, and severe liver problems (fatty liver) have been reported in people taking nucleoside reverse transcriptase inhibitors (NRTIs). These problems are more likely to occur in HIV-positive people taking Zerit (d4T) or Zerit in combination with Videx EC. Contact your doctor immediately if you experience nausea, vomiting, or unusual or unexpected stomach discomfort; weakness and tiredness; shortness of breath; weakness in the arms and legs; yellowing of the skin or eyes; or pain in the upper stomach area.
 
Videx EC can cause inflammation of the pancreas (pancreatitis). Pancreatitis is a rare but serious side effect that can be life-threatening in some cases. Notify your doctor immediately if you develop symptoms of pancreatitis, including nausea, vomiting, diarrhea, and abdominal pain. You should avoid alcohol while you are taking Videx EC, as alcohol can increase the risk of damage to your pancreas.
 
Videx EC is associated with a rare but potentially serious liver disorder called non-cirrhotic portal hypertension. Patients using Videx EC should be monitored for early signs of portal hypertension during routine medical visits.
 
A common side effect of Videx EC is peripheral neuropathy, which can result in pain, tingling, numbness, or burning in the hands and/or feet. Stopping Videx EC and starting another NRTI that does not usually cause peripheral neuropathy—for example, Retrovir (zidovudine) or Ziagen (abacavir)—is often the best way to stop peripheral neuropathy.
 
Other common side effects include stomach aches, nausea, diarrhea, dry mouth, and central nervous system effects (e.g., anxiety, headaches, trouble sleeping, irritability, and restlessness). Very often, these side effects improve within a few months/weeks of starting Videx EC.
 
Damage to the eyes is another serious side effect that can be caused by Videx EC. This is more likely to occur in HIV-positive children taking Videx powder or Videx EC.
 
HIV drug regimens containing NRTIs, including Videx EC, can cause increased fat levels (cholesterol and triglycerides) in the blood, abnormal body-shape changes (lipodystrophy; including increased fat around the abdomen, breasts, and back of the neck, as well as decreased fat in the face, arms, and legs), and diabetes. These side effects of HIV drug therapy are reviewed in our lessons on Lipodystrophy, Facial Lipoatrophy, and Risks To Your Heart (Hyperlipidemia).

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Can pregnant women take Videx EC?
Videx EC is classified by the FDA as a pregnancy category B drug. Pregnancy category B means that animal studies have failed to demonstrate a risk to the fetus, but there are no adequate and well-controlled studies in pregnant women. HIV-positive women who become pregnant should discuss the benefits and possible side effects of HIV treatment to help protect their babies from HIV (see our lesson called Family Planning, Pregnancy & HIV).
 
It is not known whether Videx EC passes into breast milk and what effects it may have on a nursing baby. However, to prevent HIV transmission of the virus to uninfected babies, it is recommended that HIV-positive mothers not breast-feed.

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Who should not take Videx EC?
Before taking this medication, tell your doctor if you have: kidney disease; liver disease; a history of pancreatitis; a history of lactic acidosis or elevated lactate levels; a history of peripheral neuropathy. You may not be able to take Videx, or you may require lower doses or special monitoring during treatment, if you have any of these conditions.

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Where can I learn more about clinical trials that are using Videx EC?
If you would like to find out if you are eligible for any clinical trials that include Videx EC, there is an interactive web site run by ACRIA, the AIDS Community Research Initiative of America.
 
Another useful service for finding clinical trials is AIDSinfo.nih.gov, a site run by the U.S. National Institutes of Health. They have "health information specialists" you can talk to at their toll-free number at 1-800-HIV-0440 (1-800-448-0440).