英文药名：Liptrzet(ezetimibe and atorvastatin)tablets

中文药名：阿托伐他汀依折麦布复方片

生产厂家：Merck Sharp & Dohme（默沙东）
药品介绍
FDA日前批准了一种新的降脂复方片剂，成分包括阿托伐他汀（2011年失去专利保护）和依折麦布（Zetia，默克/先灵葆雅）。复方片剂Liptruzet被批准作为饮食控制以外的辅助治疗治疗原发性或混合性高脂血症患者低密度脂蛋白胆固醇升高，以及用于降低纯合子家族性高胆固醇血症（FH）患者的胆固醇水平。
Liptruzet每天服用一次，规格包括10mg依泽麦布与10、20、40或80mg阿托伐他汀的组合。
FDA的批准对于Liptruzet生产商默克而言是“事不过三”的幸运。在2012年，FDA想默克公司发布了一个完整的回复信，表明FDA不会批准复方片剂，还需要更多的数据。FDA还在2009年拒绝了默克公司的Liptruzet申请。
辛伐他汀和依折麦布复方片剂（商品名Vytorin）是2002年在美国上市，并一直用于临床。
如先前报道，阿托伐他汀和依折麦布都能非常有效地降低低密度脂蛋白胆固醇水平，但Vytorin和依折麦布缺乏临床硬终点数据。最值得注意的是，公司因长期拖延不发表研究结果而饱受批评，甚至引起了美国国会委员会的关注。ENHANCE研究的家族性高胆固醇血症患者人群中，辛伐他汀联合依折麦布对于几个替代的影像学终点指标的疗效确实并不优于辛伐他汀单药治疗。
一项临床转归研究纳入18 000名最近发生急性冠脉综合征的患者，比较了辛伐他汀40mg联合依折麦布10mg与单用辛伐他汀40mg的疗效，预计今年将有结果。尽管这项研究将有助于阐明加用依折麦布的临床获益，但试验结果是在FDA批准依折麦布作为他汀类辅助药物用于降低胆固醇的近十年之后才公布。
2012年1月，美国FDA更新了依折麦布/辛伐他汀的处方信息，纳入了研究数据。在该项实验中，复方制剂与安慰剂相比能更有效地降低慢性肾脏病（CKD）患者的低密度脂蛋白胆固醇水平，降低主要血管事件。然而，因为无法评估依折麦布和辛伐他汀独立贡献，Vytorin的CKD适应症并没有得到批准.

WHITEHOUSE STATION, N.J., May 03, 2013 (BUSINESS WIRE) -- Merck /quotes/zigman/574389/delayed/quotes/nls/mrk MRK -1.05% , known as MSD outside the United States and Canada, today announced that the U.S. Food and Drug Administration (FDA) has approved LIPTRUZET(TM) (ezetimibe and atorvastatin) tablets for the treatment of elevated low-density lipoprotein (LDL) cholesterol in patients with primary or mixed hyperlipidemia as adjunctive therapy to diet when diet alone is not enough. LIPTRUZET (pronounced LIP-true-zett) contains ezetimibe, an efficacious LDL cholesterol lowering therapy, and atorvastatin, currently one of the most widely prescribed statins in the U.S.(1) Once-daily LIPTRUZET treats two sources of cholesterol by inhibiting both the absorption of cholesterol in the digestive tract - through ezetimibe - and the production of cholesterol in the liver - through atorvastatin.
No incremental benefit of LIPTRUZET on cardiovascular morbidity and mortality over and above that demonstrated for atorvastatin has been established.
"A significant percentage of patients are unable to lower their LDL cholesterol to recommended levels despite treatment," said Peter H. Jones, M.D., associate professor of medicine, Baylor College of Medicine. "Along with a healthy diet, LIPTRUZET (ezetimibe and atorvastatin) is an effective new lipid-lowering treatment option that may help address this unmet need as the complementary actions of its components can provide significant additional LDL lowering beyond atorvastatin therapy alone."
Indications, contraindications, and selected dosage and administration information
LIPTRUZET is indicated as adjunctive therapy to diet for the reduction of elevated total cholesterol, LDL cholesterol, apolipoprotein B, triglycerides and non-high-density lipoprotein cholesterol and to increase high-density lipoprotein (HDL) cholesterol in patients with primary (heterozygous familial and non-familial) hyperlipidemia or mixed hyperlipidemia. LIPTRUZET (ezetimibe and atorvastatin) is also indicated for the reduction of elevated total cholesterol and LDL cholesterol in patients with homozygous familial hypercholesterolemia (HoFH), as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable. No incremental benefit of LIPTRUZET on cardiovascular morbidity and mortality over and above that demonstrated for atorvastatin has been established.
LIPTRUZET is a prescription medicine and should not be taken by anyone who has active liver disease or unexplained persistent elevations in hepatic transaminases or who is hypersensitive to any component of LIPTRUZET. Women who are pregnant, nursing or who may become pregnant should not take LIPTRUZET.
LIPTRUZET is available as a once-daily tablet containing 10 mg of ezetimibe combined with 10, 20, 40, or 80 mg of atorvastatin (LIPTRUZET 10/10, 10/20, 10/40, 10/80 mg, respectively). The dosage range is 10/10 mg/day through 10/80 mg/day.
LIPTRUZET 10/10 and 10/80 mg tablets have been shown to be bioequivalent to coadministration of corresponding doses of ezetimibe and atorvastatin tablets.
LIPTRUZET 10/20 and 10/40 mg tablets have been shown to be clinically equivalent in LDL-C response to the corresponding coadministered doses of ezetimibe and atorvastatin tablets.
The recommended starting dose of LIPTRUZET is 10/10 mg or 10/20 mg taken once-daily, or 10/40 mg once-daily for patients who require a larger reduction in LDL cholesterol (greater than 55 percent). LIPTRUZET can be taken at any time of day, with or without food.
In a clinical study, LIPTRUZET powerfully lowered LDL cholesterol across all doses on average by more than 50 percent (53 to 61 percent, depending on dose)
In a multicenter, double-blind, placebo-controlled clinical study in which 628 patients with hyperlipidemia were treated for up to 12 weeks, LIPTRUZET (co-administered as ezetimibe and atorvastatin) provided LDL cholesterol reductions of 53 percent at the lowest dose (10/10 mg; mean baseline LDL-C 177 mg/dL), 54 percent at the 10/20 mg dose (mean baseline LDL-C 184 mg/dL), 56 percent at the 10/40 mg dose (mean baseline LDL-C 184 mg/dL) and 61 percent at the maximum dose (10/80 mg; mean baseline LDL-C 183 mg/dL). Individualization of drug dosage should be based on therapeutic response.
Pooled across doses, LIPTRUZET reduced LDL cholesterol by a mean 56 percent (mean baseline LDL-C 182 mg/dL) compared with 44 percent for all atorvastatin doses pooled (mean baseline LDL-C 181 mg/dL); p< 0.01. The LDL cholesterol reductions seen by atorvastatin dose were 37 percent at 10 mg (mean baseline LDL-C 185 mg/dL), 42 percent at 20 mg (mean baseline LDL-C 177 mg/dL), 45 percent at 40 mg (mean baseline LDL-C 180 mg/dL) and 54 percent at 80 mg (mean baseline LDL-C 184 mg/dL). The clinical impact of comparative differences in lipid changes between LIPTRUZET (ezetimibe and atorvastatin) and atorvastatin is not known.
In two separate clinical studies, LIPTRUZET 10/40 mg and 10/20 mg provided significantly greater LDL cholesterol reductions and helped more patients get to target LDL cholesterol levels (< 70 mg/dL or < 100 mg/dL) compared to doubling the dose of atorvastatin to 80 mg or 40 mg, respectively
In a six-week study, 556 high risk patients taking atorvastatin 40 mg but not at LDL cholesterol < 70 mg/dL were randomized to either LIPTRUZET 10/40 mg coadministered as ezetimibe and atorvastatin (n = 277; mean baseline LDL-C 89 mg/dL) or atorvastatin 80 mg (n= 279; mean baseline LDL-C 90 mg/dL). Results showed that LIPTRUZET 10/40 mg further lowered LDL cholesterol by an average of 27 percent compared to 11 percent when titrating to atorvastatin 80 mg (p<0.05).This greater additional LDL cholesterol reduction resulted in 74 percent of patients achieving LDL cholesterol <70 mg/dL as compared to 32 percent of patients taking atorvastatin 80 mg.
In a separate six-week study, 184 moderately-high risk patients taking atorvastatin 20 mg but not at LDL cholesterol < 100 mg/dL were randomized to either LIPTRUZET 10/20 mg coadministered as ezetimibe and atorvastatin (n = 92; mean baseline LDL-C 120 mg/dL) or atorvastatin 40 mg (n = 92; mean baseline LDL-C 118 mg/dL). Results showed that LIPTRUZET 10/20 mg further lowered LDL cholesterol by an average of 31 percent compared to 11 percent when titrating to atorvastatin 40 mg (p<0.05). This greater additional LDL cholesterol reduction resulted in 84 percent of patients treated with LIPTRUZET 10/20 mg achieving LDL cholesterol <100 mg/dL as compared to 49 percent of patients taking atorvastatin 40 mg.
Selected cautionary information for LIPTRUZET
LIPTRUZET contains atorvastatin, which occasionally causes myopathy defined as muscle aches or muscle weakness with increases in creatine phosphokinase (CPK) values above 10 times the upper limit of normal. Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with atorvastatin and other statins. A history of renal impairment may be a risk factor for the development of rhabdomyolysis. Such patients merit closer monitoring. Other predisposing factors for myopathy include advanced age (greater-than or equal to65 years) and hypothyroidism.
All patients starting therapy with LIPTRUZET should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if muscle signs or symptoms persist after discontinuing LIPTRUZET (ezetimibe and atorvastatin).Therapy should be discontinued immediately if markedly elevated CPK levels occur or if myopathy is diagnosed or suspected.
The concomitant use of higher doses of atorvastatin with certain drugs such as cyclosporine and strong CYP3A4 inhibitors increases the risk of myopathy/rhabdomyolysis. This includes an increased risk of myopathy when used with fibric acid derivatives, erythromycin, clarithromycin, hepatitis C protease inhibitors, combinations of HIV protease inhibitors, niacin, or azole antifungals. Physicians should carefully weigh the potential benefits and risks of combined therapy with any of these drugs, consider lower doses of LIPTRUZET, and carefully monitor patients for signs and symptoms of myopathy early during therapy and when titrating the dose of either drug.
Avoid LIPTRUZET with cyclosporine, tipranavir plus ritonavir, telaprevir, or gemfibrozil. Use caution when prescribing LIPTRUZET with a fenofibrate, and immediately discontinue both drugs if myopathy if diagnosed or suspected. Cases of myopathy, including rhabdomyolysis, have been reported with atorvastatin coadministered with colchicine, and caution should be used when prescribing LIPTRUZET with colchicine.
The dose of LIPTRUZET should not exceed 10/20 mg daily in patients receiving clarithromycin, itraconazole, saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, and 10/40 mg daily in patients receiving nelfinavir or boceprevir. Physicians should use caution and the lowest dose necessary with lopinavir plus ritonavir or saquinavir plus ritonavir.
Persistent elevations in hepatic transaminase can occur. Liver enzyme tests should be performed prior to treatment initiation and thereafter when clinically indicated. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment, promptly interrupt therapy and do not restart unless an alternate etiology is found.
Increases in HbA1c and fasting serum glucose levels have been reported with statins, including atorvastatin.
In a post-hoc analysis of a study in patients without coronary heart disease who had a stroke or transient ischemic attack within the preceding six months, a higher incidence of hemorrhagic stroke was seen in the atorvastatin 80 mg group compared to placebo. Some baseline characteristics, including hemorrhagic and lacunar stroke on study entry, were associated with a higher incidence of hemorrhagic stroke in the atorvastatin group.
In a clinical trial of LIPTRUZET, the most commonly reported side effects, regardless of cause, included increased alanine transaminase (ALT) (5 percent), increased aspartate transaminase (AST) (4 percent), and musculoskeletal pain (4 percent).
Availability
LIPTRUZET (ezetimibe and atorvastatin) will be available for wholesalers to order the week of May 6.
About Merck
Today's Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit www.merck.com and connect with us on Twitter, Facebook and YouTube.