Pharmacological Class:
Cholesterol absorption inhibitor + HMG-CoA reductase inhibitor.

Active Ingredient(s):
Ezetimibe/atorvastatin; 10mg/10mg, 10mg/20mg, 10mg/40mg, 10mg/80mg; tabs.

Company
Merck & Co., Inc.
Indication(s):
To reduce elevated total-C, LDL-C, Apo B, TG, and non-HDL-C, and to increase HDL-C in primary (heterozygous familial and non-familial) or mixed hyperlipidemia. To reduce elevated total-C and LDL-C in homozygous familial hypercholesterolemia (HoFH), as an adjunct to other lipid-lowering treatments (eg, LDL apheresis) or if such treatments are unavailable. Limitations of use: No incremental benefit on cardiovascular morbidity/mortality over and above that demonstrated for atorvastatin has been established. Not studied in Fredrickson type I, III, IV, and V dyslipidemias.

Pharmacology:
Ezetimibe reduces blood cholesterol by inhibiting cholesterol absorption by the small intestine. Atorvastatin lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis.

Clinical Trials:
In a clinical study, 628 patients were randomized to placebo, ezetimibe, atorvastatin, or coadminstered ezetimibe and atorvastatin equivalent to Liptruzet in a 12-week study.

Patients receiving all doses of the ezetimibe/atorvastatin combination were compared to those receiving all doses of atorvastatin. Results at 12 weeks demonstrated that the ezetimibe/atorvastatin combination treatment significantly reduced total-C (-41% vs. -32%), LDL-C (-56% vs. -44%), Apo B (-45% vs. -36%), TG (-33% vs. -24%), and non-HDL-C (-52% vs. -41%), and significantly increased HDL-C (7% vs. 4%) compared to all doses of atorvastatin pooled, respectively.

For more information on clinical studies: see full labeling.

Legal Classification:
Rx

Adults:
Swallow whole. Usual range: 10mg/10mg to 10mg/80mg. Initially 10mg/10mg or 10mg/20mg; for LDL-C reduction >55%: may start at 10mg/40mg; monitor lipids within ≥2wks and adjust dose as needed. HoFH: 10mg/40mg or 10mg/80mg. Concomitant bile acid sequestrants: give Liptruzet dose either ≥2hrs before or ≥4hrs after bile acid sequestrant administration. Concomitant lopinavir/ritonavir: use lowest dose. Concomitant clarithromycin, itraconazole, saquinavir/ritonavir, darunavir/ritonavir, fosamprenavir, or fosamprenavir/ritonavir: max 10mg/20mg. Concomitant nelfinavir or boceprevir: max 10mg/40mg.

Children:
Not established.

Contraindication(s):
Active liver disease. Unexplained persistent elevated hepatic transaminases. Pregnancy (Category X). Nursing mothers.

Warnings/Precautions:
Increased risk of myopathy/rhabdomyolysis (with high doses). Discontinue if elevated CPK (>10 X ULN) levels occur or myopathy is diagnosed or suspected; withhold if a predisposition in renal failure secondary to rhabdomyolysis develops. Monitor liver function prior to starting therapy and repeat as clinically indicated. History of liver disease or renal impairment; monitor closely. Substantial alcohol consumption. Elderly.

Interaction(s)
See Adult dose. Avoid with concomitant cyclosporine, tipranavir/ritonavir, telaprevir, gemfibrozil. Potentiated by strong CYP3A4 inhibitors, grapefruit juice (>1.2L/day). Caution with lopinavir/ritonavir, colchicine, fenofibrates, niacin ≥1g/day; consider dose reduction of Liptruzet. May increase serum levels of digoxin (monitor), oral contraceptives. May be antagonized by cholestyramine, CYP3A4 inducers (eg, efavirenz, rifampin); coadminister rifampin simultaneously. Monitor oral anticoagulants. Caution with drugs that decrease levels or activity of endogenous steroid hormones (eg, ketoconazole, spironolactone, cimetidine).

Adverse Reaction(s)
Increased ALT/AST, musculoskeletal pain, arthralgia, abdominal pain, nausea; increased in HbA1c or fasting serum glucose; myopathy, rhabdomyolysis; rare: immune-mediated necrotizing myopathy.

How Supplied:
Tabs—30, 90

LAST UPDATED:
6/7/2013

默克公司新型降固醇药物Liptruzet获美FDA批准
2013年5月3日，美国食品药品管理局（FDA）批准一款新型降血脂复方药物Liptruzet，该复方药物由阿托伐他汀（专利权于2011年过期）和依泽替米贝(Zetia, 默沙东/先灵葆雅)组成。Liptruzet被批准用于降低与饮食改变相关的原发性或混合性高脂血症患者升高的低密度胆固醇水平，以及降低纯合子家族性高胆固醇血症(FH)患者的胆固醇水平。
Liptruzet是一种日服一次的药片，目前有四种规格，分别为每片10mg依泽替米贝加10mg、20mg、40mg或80mg的阿托伐他汀。
默沙东在美国还有一款上市的降血脂复方药物维妥力（2002年上市），该药物是辛伐他汀和依泽替米贝的复方制剂。
阿托伐他汀和依泽替米贝在降低低密度胆固醇水平方面都很有效，但维妥力和依泽替米贝由于缺乏硬性的临床疗效指标数据而一直被困扰。最主要的是，默沙东因长时间推迟发布ENHANCE临床研究数据而受到指责，甚至引起美国国会的重视。在ENHANCE临床研究中，辛伐他汀与依泽替米贝的复方药物对家族性高胆固醇血症患者人群在几项疗效指标上几乎与辛伐他汀单方制剂一样。
IMPROVE-IT临床研究结果预计在今年能够获得，该试验是在患有急性冠脉综合征的18000名患者中比较辛伐他汀（40mg）+依泽替米贝（10mg）与单独使用辛伐他汀（40mg）的临床效果。虽然研究结果将有助于搞清楚添加依泽替米贝所能获得的临床收益，但这个结果的获得也是在依泽替米贝被批准后大约十年的时间了，当时依泽替米贝被批准作为降血脂的他汀类药物的辅助药物。
2012年1月份，FDA依据SHARP试验研究数据更新了依泽替米贝与辛伐他汀复方药物的处方信息。临床试验中，复方药物与安慰剂相比能更加有效地降低慢性肾脏疾病(CKD)患者的低密度胆固醇水平，并且有较少的主要血管事件。但是，维妥力的一种慢性肾脏疾病适应症没有获得批准，“因为不能评价依泽替米贝和辛伐他汀在药物中单独的作用。”
FDA Approves Merck’s LIPTRUZET™ (ezetimibe and atorvastatin), a New Product That Can Help Powerfully Lower LDL Cholesterol

LIPTRUZET Approved for Patients with Primary or Mixed Hyperlipidemia, as an Adjunct to Diet When Diet Alone Is Not Enough
LIPTRUZET Approved for Patients with Primary or Mixed Hyperlipidemia, as an Adjunct to Diet When Diet Alone Is Not Enough
WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)--Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced that the U.S. Food and Drug Administration (FDA) has approved LIPTRUZET™ (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 (≥65 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).