LOWER(atorvastatin + ezetimibe )依折麦布阿托伐他汀钙片

TM 
For the use of a Registered Medical Practitioner or a Hospital or a Laboratory only
LOWER
Fixed dose combination of Atorvastatin and Ezetimibe
DESCRIPTION
Fixed dose combination of Atorvastatin and Ezetimibe contains Atorvastatin which is chemically[R-(R*, R*)]-2-(4-fluorophenyl)-ß,d-dihydroxy-5- (1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid, Calcium salt and Ezetimibe which is(3R,4S)-1-(4-Fluorophenyl)-(3R)-[(3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxyphenyl)-2-azetidinone.
LowerTM is a yellow coloured, oblong, biconvex, film coated tablet.
TM
COMPOSITION
Lower
Each film-coated tablet contains:
Atorvastatin Calcium equivalent to Atorvastatin........... 10 mg
Ezetimibe.......................................... 10 mg
Colours: Ferric Oxide and Titanium Dioxide
LDL cholesterol in plasma. HMG-CoA reductase inhibitors may also lower plasma cholesterol
1
2,3
CLINICAL PHARMACOLOGY
Mechanism of action
Atorvastatin
Atorvastatin belongs to the category of statins, which inhibits 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Synthesis of meva lonic acid is impeded, which is a rate-limiting step in cholesterol biosynthesis. This results in a decrease in intracellular cholesterolleading to an increase in the number of synthesis of LDL receptors and increased clearance oflevels by decreasing hepatic production of VLDL and LDL cholesterol.
Ezetimibe
Ezetimibe is a selective cholesterol absorption inhibitor, which potently and selectively preventsabsorption of cholesterol from dietary and biliary sources by preventing transport of cholesterolthrough the intestinal wall. This reduces the overall delivery of cholesterol to the liver, thereby
promoting the synthesis of LDL receptors and a subsequent reduction in serum LDL-C.Ezetimibedoes not affect the absorption of fat-soluble vitamins
4
RATIONALE OF COMBINATION
Atorvastatin is a selective HMG-CoA reductase inhibitor and causes a decrease in intracellularcholesterol levels and an increased clearance of LDL cholesterol in plasma. Ezetimibe is aselective cholesterol absorption inhibitor, which potently and selectively prevents absorption of
cholesterol through the intestinal wall.
Since decrease in LDL receptors and HDL cholesterol is observed in hyperlipidemia,the use ofboth Atorvastatin and Ezetimibe in combination produces additive effects in hyperlipidemia.
Atorvastatin when used in combination with Ezetimibe causes manifold reduction in LDLcholesterol levels as compared to double the dose of the individual drug when used alone4.
Moreover, the use of Ezetimibe with Atorvastatin allows for an enhanced effect of the statin at alower dose and reduction in associated side effects.
Ezetimibe is rapidly absorbed and conjugated after oral administration. T   of Ezetimibe and administration with their long t  for elimination supporting once daily therapy. The T   for
PHARMACOKINETICS
Atorvastatin
After oral administration, Atorvastatin is rapidly absorbed, with peak serum concentrationsreaching within 1 to 2 hours. Extent of absorption increases in proportion to Atorvastatin dose.
The absolute bioavailability of Atorvastatin is approximately 14% and the systemic availability ofHMG-CoA reductase inhibitory activity is approximately 30%.
Mean volume of distribution is approximately 381 liters. Atorvastatin is ≥ 98% bound to plasmaproteins.
Atorvastatin is extensively metabolized to ortho-and para hydroxylated derivatives and variousbeta-oxidation products. Approximately 70% of circulatory inhibitory activity for HMG-CoA
reductase is attributed to active metabolites.
Atorvastatin and its metabolites are eliminated primarily in bile following hepatic and/or extra-hepatic metabolism; however the drug does not appear to undergo enterohepatic recirculation.
Mean plasma elimination half life of Atorvastatin in humans is approximately 14 hrs, but the halflife of inhibitory activity for HMG-CoA reductase is 20-30 hours due to contribution of active
metabolites.
Ezetimibe
Ezetimibe-glucuronide are 4-12 hrs and 1-2 hrs respectively. Concomitant food administration(high fat or non-fat meals) has no effect on the extent of absorption of Ezetimibe. Ezetimibe canbe administered with or without food.
Ezetimibe and Ezetimibe-glucuronide are highly bound (>90%) to human plasma proteins.
In humans, Ezetimibe gets rapidly metabolized to Ezetimibe-glucuronide. Ezetimibe and
Ezetimibe glucuronide are the major drug-derived compounds detected in plasma, constitutingapproximately 10-20% and 80-90% of the total drug in plasma, respectively. Both Ezetimibe andEzetimibe-glucuronide are slowly eliminated from plasma with a half-life of approximately 22
hours for both Ezetimibe and Ezetimibe-glucuronide.
From the pharmacokinetic profile, it is clear that both the drugs are rapidly absorbed after oralAtorvastatin and Ezetimibe glucuronide (pharmacologically active metabolite of Ezetimibe) are
also same (i.e. 1-2 hours) which further supports their use in fixed dose combination as a singledose. Further Atorvastatin and Ezetimibe can be administered as a single dose at any time of theday with or without food.
Based on the studies of Atorvastatin alone, the C   of Atorvastatin was 42.8% higher in elderly SPECIAL POPULATIONS
Elderly
Treatment of Atorvastatin and Ezetimibe individually in adults greater than 70 years is same asthose below 70 years of age.
patients than in young participants and 17.6% higher in women than men. In addition, the meanarea under the concentration time curve and half life were 27.3% greater and 36.2% longer,respectively, in elderly than in young adults and 11.3% lower and 19.9% shorter, respectively, inwomen than in men5
In a multiple dose study with Ezetimibe given 10mg once daily for 10 days, plasmaconcentrations for total Ezetimibe were about 2-fold higher in older (>65 years) healthy subjectscompared to younger subjects.
Pediatric use
Treatment of Atorvastatin and Ezetimibe is not recommended in children below 10 years of age.
Hepatic dysfunction
The pharmacokinetics and tolerability of this combination in patients with impaired hepaticfunction has not been studied. Since Atorvastatin and Ezetimibe are both extensively metabolized
by the liver, its use in patients with hepatic impairment is not recommended.
Renal dysfunction
There is no data available on the pharmacokinetics of this combination in patients with renalimpairment. Based on studies using Atorvastatin alone, renal disease does not influence theplasma concentrations or LDL cholesterol levels of Atorvastatin.
1
placebo-controlled, dose-response studies in patients with hypercholesterolemia, Atorvastatin
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7
primary hypercholesterolemia, Ezetimibe significantly lowered total LDL-C, apo B and TG, and
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CLINICAL STUDIES
Atorvastatin
Atorvastatin reduces total-C, LDL-C, VLDL-C, apo B, and TG, and increases HDL-C in patientswith hypercholesterolemia and mixed dyslipidemia. Therapeutic response is seen within 2 weeks,and maximum response is usually achieved within 4 weeks and maintained during chronictherapy.
Atorvastatin is effective in a wide variety of patient populations with hypercholesterolemia, withand without hypertriglyceridemia, in men and women, and in the elderly. In two multicenter,given as a single dose over 6 weeks significantly reduced total-C, LDL-C, apo B, and TG.
Ezetimibe
In pooled analysis of two, phase III studies on effectiveness and tolerability of Ezetimibe inpatients with primary hypercholesterolemia, Ezetimibe has shown a significant decrease inplasma LDL-C levels.
In two, multicenter, double blind, placebo controlled, 12 week studies in 1719 patients withincreased HDL-C compared to placebo
Atorvastain and Ezetimibe provided significant incremental reduction in LDL-C and triglycerides
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Table: Response to Atorvastatin and Ezetimibe combination in patients of 
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Co-administration of Atorvastatin and Ezetimibe
In a prospective, randomized, double blind trial conducted for effect of Ezetimibe co-administeredwith Atorvastatin in 628 patients with primary hypercholesterolemia; the coadministration ofand increases in HDL-C.
Primary Hypercholesterolemia: Percent changes from baseline

Parameters	Atorvastatin 10 mg + Ezetimibe 10 mg	Atorvastatin 20mg + Ezetimibe 10 mg	Atorvastatin 80 mg
LDL-C	- 50%	- 54%	-51%
Triglycerides	- 31%	- 30%	-31 %
HDL-C	9%	9%	3 %

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Another study demonstrated that adding Ezetimibe 10mg to Atorvastatin 10mg resulted in an LDL
4
10
The mean reduction in the levels of LDL-C,triglycerides from baseline with Atorvastatin10 mg andEzetimibe 10 mg co-administration was 50% and 31% respectively while mean increase in HDL
was 9%. The mean reduction in the levels of LDL-C,triglycerides from baseline with Atorvastatin20 mg and Ezetimibe 10 mg was 54% and 30% respectively while mean increase in HDL was
9%. LDL-C and triglyceride reductions with Ezetimibe plus 10 mg Atorvastatin ( 50% and 31%)and 80 mg Atorvastatin alone (51% and 31%) were similar while mean increase in HDL withAtorvastatin 10 mg plus Ezetimibe 10 mg was more than Atorvastatin 80 mg alone (9% and 3%).
cholesterol lowering that is comparble to a 3 step titration of the statin dose to 80mg.
In a study on efficacy and safety of Ezetimibe co-administered with Atorvastatin in patients withhomozygous familial hypercholesterolemia, it was concluded that the co-administration in patientswith homozygous familial hypercholesterolemia (HoFM) produces clinically important LDL-Creductions compared with best current therapy.
INDICATIONS AND USAGE
The FDC is indicated for the treatment of patients with primary hypercholesterolemia.
CONTRAINDICATIONS
Patients with known hypersensitivity to Atorvastatin and/or Ezetimibe.
Evidence of acute liver disease or unexplained persistent elevations of serum transaminases.
WARNINGS AND PRECAUTIONS
Atorvastatin
Hepatic dysfunction
Atorvastation should be used with caution in patients who consume substantial quantity of alcoholand /or have a history of liver disease.
Skeletal muscle
Caution should be taken in rare cases of rhabdomyolysis with acute renal failure secondary tomyoglobinuria. Uncomplicated myalgia has also been reported in Atorvastatin-treated patients.
Endocrine Function
HMG-CoA reductase inhibitors interfere with cholesterol synthesis and theoretically might bluntadrenal and/or gonadal steroid production. Caution should be exercised if an HMG-CoA
reductase inhibitor is administered concomitantly with drugs that may decrease the levels oractivity of endogenous steroid hormones, such as Ketoconazole, Spironolactone and Cimetidine.
Renal dysfunction
Renal disease has no influence on the plasma concentration or LDL-C reduction ofAtorvastatin.Thus, dose adjustment in patients with renal dysfunction is not necessary.
Pregnancy and lactation
If a woman becomes pregnant while taking Atorvastatin, it should be discontinued and the patientadviced again as to the potential hazards to the fetus.
Women taking Atorvastatin should not breast-feed because of the potential for adverse reactionsin nursing infants.
Ezetimibe
Hepatic dysfunction
Ezetimibe is not recommended in patients with moderate or severe hepatic insufficiency.
Renal dysfunction
No dosage adjustment is recommended in patients with moderate or severe renal insufficiency.
Pregnancy and lactation
There are no adequate and well-controlled studies of Ezetimibe in pregnant women. Ezetimibeshould be used in pregnancy and lactation only if potential benefit justifies the risk to the fetus.
DRUG INTERACTIONS
Atorvastatin
The risk of myopathy during treatment with drugs of this class is increased with concurrentadministration of Cyclosporine, Fibric acid derivatives, Niacin, Erythromycin, Azole antifungals.
When Atorvastatin is co-administered with antacids, plasma concentration of Atorvastatin isdecreased approximately by 35%.Plasma concentration of Atorvastatin was decreasedapproximately 25% when Colestipol and Atorvastatin were co-administered. When multiple doses
of Atorvastatin and Digoxin were co-administered, steady-state plasma Digoxin concentrationwas increased by approximately 20%. In healthy individuals, plasma concentrations ofAtorvastatin increased approximately 40% with co-administration of Erythromycin.
Co-administration of Atorvastatin and an oral contraceptive increased AUC values for Norethindroneand Ethinyl- estradiol by approximately 30% and 20% respectively.
Ezetimibe Cholestyramine:Concomitant cholestyramine administration decreases the mean AUCof total Ezetimibe by approximately 55%.
Fibrates : The safety and effectiveness of Ezetimibe administered with fibrates have not beenestablished.
Cyclosporine : Total Ezetimibe level increased 12-fold in one renal transplant patient receivingmultiple medications including Ezetimibe.
ADVERSE REACTIONS
Atorvastatin
The most frequent adverse events were constipation, flatulence, abnormally elevated liverfunction tests, arthralgia, dyspepsia and abdominal pain.Muscle tenderness, rhabdomyolysis andhypersensitivity reactions were also reported.
Ezetimibe
Fatigue, abdominal pain, diarrhea, sinusitis, arthralgia, backpain and coughing were seen in ≥2%
of patients treated with Ezetimibe alone.
Co-administration of Atorvastatin and Ezetimibe
In general,adverse experiences were similar between Ezetimibe administered with HMG-CoA
reductase inhibitors and HMG-CoA reductase inhibitors alone. Frequency of increased
transaminases was slightly higher in patients receiving Ezetimibe administered with HMG-CoA
reductase inhibitor.
OVERDOSE AND TREATMENT
There is no specific treatment for overdose of FDC. In an event of overdosage, the patient shouldbe treated symptomatically, and supportive measures instituted as required.
DOSAGE AND ADMINISTRATION
The Fixed Dose Combination (FDC) is recommended for oral administration as once daily
therapy or as directed by the physician.
The patient should be placed on standard cholesterol lowering diet before receiving the FDC andshould be continued on this diet during treatment.The FDC can be administered as a single dose
at any time of the day with or without food.Therapy should be individualised according to goal ofthe therapy and response.After initiation of the therapy, lipid levels should be analysed within 2-4
weeks and dose adjusted accordingly.
STORAGE INSTRUCTIONS
o
Store at a temperature below 30C, protect from light and moisture.
KEEP THE MEDICINE OUT OF REACH OF CHILDREN.
REFERENCES
1.  Lea Andrew P and McTavish D. Atorvastatin: A review of its pharmacology andtherapeutic potential in the management of hyperlipidemias. Drugs 1997; 53(5): 828 – 47.
2.  Leitersdorf E. Selective cholesterol absorption inhibition: A novel strategy in lipid-loweringmanagement. Int J Clin Pract 2002; 56(2): 116 – 119.
3.  von Heek M,Farley C,Compton DS et al.Ezetimibe selectively inhibits intestinalcholesterol absorption in rodents in presence and absence of exocrine pancreaticfunction.Br J Phamacol 2001; 134: 409-417.
4.  Jim McKeney. Combination therapy for elevated low density lipoprotein cholesterol: Thekey to coronary artery Disease Risk Reduction. Am J Cardiol 2002; 90(suppl.):8K-20K
5.  Gibson DM, Bron NJ, Richens A et al. Effects of age and gender on pharmacokinetics ofAtorvastatin in humans. J Clin Pharmacol 1996; 36: 242 - 46.
6.  Yee Helen C and Fang Nancy T. Atorvastatin in the treatment of primaryhypercholesterolemia and mixed dyslipidemias. The Annals of Pharmacology, 1998;
32:1030 - 1043.
7.  Zetia. Physician’s Desk Reference, 2004: Pp 2118 - 2123
8.  Bays HE, Moore PB, Drehbol MA et al. Effectiveness and tolerablity of Ezetimibe inpatients with primary hypercholesterolemia: Pooled analysis of two phase III studies. ClinTher 2001; 23(8): 1209-30
9.  Ballantyne CM, Houri J, Notarbartolo A et al. Effect of Ezetimibe co-administered withAtorvastatin in 628 patients with primaryhypercholesterolaemia.Circulation 2003; 107
:2409-2415
10. Bruckert E. Efficacy and safety of Ezetimibe co-administered with Atorvastatin orSimvastatin in patients with homozygous familial hypercholesterolaemia. Circulation
2002; 105:2469 - 75

2013年5月23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和依泽替米贝组成。
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4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。
药理类别：
胆固醇吸收抑制剂+ HMG-CoA还原酶抑制剂。
活性成分（S）：
依泽替米贝/阿托伐他汀，10mg/20mg 10mg/10mg 10mg/40mg，10mg/80mg的标签。
公司
默克公司
指示（S）：
为了降低升高的总胆固醇，LDL-C，载脂蛋白B，甘油三酯（TG），非HDL-C，并增加HDL-C初级（杂合子家族性和非家族性）或混合型高脂血症。为了降低升高的总胆固醇和LDL-C纯合子家族性高胆固醇血症（HoFH），作为辅助其他降脂治疗（例如，LDL单采），或者如果这样的治疗是不可用的。使用限制：无增量效益和心血管疾病的发病率/死亡率高于阿托伐他汀证明已经建立。没有研究在弗雷德里克森I型，III，IV和V血脂异常。
药理作用：
依折麦布降低血液中的胆固醇被小肠通过抑制胆固醇的吸收。阿托伐他汀是通过抑制HMG-CoA还原酶和胆固醇的合成，降低血浆胆固醇和脂蛋白水平。
临床试验：
在临床研究中，628例患者随机安慰剂相比，依折麦布，阿托伐他汀，或coadminstered的依折麦布和阿托伐他汀相当于Liptruzet在为期12周的研究。
接收所有剂量的阿托伐他汀的患者接受依折麦布/阿托伐他汀的剂量进行比较。在12周的结果表明，依折麦布/阿托伐他汀联合治疗显着降低总胆固醇（-41％和-32％），LDL-C（-56％与-44％），载脂蛋白B（-45％与-36％），TG（-33％和-24％）和非HDL-C（-52％和-41％），相比显着升高HDL-C（7％和4％）汇集所有剂量的阿托伐他汀。
有关临床研究的更多信息：看到完整的标签。
法律分类：
接收
成人：
整片吞服。平常范围：10mg/10mg的到10mg/80mg。最初10mg/10mg或10mg/20mg的LDL-C减少> 55％：可能开始在10mg/40mg;血脂显示器内≥2wks和需要调整剂量。 HoFH：10mg/40mg或10mg/80mg的。伴随胆汁酸螯合剂：给的Liptruzet剂量要么≥2小时前或≥4小时后，胆汁酸螯合剂管理。伴随洛匹那韦/利托那韦：使用最低剂量。伴随瑞那韦/利托那韦，克拉霉素，伊曲康唑，沙奎那韦/利托那韦，福沙那韦，福沙那韦/利托那韦：10mg/20mg最大。伴随奈非那韦或boceprevir治疗：10mg/40mg最大。
儿童：
不成立的。
禁忌（S）：
活动性肝病。不明原因持续肝转氨酶升高。怀孕（X类）。哺乳期的母亲。
警告/注意事项：
肌病/横纹肌溶解症的风险增加（高剂量）。停止CPK升高（> 10×ULN）水平出现或诊断或怀疑性肌病;代扣代缴，如果继发于横纹肌溶解症的倾向，肾功能衰竭的发展。监测肝功能开始之前临床治疗和重复。肝脏疾病或肾功能不全史，密切监察。大量的酒精消费。老年人。
互动（补）
成人剂量。避免环孢素伴，替拉那韦/利托那韦，telaprevir的，吉非贝齐。增强的强CYP3A4抑制剂，西柚汁（> 1.2L/day）。注意与洛匹那韦/利托那韦，秋水仙碱，fenofibrates，烟酸≥1g/day;考虑剂量减少Liptruzet。可能会增加血清地高辛（显示器），口服避孕药。可能是拮抗消胆胺，CYP3A4诱导剂（如依非韦伦，利福平）;利福平同时coadminister。监控口服抗凝血剂。注意用药物，减少内源性类固醇激素的水平或活动（如酮康唑，安体舒通，西咪替丁）。
不良反应（S）
增加ALT / AST，肌肉疼痛，关节痛，腹痛，恶心，提高糖化血红蛋白或空腹血糖;肌病，横纹肌溶解症;罕见：免疫介导的坏死性肌病。
如何提供：
标签-30，90