THERAPEUTIC CLASS:-
Vanish (ezetimibe/simvastatin) is a lipid- lowering product that selectively inhibits the intestinal absorption of cholesterol and related plant sterols and inhibits the endogenous synthesis of cholesterol.

ACTIVE INGREDlENTS:-
Vanish is available for oral use as film coated tablets containing 10 mg of ezetimibe  and 40 mg of simvastatin (Vanish 10 /40) 
Inactive ingredients:
Lactose monohydrate, Magnesium stearate, Butylated hydroxyanisol ,Avicel, Croscarmellose , HPMC , Titanium Dioxide, PEG 6000.

Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is indicated as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other non pharmacologic measures alone has been inadequate. 
• Primary Hypercholesterolemia
Vanish is indicated for as adjunctive therapy to diet for the reduction of elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), triglycerides (TG), and non-high-density lipoprotein cholesterol (non-HDL-C), and to increase high-density lipoprotein cholesterol (HDL-C) in patients with primary (heterozygous familial and non-familial) hypercholesterolemia or mixed hyperlipidemia. 
• Homozygous Familial Hypercholesterolemia (HoFH) 
Vanish is indicated for the reduction of elevated total-C and LDL-C levels in patients with homozygous familial hypercholesterolemia, patients may also receive adjunctive treatments (e.g.LDL apheresis)
• Limitations of Use 
No incremental benefit of Vanish on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin has been established. Vanish has not been studied in Fredrickson type I, III, IV, and V dyslipidemia.

The patient should be placed on a standard cholesterol-lowering diet before receiving vanish and should continue on this diet during treatment with vanish. The dosage should be individualized according to the baseline LDL-C level, the recommended goal of therapy, and the patient’s response. Vanish should be taken as a single daily dose in the evening, with or without food.
The dosage range is 10/10 mg/day through 10/80 mg/day. The recommended usual starting dose is 10/20 mg/day. Initiation of therapy with 10/10 mg/day may be considered for patients requiring less aggressive LDL-C reductions. Patients who require a larger reduction in LDL-C (greater than 55%) may be started at 10/40 mg/day. After initiation or titrations of vanish, lipid levels may be analyzed after 2 or more weeks and dosage adjusted if needed.
• Dosage in Patients with Homozygous Familial Hypercholesterolemia 
Should be as prescribed by the physician. Vanish should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable. 
Use in the elderly
No dosage adjustment is required for elderly patients.
Use in pediatric patients: treatment with vanish is not recommended 
Use in hepatic impairment
No dosage adjustment is required in patients with mild hepatic insufficiency (child – Pugh score 5 or 6) treatment with vanish is not recommended in patients with moderate (child – Pugh score 7 or 9) or severe (child – Pugh score >9) liver dysfunction. (See precautions) 
Use in renal impairment
No dose adjustment is required in patients with moderate renal insufficiency. If treatment in patients with severe renal insufficiency (creatinine clearance ≤30 ml/min) is deemed necessary, dosages above 10/10 mg/day should be implemented cautiously.
Co administrations with Other medicines 
Dosing of ezetimibe/ simvastatin should occur either ≥2 hours before or ≥4 hours after administration of a bile acid sequestrant.
In patients taking cyclosporine or danazol, or ≥ 1 g/day of niacin concomitantly with vanish, the dose of vanish should not exceed 10/10 mg/day. (See precautions, myopathy/rhabdomylosis and drug interaction).
In patients taking amiodarone or verapamil concomitantly with vanish,  the dose of vanish should be as prescribed by physician (See precautions, myopathy/rhabdomylosis and drug interaction).
The safety and effectiveness of ezetimibe administered with fibrates have not been established. Therefore, the combination of vanish and fibrates should be avoided. (See precautions, myopathy/rhabdomylosis and drug interaction).
There is an increased risk of myopathy when simvastatin is used concomitantly with fibrates (especially gemfibrozil). Therefore, although not recommended if vanish is used in Combination with gemfibrozil the dose should not exceed 10/10 mg daily (See precautions, myopathy/rhabdomylosis and drug interaction).

- Hypersensitivity to the active substance or to any of the excipients.
- Active liver disease or unexplained persistent elevations of serum. transaminases.
- Pregnancy and nursing (see pregnancy and nursing mothers).

Myopathy/Rhabdomyolysis
Simvastatin, like other inhibitors of HMG-CoA reductase, occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above ten times the upper limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and very rare fatalities have occurred. The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Predisposing factors for myopathy include advanced age (≥ 65 years) , uncontrolled hypothyroidism, and renal impairment.
Because vanish contains simvastatin, the risk of myopathy/rhabdomylosis is increased by concomitant use of vanish with the following:
Potent inhibitors of CYP3A4, e.g., Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors or nefazodone, particularly with higher doses of vanish (see drug interactions)

Other drugs:
Gemfibrozil and other fibrates or  ≥1 g/day of niacin  particularly with higher doses of vanish  (see drug interactions)
Cyclosporine or Danazol particularly with higher doses of vanish (see drug interactions)
Amiodarone or Verapamil with higher doses of vanish (see drug interactions). Than ongoing clinical trial, myopathy has been reported in 6% of patients receiving simvastatin 80 mg and amiodarone.
Using amiodarone with simvastatin in dose more than 20 mg may increase risk of rhabdomylosis 
Diltiazem: patients on diltiazem treated concomitantly with vanish 10/80 have a slightly increased risk of myopathy. in clinical studies , the risk of myopathy in patients taking simvastatin 40 mg with diltiazem was similar to that in patients taking simvastatin 40 mg without diltazem (see drug interactions) 
As with other HMG-CoA reductase inhibitors, the risk of myopathy/rhabdomylosis is dose related of simvastatin.
In a clinical trial database In which 41,050 patients were treated with simvastatin, with 24,747 (approximately 60%) treated for at least 4 years , the incidence of myopathy was approximately 0.02%, 0.08% and 0.53% zt 20,40 and 80 mg/day , respectively . in these trials, patients were carefully monitored and some interacting medicinal products were excluded.
In post marketing experience with ezetimibe, cases of myopathy and rhabdomylosis have been reported. Most patients who developed rhabdomylosis were taking a statin prior to intiating ezetimibe. However, rhabdomylosis has been reported very rarely with ezetimibe monotherapy and very rarely with the addition of ezetimibe to agents known to be associated with increased risk of rhabdomylosis , such as fibrates.

Consequently: 
The use of vanish concomitantly with potent CYP3A4 inhibitors, (eg. itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors or nefazodone) should be avoided .If treatment with itraconazole, ketoconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with vanish must be suspended during the course of treatment. Concomitant use with other medicines as having a potent inhibitory effect on CYP3A4 at therapeutic doses should be avoided unless the benefits of combined therapy outweigh the increased risk.
The safety and effectiveness of ezetimibe administered with fibrates have not been established. Therefore the concomitant use of vanish and fibrates should be avoided.
The dose of simvastatin should not exceed 10 mg daily in patients receiving concomitant medication with cyclosporine, danazol or gemfibrozil. The combined use of simvastatin with gemfibrozil should be avoided, unless the benefits are likely to outweigh the increased risks of this drug combination. The benefits of the combined use of simvastatin 10 mg daily with other fibrates (except fenofibrate), ciclosporin or danazol should be carefully weighed against the potential risks of these combinations. Caution should be used when prescribing fenofibrate with simvastatin, as either agent can cause myopathy when given alone. The combined use of simvastatin at doses higher than 20 mg daily with amiodarone or verapamil should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy .The combined use of simvastatin at doses higher than 40 mg daily with diltiazem or amlopidine should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy .There is an increased risk of myopathy when simvastatin is used concomitantly with fibrates (especially gemfibrozil) the combined use of simvastatin with gemfibrozil should be avoided, unless the benefits are likely to outweigh the increased risks of this drug combination. The dose of simvastatin should not exceed 10 mg daily for patients receiving concomitant medication with gemfibrozil. Therefore, although not recommended, if vanish is used in combination with gemfibrozil, the dose should not exceed 10/10 mg daily. The dose of vanish should not exceed 10 /10 mg daily in patients receiving concomitant medication with cyclosporine, danazol or ≥ 1 g/day of niacin. The benefits of the use of vanish in patients receiving cyclosporine, danazol, or niacin should be carefully weighed against the risks of these drug combinations and caution should be exercised when initiating vanish in the setting of cyclosporine (see drug interactions).The dose of vanish should not exceed 10/20 mg daily in patients receiving concomitant medication with amiodarone or verapamil. The combined use of vanish at doses higher than 10/20mg daily with amiodarone or verapamil should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy.
All patients starting therapy with vanish, or whose dose of vanish is being increased, should be advised of the risk of myopathy and told to report promptly any unexpected muscle pain, tenderness or weakness. Vanish therapy should be discontinued immediately if myopathy is diagnosed or suspected. The presence of these asymptoms , and / or a CK level >10 times the upper limit of normal indicates myopathy. In most cases, when patients were promptly discontinued from simvastatin treatment, muscle symptoms and CK increase resolved. Periodic CK determinations may be considered in patients starting therapy with vanish or whose dose is being increased, but there is no assurance that such monitoring will prevent myopathy.
Many of the patients who have developed Rhabdomylosis on therapy with simvastatin have had complicated medical histories, including renal insufficiency usually as a consequence of long- standing diabetes mellitus. Such patients taking vanish merit closer monitoring. Therapy with vanish should be temporarily stopped a few days prior to elective major surgery and when any major medical or surgical condition supervenes. 

Liver enzymes:
In controlled co-administration trials in patients receiving ezetimibe with simvastatin, consecutive transaminase elevations (≥ 3 X ULN) have been observed . (See side effects)
It is recommended that LFTs be performed before treatment with vanish begins and thereafter when clinically indicated. Patients titrated to the 10/80 mg dose should receive an additional test prior to titration, 3 months after titration to the 10/80 mg dose, and periodically thereafter (e.g., semiannually) for the first year of treatment.
Special attention should be paid to patients who develop elevated serum transaminase levels, and in these patients, measurements should be repeated promptly and then performed more frequently. If the transaminase levels show evidence of progression, particularly if they rise to 3X ULN and are persistent, the drug should be discontinued.
Vanish should be used with caution in patients who consume substantial of alcohol and/or have a past history of liver disease. Active liver disease or unexplained persistent transaminase elevations are contraindicated to the use of vanish
Hepatic insufficiency 
Due to the unknown  effects of the uncreased exposure to ezetimibe in patients with a moderate or sever hepatic insufficiency. vanish is not recommended in these patients .
Fibrates 
The safety and efficacy of ezetimibe administrated with fibrates have not been established , therefore co-adminstration of vanish and fibrates is not recommended ( see drug interaction )
Cyclosporine
Caution shoul be exercised when initiating  vanish in the setting of cyclosporine 
Cyclosporine concentrations should be monitored in patients recieving vanish  and cyclosporine ( see drug interactions ) 
Anticoagulants 
Vanish is added to warfarin , another coumarin anticoagulants , or fluindione , the international normalized ratio( INR ) should be appropriately monitored ( see drug interactions) 
Pregnancy 
Women who are pregnant or may become pregnant , serum cholesterol and triglycerids   increase during normal pregnancy , and cholesterol or cholesterol derivatives are essential to fetal development . because HMG-COA reductase inhibitor ( statins ) such as simvastatin , decrease cholesterol synthesis and possibly the synthesis of other biological active substances derived from cholesterol , vanish may cause fetal harm when administrated to pregnant women 
Atherosclerosis is a chronic process , and ordinarily discontinuation of lipid – lowering drugs during pregnancy should have  little impact on the long term risk associated with primary hypercholesterolemia 
Vanish is contraindicated during pregnancy 
Simvastatin 
The safety of simvastatin in pregnant women has not been established  . no controlled trials with simvastatin have been conducted in pregnant women . rare reports of congenital anomalies following intrauterine exposure to HMG-COA reductase inhibitors have been received however in an analysis of approximately 200 prospectively followed pregnancies exposed during first trimester to simvastatin or another closely related HMG-COA reductase inhibitors , the incidence of congenital anomalies was comparable to the seen in the general population .the number of pregnancy was statically sufficient to exclude a 2.5 fold or greater increase in congenital anomalies over the background incidence .
Although there is no evidence that the incidence of congenital anomalies in offspring of patient  taking simvastatin  or another closely related HMG-COA reductase inhibitors differs from that observed in the general population , maternal treatment with simvastatin may reduce the fetal levels of mevalonate which is precursor of cholesterol biosynthesis . for this reason , vanish should not be used in women who pregnant , trying to become pregnant or suspected they are  pregnant ,treatment with vanish should be suspended for the duration of pregnancy or until it has been determind that the woman is not pregnant ( see contraindication )
Ezetimibe 
No clinical data on exposed pregnancies are available for ezetimibe . when ezetimibe was given with simvastatin no teratogenic effect were observed in embryo-fetal development studies in pregnant rats . in a pregnant rabbit a low incidence of skeletal malformation was observed .
Nursing mothers 
Studies in rats have shown that ezetimibe is excreted in milk it is not known wither the active component of vanish are excreted into human breast milk , therefore women who are nursing should not take vanish 

CYP3A4 interaction 
In preclinical studies , it has been shown that ezetimibe dos not induce cytochrom P450 drug metabolizing enzymes . no clinical significant pharmacokinetic interactions have been observed between ezetimibe  and drug known to be metabolized by cytochromes P450 , 1A2 , 2D6 , 2C8 , 2C9  and 3A4 , or N- acetyltransferase . simvastatin is metabolized by CYP3A4 but has no CYP3A4 inhibitory activity ; therefore it is not expected to affect the plasma concentrations of other drugs metabolized by CYP3A4 .potent inhibitor of  CYP3A4 ( below ) increase the risk of myopathy by reducing the elimination of simvastatin component of vanish . see precutions , myopathy / rhabdomyolsis , itroconazole , ketoconazole, erythromycin , clarithromycin , telithromycin , HIV protease inhibitors , nefazodone .
Interaction with lipid lowering drugs that can cause myopathy when given alone
The risk of myopathy is also increased by the following lipid lowering drugs that are not potent inhibitors of CYP3A4 , but which can cause myopathy when given alone .
See precaution  , myopathy / rhabdomyolysis , 
Gemfibrozil , other fibrats 
Niacin ( nicotinic acid ) ( ≥ 1 gm /day )
Other drug interactions 
Cyclosporine or Danazol : the risk of myopathy /rhabdomyolysis is increased by concomitant administration of cyclosporine or danazol particulary with  a higher doses of vanish ( see precautions , myopathy / rhabdomyolysis). The degree of increase in ezetimibe exposure may be greater in patient with sever renal impairment . in patients treated with cyclosporine , the potential effects of the increased exposure to ezetimibe from concomitant use should be carefully weighted against the benefits of alterations in lipid levels provided by ezetimibe .
Amiodarone or verapamil : the risk of myopathy / rhabdomyolysis is increased by concomitant administration of amiodarone or verapamil with a higher doses of vanish ( see precautions , myopathy / rhabdomyolysis ).
Cholestyramine : concomitant cholestyramine administration decrease the mean AUC of total ezetimibe ( ezetimibe + ezetimibe glucoronide )approximately 55 % . incremental LDL-C reduction due to adding vanish to cholestyramine may lessened by this interaction 
Delitiazem : patients on dilitiazem treated concomitantly with vanish have a slightly increased risk of myopathy ( see precautions , myopathy / rhabdomyolysis ).
Do not exceed 40 mg simvastatin daily 
The combined use of simvastatin in patients receiving diltiazem should not exceed 40 mg daily unless the clinical benefits is likely to out weight the increased risk of myopathy 
Fibrates : concomitant fenofibrate or gemfibrozil administration increase total ezetimibe concentrations approximately 1.5 –and  1.7 – fold , respectively ; however , these increases are not considered clinically significant .
The safety and effectiveness of vanish administrated with fibrates have not been established .fibrates may increase cholesterol execretion into the bile , leading to cholelithiasis .in a preclinical study on dogs , ezetimibe increase cholesterol in the gallbladder bile although the relevance of this preclinical finding to humans is unknown , co – administration of vanish with fibrates is not recommended until use in patients is studied 
Other interactions 
Grapefruit juice contains one or more components that inhibit CYP3A4 and can increase the plasma levels of drugs metabolized by CAP3A4 . the effect of typical consumption ( one 250 ml glass daily ) is a minimal ( 13%increase in active plasma HMG – COA reductase inhibitory activity as measured by the area under the concentration – time curve ) and of no clinical relevance .however very larg quantities ( over 1 litter daily ) significantly increase the plasma levels of  HMG-COA reductase inhibitory activity during simvastatin therapy and should be avoided while taking vanish ( see precautions,  myopathy / rhabdomyolysis )
Antacids :
Concomitant antacid administration decrease the rate of absorption of ezetimibe but had no effect on the bioavilability of ezetimibe . this decreased rate of absorption is not considered clinically significant .
Digoxin :
In one study , concomitant administration of digoxin with simvastatin resulted in a slight elevation  in plasma digoxin concentrations . patients taking digoxin should be monitored appropriately when vanish is initiated 
Side effects 
Vanish ( or co administration of ezetimibe and simvastatin equivalent to vanish ) has been evaluated for the safety in more than 3800 patients in clinical trails . vanish was generally well tolerated .
The following common ( ≥1/1000 , < 1 / 10 ) drug related adverse experiences were reported in patients taking vanish ( n = 1236) during three similarly designed , placebo –controlled trials : 
Gastrointestinal disorders : flatulence 
Musculoskeletal and connective tissue disorders : myalgia 
Nervous system disorders : headache 
Post markting experience :
The adverse reactions reported for vanish are consistant with those previously reported with ezetimibe and/or simvastatin 
Additional adverse events reported commonly with ezetimibe during clinical trials :
Gastrointestinal disorders  : abdominal pain , diarrhea , general disorders and administration site conditions : fatigue . during post-marketing use the following adverse events were reported ,regardless to casuality assessment : blood and lymphatic system disorders : thrombocytopenia : hepato- biliary disorders : cholilithasis , cholecystitis, hepatitis : musculoskeletal , connective tissue and bone disorders : arthralgia , and very rarely myopathy / rhabdomolysis ( see precaution ) laboratory values : increased CPK ; elevation of liver transaminases ; skin and subcutaneous tissue disorders : hypersensitivity reactions , including rash and urticaria ( rare  1/10000 < 1/1000 ) and anaphylaxis and angiodema ( very rare  <1/10000) gastrointestinal disorders ; nausea ( rare ) ; pancreatitis ( very rare ) 
Additional adverse events reported rarely with simvastatin during clinical studies and or post marketing use :
Blood and lymphatic system disorders : anemia ; gastrointestinal disorders : abdominal pain , constipation , diarrhea , dyspepsia , nausea , vomiting and pancreatitis : general disorders and administration site conditions : asthenia , hepatic disorders : hepatitis / jaundice : musculoskeletal connective tissue and bone disorders : muscle cramps , myopathy , rhabdomyolisis ( see precautions ) nervous system disorders : dizziness , paresthesia , peripheral neuropathy ; skin and subcutaneous tissue disorders : alopecia , pruritus , rash and apparent hypersensitivity syndrome has been reported rarely which has included some of the following features : angioedema , lupus like syndrome polymyalgia rheumatica , dermatomyositis , vasculaitis , thrombocytopenia , eosinophelia , ESR increased , arthritis , arthralgia , urticaria , photosensitivity , fever , flushing , dyspenea and malaise 
Laboratory values in controlled clinical co administration trails . the incidence of clinically important elevations in serum transaminasis ( ALT and or AST  ≥ 3 x ULN ,consecutive ) was 1.7 % for patients treated with vanish these elevations were generally asymptomatic , not associated with cholestasis and returned to baseline after discontinuation of therapy or with continued treatment ( see precautions ) 
Clinically important elevations of CK ( ≥10ULN ) were seen in 0.2 % of patients treated with vanish 

Vanish 
No specific treatment of oder dosage with vanish can be recommended . in the event of an over dose, symptomatic and supportive measures should be employed . co administration of ezetimibe ( 1000 mg / kg ) and simvastatin ( 1000 mg / kg ) was well tolerated in acute oral toxicity studies in mice and rats .
No clinical signs of toxicity were observed in these animals . the estimated oral LD 50 for both species was ezetimibe ≥ 1000 mg / kg .
Ezetimibe 
In clinical studies , administration of ezetimibe 50 mg / day to 15 healthy subjects for up to 14 days , or 40 mg / day to 18 patients with a primary hypercholesterolemia for up to 56 days , was generally well tolerated 
A few cases of over dosage have been reported : most have been associated with adverse experiences 
Reported adverse experiences have not been serious 
Simvastatin 
A few cases of over dosage have been reported ; the maximum dose taken was 3.6 g . all patients recovered without sequelae 

Store at temperature not exceeding 30 Cº ,  in a dry place 

Pack of 1 strip ( AL / PVC ) 7 film coated tablets and an inner leaflet.
keep out of reach of children.