Ezetimibe/simvastatin

What is Ezetimibe/simvastatin?

• Ezetimibe/simvastatin (Vytorin), which contains a cholesterol absorption inhibitor and an HMG-CoA reductase inhibitor (statin), used to lower the level of your "bad" cholesterol (LDL) ,to increase the level of your "good" cholesterol (HDL) and to lower the level of fat in your blood (triglycerides).

What are the uses of this medicine?

This medicine is used as adjunctive therapy to diet to:

• reduce elevated total-C, LDL-C, Apo B, TG, and non-HDL-C, and to increase HDL-C in patients with primary (heterozygous familial and non-familial) hyperlipidemia or mixed hyperlipidemia.
• reduce elevated total-C and LDL-C in patients with homozygous familial hypercholesterolemia (HoFH), as an adjunct to other lipid-lowering treatments.

How does this medicine work?

• An orally bioavailable combination agent containing the cholesterol absorption inhibitor ezetimibe and the hepatic hydroxymethyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitor simvastatin, with lipid-lowering activity.
• Upon oral administration, ezetimibe binds to the sterol transporter Niemann-Pick C1-Like 1 (NPC1L1) at the brush border of the small intestine and inhibits the intestinal absorption of biliary and dietary cholesterol and related phytosterols.
• This decreases blood cholesterol levels, decreases the delivery of intestinal cholesterol to the liver, reduces hepatic cholesterol stores and enhances the clearance of cholesterol from the bloodstream.
• Upon administration of simvastatin and subsequent hydrolyzation to its active beta-hydroxyacid form, this statin competitively inhibits HMG-CoA reductase, the enzyme which catalyzes the conversion of HMG-CoA to mevalonate, which is an essential step in cholesterol synthesis.
• Ezetimibe and simvastatin together reduce blood levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), triglycerides (TGs), very-low-density lipoproteins (VLDL), and apolipoprotein B (Apo B), and increase the plasma concentration of high-density lipoprotein cholesterol (HDL-C).
• Higher cholesterol blood levels appear to be associated with an increased risk in the proliferation of certain cancer cells, such as prostate cancer cells.

Who Should Not Use this medicine ?

This medicine cannot be used in patients who take:

Certain anti-fungal medicines including:

• itraconazole
• ketoconazole
• posaconazole
• voriconazole

• HIV protease inhibitors (indinavir, nelfinavir, ritonavir, saquinavir, tipranavir, or atazanavir)
• Certain hepatitis C virus protease inhibitors (such as boceprevir or telaprevir)

• Certain antibiotics, including:
• erythromycin
• clarithromycin
• telithromycin
• nefazodone

• medicines containing cobicistat
• A fibric acid medicine for lowering cholesterol called gemfibrozil
• cyclosporine
• danazol

What drug interactions can this medicine cause?

• Strong CYP3A4 Inhibitors, (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol use is Contraindicated with Vytorin.
• Coadministration of Vytorin with lipid-modifying doses (≥1 g/day) of niacin is not recommended in Chinese patients.
• Patients taking digoxin should be monitored appropriately when Vytorin is initiated.
• The safety and effectiveness of Vytorin administered with fibrates have not been established.
• Cases of myopathy, including rhabdomyolysis, have been reported with simvastatin coadministered with colchicine, and caution should be exercised when prescribing Vytorin with colchicine.
• Cases of rhabdomyolysis have been reported with Vytorin administered with daptomycin. Temporarily suspend Vytorin in patients taking daptomycin.

Is this medicine FDA approved?

• Initial U.S. Approval: 2004

How should this medicine be used?

Recommended dosage:

• Dose range is 10/10 mg/day to 10/40 mg/day.
• Recommended usual starting dose is 10/10 or 10/20 mg/day.
• Due to the increased risk of myopathy, including rhabdomyolysis, use of the 10/80-mg dose of Vytorin should be restricted to patients who have been taking Vytorin 10/80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity.
• Patients who are currently tolerating the 10/80-mg dose of Vytorin who need to be initiated on an interacting drug that is contraindicated or is associated with a dose cap for simvastatin should be switched to an alternative statin or statin-based regimen with less potential for the drug-drug interaction.
• Due to the increased risk of myopathy, including rhabdomyolysis, associated with the 10/80-mg dose of Vytorin, patients unable to achieve their LDL-C goal utilizing the 10/40-mg dose of Vytorin should not be titrated to the 10/80-mg dose, but should be placed on alternative LDL-C-lowering treatment(s) that provides greater LDL-C lowering.
• Dosing of Vytorin should occur either ≥2 hours before or ≥4 hours after administration of a bile acid sequestrant.

Administration:

• Take Vytorin exactly as your doctor tells you to take it.
• Do not change your dose or stop taking Vytorin without talking to your doctor.
• Take Vytorin 1 time each day in the evening.
• Take Vytorin with or without food.
• While taking Vytorin, continue to follow your cholesterol-lowering diet and to exercise as your doctor told you to.
• If you miss a dose, do not take an extra dose. Just resume your usual schedule.
• Your doctor should do fasting blood tests to check your cholesterol while you take Vytorin. Your doctor may change your dose of Vytorin if needed.
• If you take too much Vytorin, call your doctor or Poison Control Center at 1-800-222-1222 or go to the nearest hospital emergency room right away.

What are the dosage forms and brand names of this medicine?

This medicine is available in fallowing doasage form:

• As Tablets (ezetimibe mg/simvastatin mg): 10/10, 10/20, 10/40, 10/80

This medicine is available in fallowing brand namesː

• Vytorin

What side effects can this medication cause?

The most common side effects of this medicine include:

• headache
• increased liver enzyme levels
• muscle pain
• upper respiratory infection
• diarrhea

Additional side effects that have been reported in general use with Vytorin or with ezetimibe or simvastatin tablets (tablets that contain the active ingredients of Vytorin) include:

• allergic reactions including swelling of the face, lips, tongue, and/or throat that may cause difficulty in breathing or swallowing (which may require treatment right away), rash, hives; joint pain; inflammation of the pancreas; nausea; dizziness; tingling sensation; depression; gallstones; trouble sleeping; poor memory; memory loss; confusion; erectile dysfunction; breathing problems including persistent cough and/or shortness of breath or fever.

Vytorin may cause serious side effects, including:

• Muscle pain, tenderness and weakness (myopathy)
• Liver problems

What special precautions should I follow?

• Patients should be advised of the increased risk of myopathy, including rhabdomyolysis, with the 10/80-mg dose.
• Patients should be advised to report promptly any unexplained and/or persistent muscle pain, tenderness, or weakness. Vytorin should be discontinued immediately if myopathy is diagnosed or suspected.
• Risks of Skeletal muscle effects (e.g., myopathy and rhabdomyolysis) increase with higher doses and concomitant use of certain medicines. Predisposing factors include advanced age (≥65), female gender, uncontrolled hypothyroidism, and renal impairment. Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported.
• Liver enzyme abnormalities were obsereved with Vytorin. Persistent elevations in hepatic transaminases can occur. Check liver enzyme tests before initiating therapy and as clinically indicated thereafter.
• Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including simvastatin.

What to do in case of emergency/overdose?

Management of overdosage:

• No specific treatment of overdosage with Vytorin can be recommended. In the event of an overdose, symptomatic and supportive measures should be employed.

Can this medicine be used in pregnancy?

• Vytorin is contraindicated in women who are or may become pregnant.

Can this medicine be used in children?

• Vytorin has not been studied in patients younger than 10 years of age or in pre-menarchal girls.

What are the active and inactive ingredients in this medicine?

• Active Ingredients: ezetimibe and simvastatin
• Inactive Ingredients: butylated hydroxyanisole NF, citric acid monohydrate USP, croscarmellose sodium NF, hypromellose USP, lactose monohydrate NF, magnesium stearate NF, microcrystalline cellulose NF, and propyl gallate NF.

Who manufactures and distributes this medicine?

• Distributed by: Merck Sharp & Dohme Corp., a subsidiary of

MERCK & CO., INC., Whitehouse Station, NJ

What should I know about storage and disposal of this medication?

• Store Vytorin at room temperature between 68°F to 77°F (20°C to 25°C).
• Keep Vytorin in its original container until you use it.
• Keep Vytorin in a tightly closed container, and keep Vytorin out of light.
• Keep Vytorin and all medicines out of the reach of children.

• Dailymed label info on Ezetimibe/simvastatin
• FDA Ezetimibe/simvastatin

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