Ezetimibe Simvastatin (Vytorin) is a combination of two drugs. Ezetimibe (Zetia) inhibits the intestinal absorption of fats while simvastatin inhibits the rate-limiting enzyme (HMG CoA-reductase inhibitor) involved in the biosynthesis of lipids.

Ezetimibe Simvastatin (Vytorin) Uses:

• Homozygous familial hypercholesterolemia:

  • As an adjunct to diet for the reduction of elevated total cholesterol (total-C) and low-density lipoprotein cholesterol (LDL-C) in patients with homozygous familial hypercholesterolemia, as an adjunct to other lipid-lowering treatments (eg, LDL apheresis), or if such treatments are unavailable

• Primary hyperlipidemia:

  • As an adjunct to diet for the reduction of elevated total-C, apolipoprotein B (apo B), LDL-C, triglycerides, and non-high-density lipoprotein cholesterol (HDL-C), and to increase HDL-C in patients with primary (heterozygous familial and nonfamilial) hyperlipidemia or mixed hyperlipidemia

• Ezetimibe Simvastatin (Vytorin) Guideline recommendations:

  • Simvastatin:
    • Primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD) to reduce the risk of ASCVD in select adult patients.
  • Limitations of use:
    • No incremental benefit of ezetimibe/simvastatin on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin has been established. Ezetimibe/simvastatin has not been studied in Fredrickson Type I, III, IV, and V dyslipidemias.

Ezetimibe Simvastatin (Vytorin) Dose in Adults

Note:

• Dosing limitation: Simvastatin 80 mg is limited to patients that have been taking this dose for >12 consecutive months without evidence of myopathy and are not currently taking or beginning a simvastatin dose-limiting or contraindicated interacting medication.
• If the patient is unable to achieve the low-density lipoprotein-cholesterol (LDL-C) goal using the 40 mg dose of simvastatin, increasing to 80 mg dose is not recommended. Instead, switch patients to an alternative LDL-C-lowering treatment providing greater LDL-C reduction.
• After initiation or titration, monitor lipid response after more than 2 weeks and adjust the dose as necessary.

Ezetimibe Simvastatin (Vytorin) Dose in the treatment of Homozygous familial hypercholesterolemia:

• Oral: Ezetimibe 10 mg and simvastatin 40 mg in the evening once in a day.

Ezetimibe Simvastatin (Vytorin) Dose in the treatment of Primary hyperlipidemia:

• Initial: Ezetimibe 10 mg and simvastatin 10 to 20 mg orally in the evening once in a day.
• Consider to patients who require more than 55% reduction in LDL-C at ezetimibe 10 mg and simvastatin 40 mg in the evening once in a day.
• Dosing range: Ezetimibe 10 mg and simvastatin 10 to 40 mg one time in the daily routine.

Ezetimibe Simvastatin (Vytorin) Dosage adjustment with concomitant medications: Oral:

Note: Patients currently tolerating and requiring a dose of simvastatin 80 mg who require initiation of an interacting drug with a dose cap for simvastatin should be switched to an alternative statin with less potential for drug-drug interaction.

• Amiodarone, amlodipine, or ranolazine:
  • Simvastatin dose should not exceed 20 mg once in a day.
• Diltiazem, dronedarone, or verapamil:
  • Simvastatin dose should not exceed 10 mg one time in the daily routine.
• Lomitapide:
  • Reduce simvastatin dose by 50% when initiating lomitapide.
  • Simvastatin dose should not exceed 20 mg once a day (or 40 mg one time daily for those patients who previously tolerated simvastatin 80 mg daily for 1 year or more than 1 year without evidence of muscle toxicity).

Ezetimibe Simvastatin (Vytorin) Dose in Childrens

Note:

• A lower, conservative dosing regimen may be required in patients predisposed to myopathy, including patients of Chinese descent or those concurrently receiving other lipid-lowering agents (eg, niacin, fibric acid derivatives), amiodarone, amlodipine, diltiazem, dronedarone, ranolazine, verapamil (see the following conservative, maximum adult doses)

Ezetimibe Simvastatin (Vytorin) Dose in the treatment of Heterozygous familial hypercholesterolemia:

• Children of 10 years or more than 10 years and Adolescents (males and post menarchal females):

  • Initial: Ezetimibe 10 mg and simvastatin 10 to 20 mg orally in the evening once in a day.
  • The reported final dosing range: Ezetimibe 10 mg and simvastatin 10 to 40 mg one time daily;
  • The maximum dose: Ezetimibe 10 mg and simvastatin 40 mg

Ezetimibe Simvastatin (Vytorin) Dosing adjustment with concomitant medications:

• There are no recommendations in the manufacturer's labeling for patients less than 18 years.
• In adolescents 18 years or more than 18 years, the following have been suggested:
  • Diltiazem or verapamil:
    • Maximum daily simvastatin dose: 10 mg per day.
  • Amiodarone or amlodipine:
    • Maximum daily simvastatin dose: 20 mg per day.

Pregnancy Risk Factor X

• Women who are pregnant or may become pregnant should not use this medication.
• Talk to individual agents.

Use of Ezetimibe Simvastatin during breastfeeding

• It is unknown if breast milk contains simvastatin or ezetimibe.
• Breastfeeding women should not use this medication. Refer to individual agents.

Ezetimibe Simvastatin (Vytorin) Dose in Kidney Disease:

• GFR ≥60 mL/minute/1.73 m²:

  • No dosage adjustment required.

• GFR <60 mL/minute/1.73 m²:

  • Ezetimibe 10 mg and simvastatin 20 mg once in the evening daily (higher doses should be used with caution).

Ezetimibe Simvastatin (Vytorin) Dose in Liver disease:

Its use is contraindicated in patients with active liver disease or unexplained transaminase elevations.

Side Effects of Ezetimibe Simvastatin (Vytorin):

• Central nervous system:

  • Headache

• Gastrointestinal:

  • Diarrhea

• Hepatic:

  • Increased serum ALT

• Infection:

  • Influenza

• Neuromuscular & skeletal:

  • Myalgia
  • Limb pain
  • Myopathy

• Respiratory:

  • Upper respiratory infection

Contraindications to Ezetimibe Simvastatin (Vytorin):

• Hypersensitivity to simvastatin, ezetimibe, or any component of this medication;
• Coadministration with strong CYP3A4 inhibitors like:
  • ketoconazole,
  • itraconazole,
  • voriconazole,
  • posaconazole,
  • Telaprevir
  • nefazodone,
  • boceprevir
  • Erythromycin
  • Clarithromycin
  • telithromycin,
  • cobicistat-containing products,
  • gemfibrozil,
  • Cyclosporine, or
  • danazol;
• Active liver disease, persistent elevations in liver transaminases that are not explained;
• Use in pregnant women;
• Breastfeeding

Warnings and precautions

• Diabetes mellitus:

  • HMG-CoA reductase inhibits have been shown to increase HbA and fasting glucose. However, statin therapy has many benefits that outweigh the risks of dysglycemia.

• Hepatotoxicity:

  • Rare are postmarketing reports that indicate a fatal or non-fatal liver failure.
  • If severe hepatotoxicity occurs with clinical symptoms, hyperbilirubinemia, jaundice or other signs during treatment, interrupt therapy.
  • If simvastatin isn't being used for another reason, do not take it again.
  • The potential for adverse hepatic effects from ethanol may be increased. Patients should be instructed to limit their ethanol intake.
  • At baseline, liver enzyme tests should be performed. However, routine periodic monitoring of liver enzymes may not be necessary.

• Immune-mediated necrotizing myopathy, (IMNM).

  • For treatment, immunosuppressive therapy (e.g., azathioprine or corticosteroids), may be used.
  • IMNM, an autoimmune-mediated form of myopathy, has been described (rarely) using HMG-CoA reductase inhibition therapy. IMNM is a proximal weakness of the muscles with elevated CPK levels that persists despite discontinuation HMG-CoA reductase inhibition therapy. Additionally, muscle biopsy might show necrotizing myopathy, with limited inflammation.

• Myopathy and rhabdomyolysis

  • Patients who have received HMG-CoA reductase inhibits have experienced rhabdomyolysis and/or myopathy.
  • The dose-related risk increases with high doses (simvastatin80 mg), concurrent use other lipid-lowering drugs (fibric acids derivatives or niacin at dosages greater than 1 gram per day or more that 1 g per daily), other interacting drugs, such as moderate-to-strong CYP3A4 inhibitions, age 65 or more, female gender, uncontrolled hyperthyroidism and renal dysfunction.
  • Myopathy and rhabdomyolysis have also been reported using ezetimibe monotherapy.
  • Patients taking colchicine or other myopathy drugs should be cautious. These patients are more likely to develop myopathy.
  • Patients should be taught to report any unexplained pain, tenderness or weakness in their muscles.

• Ethanol

  • Be aware of patients who have had liver disease in the past or those who drink a lot of alcohol.

• Hepatic impairment

  • It is not recommended for use in patients with liver disease or undiagnosed transaminase elevations.

• Renal impairment

  • Patients with severe renal impairment should not be given simvastatin unless they have previously tolerated simvastatin in doses of 5 mg or greater than 5mg.
  • Simvastatin should not be taken in excess of 20 mg daily. Patients with moderate-to-severe kidney impairment (i.e. CrCl 60 mL/minute/1.73m2) should be monitored closely for any adverse reactions (eg, myopathy).
  • For mild-to-moderate impairment, an initial dosage adjustment is not required.
  • Myopathy may also be more likely if there is renal impairment.

Monitoring parameters:

2013 ACC/AHA Blood Cholesterol Guideline recommendations: Lipid panel (total cholesterol, HDL, LDL, triglycerides):

• Baseline lipid panel;
• fasting lipid profile within 4 to 12 weeks after initiation or dose adjustment and every 3 to 12 months (as clinically indicated) thereafter.
• If 2 consecutive LDL levels are less than 40 mg/dL, consider decreasing the dose.

Hepatic transaminase levels:

• Baseline measurement of hepatic transaminase levels (ie, ALT);
• measure hepatic function if symptoms suggest hepatotoxicity (eg, unusual fatigue or weakness, abdominal pain, loss of appetite, dark-colored urine, or yellowing of skin or sclera) during therapy.

CPK:

• CPK should not be routinely measured.
• Baseline CPK measurement is reasonable for some individuals (eg, family history of statin intolerance or muscle disease, clinical presentation, concomitant drug therapy that may increase risk of myopathy).
• May measure CPK in any patient with symptoms suggestive of myopathy (pain, tenderness,  cramping, stiffness, weakness, or generalized fatigue).
• Evaluate for new-onset diabetes mellitus during therapy; if diabetes develops, continue statin therapy, and encourage adherence to a heart-healthy diet, a healthy body weight, physical activity, and tobacco cessation.
• If the patient develops a confusional state or memory impairment, may evaluate the patient for nonstatin causes (eg, exposure to other drugs), systemic and neuropsychiatric causes, and the possibility of adverse effects associated with statin therapy.

Manufacturer's labeling:

• Baseline liver function tests and repeat when clinically indicated thereafter. Upon initiation or titration, the lipid panel should be analyzed after 2 weeks or more than 2 weeks.

How to administer Ezetimibe Simvastatin (Vytorin)?

• Oral: May be administered without regard to meals.
• Administer in the evening for maximal efficacy.
• Ezetimibe/simvastatin should be taken for 2 hours or more than 2 hours before or 4 hours or more than 4 hours after administration of a bile acid sequestrant.

Mechanism of action of Ezetimibe Simvastatin (Vytorin):

Ezetimibe:

• It reduces cholesterol absorption at the small intestinal brush border, which results in a decrease in cholesterol delivery to the liver. 
• Ezetimibe blocks Niemann-Pick C1Like1(NPC1L1) which is a sterol transporter.

Simvastatin:

• A methylated derivative of lovastatin that acts by competitively inhibiting 3-hydroxy3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the rate-limiting step in cholesterol biosynthesis. HMG-CoA inhibitors are able to lower high-sensitivity CRP (hsCRP) levels.
• They also have pleiotropic effects such as improved endothelial function and reduced inflammation at the site where the coronary plaque is formed. See individual agents.

Bioavailability:

• Vytorin is equivalent to simvastatin and coadministered ezetimibe.

International Brand Names of Ezetimibe and simvastatin:

• Vytorin
• Inegy
• Ridolip-S
• Simpex Duo
• Simvative
• Simvazet
• Starstat-EZ
• Tiazomet-S
• Vasotenal EZ
• Vytorin
• Actimibe Plus
• Adacai
• Beartorin
• Colmibe
• Duolip
• Ezesimteva
• Zintrepid
• Zytovyrin S

Ezetimibe and simvastatin Brand Names in Pakistan: