Ezetimibe and simvastatin

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

You should not use this medicine if you are allergic to simvastatin (Zocor) or ezetimibe (Vytorin, Zetia), or if you have:

• active liver disease;

• abnormal liver function tests; or

• if you are pregnant or breast-feeding.

The following drugs can increase your risk of serious muscle problems if you take them together with ezetimibe and simvastatin. These drugs should not be used while you are taking simvastatin:

• cyclosporine;

• danazol;

• gemfibrozil;

• nefazodone;

• an antibiotic--clarithromycin, erythromycin, telithromycin;

• antifungal medication--itraconazole, ketoconazole, posaconazole, voriconazole;

• hepatitis C medications--boceprevir, telaprevir; or

• HIV/AIDS medication--atazanavir, cobicistat (Stribild, Tybost), indinavir, nelfinavir, ritonavir, saquinavir, tipranavir.

Before you start taking ezetimibe and simvastatin, tell your doctor if you are already using any of these other medicines:

• amiodarone;

• amlodipine (sometimes in combination medicines--Caduet, Exforge, Lotrel, Tekamlo, Tribenzor, Twynsta, Amturnide);

• diltiazem;

• dronedarone;

• ranolazine; or

• verapamil.

To make sure ezetimibe and simvastatin is safe for you, tell your doctor if you have:

• a thyroid disorder;

• a history of liver or kidney disease;

• a history of liver problems caused by alcohol;

• low blood pressure;

• an electrolyte imbalance (such as low levels of potassium or magnesium in your blood);

• untreated or uncontrolled seizures;

• if you drink large amounts of alcohol;

• if you are older than 65; or

• if you are of Chinese descent.

FDA pregnancy category X. This medication can harm an unborn baby or cause birth defects. Do not take ezetimibe and simvastatin if you are pregnant. Use effective birth control. Stop using the medicine and tell your doctor right away if you become pregnant.

It is not known whether ezetimibe and simvastatin passes into breast milk or if it could harm a nursing baby. Do not breast-feed while using this medicine.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For ezetimibe and simvastatin, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to ezetimibe and simvastatin or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of ezetimibe and simvastatin combination in children 10 to 17 years of age. However, safety and efficacy of ezetimibe and simvastatin combination in children younger than 10 years of age have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of ezetimibe and simvastatin combination in the elderly. However, elderly patients are more likely to have age-related muscle problems, which may require caution in patients receiving ezetimibe and simvastatin combination.

Pregnancy

Breast Feeding

Studies in women breastfeeding have demonstrated harmful infant effects. An alternative to this medication should be prescribed or you should stop breastfeeding while using ezetimibe and simvastatin.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking ezetimibe and simvastatin, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using ezetimibe and simvastatin with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Amprenavir
• Atazanavir
• Boceprevir
• Clarithromycin
• Cobicistat
• Cyclosporine
• Danazol
• Darunavir
• Erythromycin
• Fosamprenavir
• Gemfibrozil
• Idelalisib
• Indinavir
• Itraconazole
• Ketoconazole
• Lopinavir
• Mibefradil
• Mifepristone
• Nefazodone
• Nelfinavir
• Paritaprevir
• Posaconazole
• Ritonavir
• Saquinavir
• Telaprevir
• Telithromycin
• Tipranavir
• Voriconazole

Using ezetimibe and simvastatin with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Acenocoumarol
• Amiodarone
• Amlodipine
• Azithromycin
• Bezafibrate
• Carbamazepine
• Ceritinib
• Ciprofibrate
• Ciprofloxacin
• Clofibrate
• Colchicine
• Conivaptan
• Dabigatran Etexilate
• Dalfopristin
• Daptomycin
• Delavirdine
• Diltiazem
• Eltrombopag
• Eslicarbazepine Acetate
• Fenofibrate
• Fenofibric Acid
• Fluconazole
• Fusidic Acid
• Gemfibrozil
• Lomitapide
• Lumacaftor
• Niacin
• Pazopanib
• Quinupristin
• Ranolazine
• Risperidone
• Simeprevir
• Tadalafil
• Verapamil
• Warfarin

Using ezetimibe and simvastatin with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Albiglutide
• Alitretinoin
• Bosentan
• Cholestyramine
• Clopidogrel
• Colestipol
• Cyclosporine
• Dasatinib
• Digoxin
• Dronedarone
• Efavirenz
• Fenofibrate
• Fenofibric Acid
• Fosphenytoin
• Interferon Beta
• Levothyroxine
• Oat Bran
• Oxcarbazepine
• Pectin
• Phenytoin
• Rifampin
• St John's Wort
• Ticagrelor

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using ezetimibe and simvastatin with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use ezetimibe and simvastatin, or give you special instructions about the use of food, alcohol, or tobacco.

• Cranberry Juice
• Grapefruit Juice

Other Medical Problems

The presence of other medical problems may affect the use of ezetimibe and simvastatin. Make sure you tell your doctor if you have any other medical problems, especially:

• Alcohol abuse, or history of or
• Chinese ancestry or
• Diabetes or
• Hypothyroidism (an underactive thyroid), not well controlled or
• Liver disease, history of—Use with caution. May cause side effects to become worse.

• Electrolyte disorders, severe or
• Endocrine disorders, severe or
• Epilepsy (seizures), not well-controlled or
• Hypotension (low blood pressure) or
• Kidney disease, severe or
• Major surgery or trauma, recent or
• Metabolic disorders, severe or
• Sepsis (severe infection in the blood)—Patients with these conditions may be at risk for muscle or kidney problems.

• Liver disease, active or
• Liver enzymes elevated—Should not be used in patients with these conditions.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Headache.
• Loose stools (diarrhea).

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

• Vytorin

2013 ACC/AHA Blood Cholesterol Guideline recommendations (Stone, 2013):

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 <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, loss of appetite, abdominal pain, 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, stiffness, cramping, 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, physical activity, a healthy body weight, and tobacco cessation.

If patient develops a confusional state or memory impairment, may evaluate 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, lipid panel should be analyzed after ≥2 weeks.

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache or diarrhea. Have patient report immediately to prescriber signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), abnormal heartbeat, swelling of arms or legs, urinary retention, change in amount of urine passed, painful urination, polyuria, muscle pain, muscle tenderness, or muscle weakness (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

CrCl 60 mL/min or greater: No dosage adjustment recommended

CrCl less than 60 mL/min with chronic kidney disease: Dose should be 10 mg ezetimibe-20 mg simvastatin orally once a day in the evening. Doses higher than this should be used with caution and close monitoring.

Administration advice:
-Ezetimibe-simvastatin should be taken as a single daily dose in the evening, without regard to meals.

Monitoring:
Hepatic: Baseline liver function tests, measured periodically thereafter as clinically indicated; signs and symptoms of serious hepatic injury
Musculoskeletal: Signs and symptoms of myopathy; CK levels

General:
-Grapefruit juice should be avoided during ezetimibe-simvastatin therapy.

Patient advice:
-All patients starting therapy with ezetimibe-simvastatin, or whose dose is being increased, should be advised of the risk of myopathy and told to report any unexplained muscle pain, tenderness, or weakness.

There are no studies of ezetimibe-simvastatin use during pregnancy; however, there are rare reports of congenital anomalies in infants exposed to statins in utero. Animal reproduction studies of simvastatin in rats and rabbits showed no evidence of teratogenicity. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Lipid-lowering drugs offer no benefit during pregnancy, because cholesterol and cholesterol derivatives are needed for normal fetal development. Atherosclerosis is a chronic process, and discontinuation of lipid-lowering drugs during pregnancy has little impact on long-term outcomes. AU TGA pregnancy category D: Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts should be consulted for further details. FDA pregnancy category X: Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits.

Use of ezetimibe-simvastatin is contraindicated. AU TGA pregnancy category: D US FDA pregnancy category: X Women of childbearing potential should be encouraged to use adequate contraception.