Simvastatin

Certain drugs interact with Zocor and should be avoided. Among them are anti-fungal drugs, some antibiotics, and an antidepressant.

• Itraconazole (Sporanox)
• Ketoconazole (Nizoral)
• Posaconazole (Noxafil)
• Voriconazole (Vfend)
• Erythromycin (E-Mycin, Erythrocin, E.E.S.)
• Telaprevir (Incivek)
• Nefazodone (Serzone)

Other drugs may also interact. For that reason, be sure to tell your doctor about any prescription, non-prescription, over-the-counter (OTC), illegal and recreational drugs, herbal remedies, nutritional and dietary supplements, and all other drugs and treatments you're taking.

Zocor and Alcohol

If you are on Zocor, you should avoid drinking too much alcohol. Ask your doctor about whether to drink and how much.

Zocor and Grapefruit

Avoid grapefruit juice and grapefruit while taking Zocor. It can cause too much of the drug to stay in your body, and that can increase the risk of side effects.

In rare cases, simvastatin can cause a condition that results in the breakdown of skeletal muscle tissue, leading to kidney failure. Call your doctor right away if you have unexplained muscle pain, tenderness, or weakness especially if you also have fever, unusual tiredness, and dark colored urine.

Never take simvastatin in larger amounts, or for longer than recommended by your doctor. Follow your doctor's dosing instructions very carefully. Taking too much of this medication may cause serious or life-threatening side effects.

Many other drugs can interact with simvastatin. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Give a list of all your medicines to any healthcare provider who treats you.

Before taking simvastatin, tell your doctor if you have ever had liver or kidney disease, diabetes, or a thyroid disorder, if you are of Chinese descent, or if you drink more than 2 alcoholic beverages daily.

Simvastatin can harm an unborn baby or cause birth defects. Do not use if you are pregnant.

Grapefruit and grapefruit juice may interact with simvastatin and lead to potentially dangerous effects. Do not consume grapefruit products while taking this medication.

• Cholesterol
• Heart Attack
• Statins (How They Work, Side Effects and Interactions)
• Stroke (Signs, Symptoms, Warning Signs)

• Importance of adhering to nondrug therapies and measures, including adherence to a heart-healthy diet, regular exercise, avoidance of tobacco products, and maintenance of a healthy weight.1 350

• Importance of obtaining fasting lipoprotein profile periodically.1

• Risk of myopathy and/or rhabdomyolysis; risk increased with higher dosages (i.e., 80 mg daily) or when used concomitantly with certain other drugs or grapefruit juice.1 90 91 92 93 Importance of patients promptly reporting unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever, or if such manifestations persist after discontinuance of therapy.1

• Risk of adverse hepatic effects.1 Importance of promptly reporting any symptoms suggestive of liver injury (e.g., fatigue, anorexia, right upper abdominal discomfort, dark urine, jaundice).1

• Risk of nonserious, reversible cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion).1 200

• Risk of increased glucose concentrations and development of type 2 diabetes.1 200 May need to monitor glucose concentrations following initiation of statin therapy.201

• Importance of advising women and adolescent girls to avoid pregnancy (i.e., using effective and appropriate contraceptive methods) during therapy and informing pregnant women of risk to fetus.1

• Importance of avoiding breast-feeding during therapy.1 If the patient has a lipid disorder and is breast-feeding, importance of contacting a clinician to discuss other antilipemic treatment options.1

• Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

• Importance of informing patients of other important precautionary information.1 (See Cautions.)

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

More common

• Dizziness
• fainting
• fast or irregular heartbeat

Less common

• Bladder pain
• bloody or cloudy urine
• blurred vision
• body aches or pain
• chills
• cough
• dark-colored urine
• difficult, burning, or painful urination
• difficulty with breathing
• difficulty with moving
• dry mouth
• ear congestion
• fever
• flushed, dry skin
• frequent urge to urinate
• fruit-like breath odor
• headache
• increased hunger
• increased thirst
• increased urination
• joint pain
• loss of consciousness
• lower back or side pain
• muscle cramps, spasms, or stiffness
• muscular pain, tenderness, wasting, or weakness
• nasal congestion
• nausea
• runny nose
• sneezing
• sore throat
• stomachache
• sweating
• swelling
• swollen joints
• troubled breathing
• unexplained weight loss
• unusual tiredness or weakness
• vomiting

Incidence not known

• Blistering, peeling, or loosening of the skin
• bloating
• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• constipation
• diarrhea
• difficulty with swallowing
• general tiredness and weakness
• indigestion
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• light-colored stools
• loss of appetite
• pains in the stomach, side, or abdomen, possibly radiating to the back
• pale skin
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• red skin lesions, often with a purple center
• red, irritated eyes
• skin rash, hives, or itching
• sores, ulcers, or white spots in the mouth or on the lips
• tightness in the chest
• troubled breathing with exertion
• unusual bleeding or bruising
• upper right abdominal or stomach pain
• weakness in the arms, hands, legs, or feet
• yellow eyes or skin

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

Less common

• Acid or sour stomach
• belching
• burning feeling in the chest or stomach
• dizziness or lightheadedness
• excess air or gas in the stomach or intestines
• feeling of constant movement of self or surroundings
• full feeling
• heartburn
• lack or loss of strength
• pain or tenderness around the eyes and cheekbones
• passing gas
• sensation of spinning
• skin rash, encrusted, scaly, and oozing
• stomach discomfort, upset, or pain
• tenderness in the stomach area
• trouble sleeping

Incidence not known

• Being forgetful
• depression
• discoloration of the skin
• hair loss or thinning of the hair
• inability to have or keep an erection
• loss in sexual ability, desire, drive, or performance

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Recommended Dosing

The usual dosage range is 5 to 40 mg/day. In patients with CHD or at high risk of CHD, Simvastatin can be started simultaneously with diet. The recommended usual starting dose is 10 or 20 mg once a day in the evening. For patients at high risk for a CHD event due to existing CHD, diabetes, peripheral vessel disease, history of stroke or other cerebrovascular disease, the recommended starting dose is 40 mg/day. Lipid determinations should be performed after 4 weeks of therapy and periodically thereafter.

Restricted Dosing for 80 mg

Due to the increased risk of myopathy, including rhabdomyolysis, particularly during the first year of treatment, use of the 80-mg dose of Simvastatin should be restricted to patients who have been taking Simvastatin 80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity [see Warnings and Precautions (5.1)].  

Patients who are currently tolerating the 80-mg dose of Simvastatin 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 with less potential for the drug-drug interaction.  

Due to the increased risk of myopathy, including rhabdomyolysis, associated with the 80-mg dose of Simvastatin, patients unable to achieve their LDL-C goal utilizing the 40-mg dose of Simvastatin should not be titrated to the 80-mg dose, but should be placed on alternative LDL-C-lowering treatment(s) that provides greater LDL-C lowering.

Coadministration with Other Drugs

Patients taking Verapamil or Diltiazem 

• The dose of Simvastatin should not exceed 10 mg/day [see Warnings and Precautions (5.1), Drug Interactions (7.3), and Clinical Pharmacology (12.3)]. 

Patients taking Amiodarone, amlodipine or Ranolazine

• The dose of Simvastatin should not exceed 20 mg/day [see Warnings and Precautions (5.1), Drug Interactions (7.3), and Clinical Pharmacology (12.3)].

Patients with Homozygous Familial Hypercholesterolemia

The recommended dosage is 40 mg/day in the evening [see Dosage and Administration, Restricted Dosing for 80 mg (2.2)]. Simvastatin should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable.

Adolescents (10-17 years of age) with Heterozygous Familial Hypercholesterolemia

  The recommended usual starting dose is 10 mg once a day in the evening. The recommended dosing range is 10 to 40 mg/day; the maximum recommended dose is 40 mg/day. Doses should be individualized according to the recommended goal of therapy [see NCEP Pediatric Panel Guidelines1 and Clinical Studies (14.2)]. Adjustments should be made at intervals of 4 weeks or more. 1 National Cholesterol Education Program (NCEP): Highlights of the Report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents. Pediatrics. 89(3):495-501. 1992.

Patients with Renal Impairment

Because Simvastatin does not undergo significant renal excretion, modification of dosage should not be necessary in patients with mild to moderate renal impairment. However, caution should be exercised when Simvastatin is administered to patients with severe renal impairment; such patients should be started at 5 mg/day and be closely monitored [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

Chinese Patients Taking Lipid-Modifying Doses (≥1 g/day Niacin) of Niacin-Containing Products

Because of an increased risk for myopathy, in Chinese patients taking Simvastatin 40 mg coadministered with lipid-modifying doses (≥1 g/day niacin) of niacin-containing products, caution should be used when treating Chinese patients with Simvastatin doses exceeding 20 mg/day coadministered with lipid-modifying doses of niacin-containing products. Because the risk for myopathy is dose-related, Chinese patients should not receive Simvastatin 80 mg coadministered with lipid-modifying doses of niacin-containing products. The cause of the increased risk of myopathy is not known. It is also unknown if the risk for myopathy with coadministration of Simvastatin with lipid-modifying doses of niacin-containing products observed in Chinese patients applies to other Asian patients. [See  Warnings and Precautions (5.1).]

• Simvastatin Tablets USP, 10 mg are brown colored, round, biconvex, film-coated tablets, debossed 'RDY' on one side and '198' on other side • Simvastatin Tablets USP, 20 mg are brown colored, round, biconvex, film-coated tablets, debossed 'RDY' on one side and '199' on other side • Simvastatin Tablets USP, 40 mg are brown colored, round, biconvex, film-coated tablets, debossed 'RDY' on one side and '200' on other side.

Simvastatin is contraindicated in the following conditions:

• Concomitant administration of strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin and nefazodone) [see Warnings and Precautions (5.1)]. • Concomitant administration of gemfibrozil, cyclosporine, or danazol [see Warnings and Precautions (5.1)]. • Hypersensitivity to any component of this medication [see Adverse Reactions (6.2)]. • Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels [see Warnings and Precautions (5.2)]. • Women who are pregnant or may become pregnant. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Because HMG-CoA reductase inhibitors (statins) decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, Simvastatin may cause fetal harm when administered to a pregnant woman. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. There are no adequate and well-controlled studies of use with Simvastatin during pregnancy; however, in rare reports congenital anomalies were observed following intrauterine exposure to statins. In rat and rabbit animal reproduction studies, Simvastatin revealed no evidence of teratogenicity. Simvastatin should be administered to women of childbearing age only when such patients are highly unlikely to conceive. If the patient becomes pregnant while taking this drug, Simvastatin should be discontinued immediately and the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)]. • Nursing mothers. It is not known whether Simvastatin is excreted into human milk; however, a small amount of another drug in this class does pass into breast milk. Because statins have the potential for serious adverse reactions in nursing infants, women who require treatment with Simvastatin should not breastfeed their infants [see Use in Specific Populations (8.3)].

Significant lethality was observed in mice after a single oral dose of 9 g/m2. No evidence of lethality was observed in rats or dogs treated with doses of 30 and 100 g/m2, respectively. No specific diagnostic signs were observed in rodents. At these doses the only signs seen in dogs were emesis and mucoid stools.

A few cases of overdosage with Simvastatin have been reported; the maximum dose taken was 3.6 g. All patients recovered without sequelae. Supportive measures should be taken in the event of an overdose. The dialyzability of Simvastatin and its metabolites in man is not known at present.

Simvastatin USP is a lipid-lowering agent that is derived synthetically from a fermentation product of Aspergillus terreus. After oral ingestion, Simvastatin USP, which is an inactive lactone, is hydrolyzed to the corresponding β-hydroxyacid form. This is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, which is an early and rate-limiting step in the biosynthesis of cholesterol.

Simvastatin USP is butanoic acid, 2,2-dimethyl-,1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4- hydroxy-6-oxo-2H-pyran-2-yl)-ethyl]-1-naphthalenyl ester, [1S-[1α,3α,7β,8β(2S*,4S*),-8aβ]]. The empirical formula of Simvastatin USP is C25H38O5 and its molecular weight is 418.57. Its structural formula is:

Simvastatin USP is a white to off-white, nonhygroscopic, crystalline powder that is practically insoluble in water, and freely soluble in chloroform, methanol and ethanol.

Simvastatin tablets USP for oral administration contain either 5 mg, 10 mg, 20 mg, 40 mg or 80 mg of Simvastatin and the following inactive ingredients: ascorbic acid, butylated hydroxy anisole, citric acid anhydrous, hydroxypropyl cellulose, hypromellose, iron oxide black, iron oxide red, iron oxide yellow, isopropyl alcohol, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinised starch, and titanium dioxide.

(sim va STAT in)

Onset of action: >3 days; Peak effect: 2 weeks

LDL-C reduction: 20 to 40 mg/day: 35% to 41% (for each doubling of this dose, LDL-C is lowered ~6%)

Average HDL-C increase: 5% to 15%

Average triglyceride reduction: 7% to 30%

Time to Peak

1.3 to 2.4 hours

Half-Life Elimination

Unknown

Protein Binding

~95%

Noncardioembolic stroke/Transient ischemic attack (secondary prevention)

Based on the American Heart Association/American Stroke Association (AHA/ASA) guidelines for the prevention of stroke in patients with stroke and transient ischemic attack (TIA), statin therapy with intensive lipid-lowering effects is recommended to reduce the risk of recurrent stroke and future cardiovascular events in patients with ischemic stroke or TIA presumed to be of atherosclerotic origin who have an LDL-C concentration ≥100 mg/dL (with or without evidence for other clinical atherosclerotic cardiovascular disease [ASCVD]) or who have an LDL-C concentration <100 mg/dL (without evidence for other clinical ASCVD).

Use is contraindicated in the setting of active liver disease.

May be administered without regard to meals. Administer in the evening for maximal efficacy.

Simvastatin is in a group of drugs called HMG CoA reductase inhibitors, or "statins." It reduces levels of "bad" cholesterol (low-density lipoprotein, or LDL) and triglycerides in the blood, while increasing levels of "good" cholesterol (high-density lipoprotein, or HDL).

Simvastatin is used to lower cholesterol and triglycerides (types of fat) in the blood.

Simvastatin is also used to lower the risk of stroke, heart attack, and other heart complications in people with diabetes, coronary heart disease, or other risk factors.

Simvastatin is used in adults and children who are at least 10 years old.

Mild to moderate renal dysfunction: No adjustment recommended
Severe renal dysfunction: Initial dose should be 5 mg orally once a day in the evening and should be closely monitored.

Mild to moderate renal dysfunction: No adjustment recommended
Severe renal dysfunction: Initial dose should be 5 mg orally once a day in the evening and should be closely monitored.

• Simvastatin works by blocking an enzyme in the liver known as HMG-CoA reductase that is responsible for the conversion of HMG-CoA to mevalonate, an important substance necessary for the synthesis of cholesterol and coenzyme Q10.
• Simvastatin also boosts the breakdown of lipids.
• Simvastatin belongs to a group of drugs known as HMG-CoA reductase inhibitors or statins.

• Simvastatin, in conjunction with dietary measures, is used in people at high risk of having a heart event to:
  • Reduce the risk of death from cardiovascular disease
  • Reduce the incidence of non-fatal heart attack and stroke
  • Reduce the need for revascularization procedures.
• People considered at increased risk of a heart event include those with diabetes, a history of stroke or a similar event, with pre-existing heart disease, or with peripheral vascular disease.
• Simvastatin is also used to reduce high levels of lipids in people with elevated cholesterol levels. Simvastatin reduces total cholesterol, LDL-cholesterol, apolipoprotein B, triglycerides and increases high-density lipoproteins.
• Simvastatin is also indicated in some genetic lipid disorders (such as heterozygous familial hypercholesterolemia) in adolescents aged 10 to 17 meeting certain criteria.
• The dosage of simvastatin does not need adjusting in mild-to-moderate kidney disease. Patients with severe kidney disease should be started on simvastatin 5mg daily and monitored.
• Generic simvastatin is available.

• Simvastatin is a prodrug, which means it is converted into its active beta-hydroxyacid form, after administration.
• Peak levels are seen within 1.3 to 2.4 hours following administration; however, it may take up to one to two weeks of regular dosing before improvements in lipid levels are seen.
• Simvastatin reduces cholesterol, Very Low-Density Lipoproteins (VLDL) and triglycerides while increasing HDL-cholesterol.

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You should not take simvastatin if you are pregnant or breast-feeding, or if you have active liver disease.

Some medicines can cause unwanted or dangerous effects when used with simvastatin. Your doctor may need to change your treatment plan if you use certain antibiotics or antifungal medicines, hepatitis C medication, heart medication, or medicines to treat HIV/AIDS.

Stop taking this medication and tell your doctor right away if you become pregnant.

Follow all directions on your prescription label. Never take this medicine in larger amounts, or for longer than prescribed. Taking too much of this medication may cause serious or life-threatening side effects.

Simvastatin is usually taken at bedtime or with an evening meal. If you take simvastatin more than once daily, take it with meals. Your doctor may occasionally change your dose to make sure you get the best results.

While using simvastatin, you may need frequent blood tests at your doctor's office.

You may need to take simvastatin on a long-term basis for the treatment of high cholesterol. You may need to stop using simvastatin for a short time if you have surgery or a medical emergency. Do not stop taking this medicine unless your doctor tells you to.

Simvastatin is only part of a complete program of treatment that also includes diet, exercise, and weight control. Follow your diet, medication, and exercise routines very closely.

Store at room temperature away from moisture, heat, and light.