Simvastatin (Flolipid, Zocor)

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Brand Names: Flolipid, Zocor
Primary Use: Antihyperlipidemic Agent, reduces elevated LDL levels
Drug Classes: Antihyperlipidemic Agents, HMG-CoA Reductase Inhibitors (statins), Metabolic Agents
Generic Drug Synonyms and Salts: Simvastatin
Related Drugs: Atorvastatin, Rosuvastatin, Pravastatin Sodium, Lovastatin, Pitavastatin, Ezetimibe; Simvastatin
Schedule: Rx (Prescription required)
FDA Established Pharmacologic Class (EPC): HMG-CoA Reductase Inhibitor
Initial FDA approval date: 12/23/1991

What is Simvastatin

Simvastatin (Flolipid or Zocor) belongs to a class of drugs called statins and is currently the 10th most prescribed drug in America. It is prescribed by a doctor to lower cholesterol in people who have been diagnosed with high cholesterol (high levels of LDL cholesterol in the blood). Doctors diagnose high cholesterol through a simple blood test. Cholesterol (and triglycerides) are fats that are made in your body. While some cholesterol is necessary for the body, too much cholesterol is dangerous to your health. Cholesterol, specifically, is made in the liver. Lowering “bad” cholesterol and triglycerides and raising “good” cholesterol decreases the risk of heart disease and helps prevent strokes and heart attacks This drug can also lower the risk for heart attack or stroke in patients with diabetes.

Note: Some research has shown a possible relationship between the use of statins and the risk of diabetes, however, the risk of developing diabetes from the use of statins is very small.

Simvastatin is available under the following different brand names: Flolipid, Zocor.

ClinCalc Drug Statistics for Simvastatin

Estimated number of prescriptions in the United States (2018)	48,007,043
Top drug rank for 2021	#10
Average total drug cost	$31.38 (USD)
Average out-of-pocket cost	$5.43 (USD)

Indications for Simvastatin

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 nonpharmacologic measures alone has been inadequate. In patients with coronary heart disease (CHD) or at high risk of CHD, ZOCOR1
can be started simultaneously with diet.

Reductions in Risk of CHD Mortality and Cardiovascular Events

In patients at high risk of coronary events because of existing coronary heart disease, diabetes, peripheral vessel disease, history of stroke or other cerebrovascular diseases, ZOCOR is indicated to:

• Reduce the risk of total mortality by reducing CHD deaths.
• Reduce the risk of non-fatal myocardial infarction and stroke.
• Reduce the need for coronary and non-coronary revascularization procedures.

Hyperlipidemia

• Reduce elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C),
• apolipoprotein B (Apo B), and triglycerides (TG), and to increase high-density lipoprotein
• cholesterol (HDL-C) in patients with primary hyperlipidemia (Fredrickson type IIa, heterozygous
• familial and nonfamilial) or mixed dyslipidemia (Fredrickson type IIb).
• Reduce elevated TG in patients with hypertriglyceridemia (Fredrickson type lV hyperlipidemia).
• Reduce elevated TG and VLDL-C in patients with primary dysbetalipoproteinemia (Fredrickson type lll hyperlipidemia).
• Reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable.

Adolescent Patients with Heterozygous Familial Hypercholesterolemia (HeFH)

ZOCOR is indicated as an adjunct to diet to reduce total-C, LDL-C, and Apo B levels in adolescent boys and girls who are at least one-year post-menarche, 10-17 years of age, with HeFH, if after an adequate trial of diet therapy the following findings are present:

1. LDL cholesterol remains ≥190 mg/dL; or
2. LDL cholesterol remains ≥160 mg/dL and
   There is a positive family history of premature cardiovascular disease (CVD) or
   Two or more other CVD risk factors are present in the adolescent patient.

The minimum goal of treatment in pediatric and adolescent patients is to achieve a mean LDL-C <130 mg/dL. The optimal age at which to initiate lipid-lowering therapy to decrease the risk of symptomatic adulthood CAD has not been determined.

Limitations of use

ZOCOR has not been studied in conditions where the major abnormality is elevation of chylomicrons (i.e., hyperlipidemia Fredrickson types I and V).

Dosages for Simvastatin (Zocor)

Presentation

Simvastatin (Zocor) is available in tablet form in the strengths indicated below.

Tablet Strength	Identifying Features
10 mg of Zocor	“MSD 735” on one side and plain on the other
20 mg of Zocor	“MSD 740” on one side and plain on the other.
40 mg of Zocor	“MSD 749” on one side and plain on the other
80 mg of Zocor	“543” on one side and “80” on the other

Storage And Handling

No. 8146 — Tablets ZOCOR 10 mg are peach, oval, film-coated tablets, coded MSD 735 on one side and plain on the other. They are supplied as follows:

• NDC 0006-0735-31 unit of use bottles of 30
• NDC 0006-0735-54 unit of use bottles of 90.

No. 8147 — Tablets ZOCOR 20 mg are tan, oval, film-coated tablets, coded MSD 740 on one side and plain on the other. They are supplied as follows:

• NDC 0006-0740-31 unit of use bottles of 30
• NDC 0006-0740-54 unit of use bottles of 90.

No. 8148 — Tablets ZOCOR 40 mg are brick red, oval, film-coated tablets, coded MSD 749 on one side and plain on the other. They are supplied as follows:

• NDC 0006-0749-31 unit of use bottles of 30
• NDC 0006-0749-54 unit of use bottles of 90.

No. 6577 — Tablets ZOCOR 80 mg are brick red, capsule-shaped, film-coated tablets, coded 543 on one side and 80 on the other. They are supplied as follows:

• NDC 0006-0543-31 unit of use bottles of 30
• NDC 0006-0543-54 unit of use bottles of 90.

Storage

Store at controlled room temperature 20 -25°C (68 -77°F).

Dosage

The usual dosage range is 5 to 40 mg/day. In patients with CHD or at high risk of CHD, ZOCOR 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 is40 mg/day. Lipid determinations should be performed after 4 weeks of therapy and periodically thereafter.

Hypercholesterolemia (High cholesterol)

Usual dosage range: 5-40 mg orally once/day

Initial: 10-20 mg orally once/day in the evening

Patients at high CHD risk: Start 40 mg/day

Children under 10 years: Safety and efficacy not established

Homozygous Familial Hypercholesterolemia (Genetic high cholesterol)

Recommended dose: 40 mg orally once/day in the evening

See limitations for 80 mg/day, listed below

Heterozygous Familial Hypercholesterolemia (Genetic high cholesterol)

Adolescents aged 10-17 years

• Initial: 10 mg orally once/day in the evening; not to exceed 40 mg/day
• Recommended dosing range: 10-40 mg/day; adjustments should be made at intervals of 4 weeks or more.

Prevention of Coronary Events

5-40 mg PO qDay in the evening

Moderate reduction of LDL-C desired: 5-10 mg PO qDay in the evening; adjust dose to achieve goal

Reduction of >40% of LDL-C desired: 40 mg PO qDay in the evening; adjust dose to achieve goal

Presence of CHD or at high risk for cardiovascular events, including patients with diabetes, PVD, history of stroke or other cerebrovascular disease: 40 mg PO qDay in the evening adjunct to diet therapy (initiate simultaneously); adjust dose to achieve goal

Primary and secondary prevention of atheroschlerotic cardiovascular disease (ASCVD)

ACC/AHA Cholesterol Guideline Recommendations (2013) for adults ≥21 years

Primary prevention

• LDL-C ≥190 mg/dL: High-intensity therapy agent atorvastatin or rosuvastatin recommended
• Type 1 or 2 diabetes (40-75 years of age): Moderate-intensity therapy: 20-40 mg simvastatin PO qDay
• Type 1 or 2 diabetes (40-75 years of age and 10 year estimated risk of ASCVD ≥7.5%): High-intensity therapy agent atorvastatin or rosuvastatin recommended
• 40-75 years of age and 10 year estimated risk of ASCVD ≥7.5% : Moderate-intensity therapy: 20-40 mg simvastatin PO qDay; may consider high-intensity therapy agent atorvastatin or rosuvastatin

Secondary prevention

• Presence of ASCVD, including stroke/TIA or peripheral arterial disease believed to be of atherosclerotic origin or post-CABG
• ≤75 years: Treat with high-intensity therapy agent atorvastatin or rosuvastatin
• >75 years: Administer 20-40 mg simvastatin PO qDay (moderate-intensity therapy); not candidate for high-intensity therapy

Dosage Modifications

Severe renal impairment (CrCl less than 30 mL/min): 5 mg once/day initially

Co-administration with dronedarone, verapamil, or diltiazem: Do not exceed 10 mg/day

Co-administration with amiodarone, amlodipine, or ranolazine: Do not exceed 20 mg/day

Co-administration with lomitapide: Reduce dose by 50%, and do not exceed 20 mg/day (or 40 mg/day in those previously tolerating 80 mg/day) when initiating lomitapide

People of Chinese descent taking lipid-modifying doses of niacin (i.e., 1 g/day or more): Increased risk of myopathy with 40 mg/day; consider lower dose

People of Asian descent should not receive 80 mg co-administered with lipid-modifying doses of niacin-containing products

Dosing Considerations

Lipid determinations should be performed after 4 weeks of therapy and periodically thereafter

Restricted dosing

• Patients tolerating 80 mg who need to be initiated on an interacting drug that is contraindicated or associated with a maximum dose should be switched to an alternative statin with less potential for drug-drug interactions
• Patients unable to achieve their LDL cholesterol goal utilizing 40 mg/day should not be titrated to 80 mg (increased risk for disease of muscle tissue) but should instead be placed on alternative LDL- cholesterol-lowering treatment that provides greater LDL- cholesterol-lowering

Overdose management

• Adverse side effects and drug reactions from overdose may include peripheral neuropathy, diarrhea, increased K+, myopathy, rhabdomyolysis, acute renal failure, elevated LFTs, and eye lens opacities
• Treatment is supportive

Possible Side Effects of Simvastatin

Simvastatin is generally well tolerated. Possible side effects may include any of the following and the side effects experienced may be transitory (clears up after a few days) or may remain. Consult your doctor immediately if you experiencing serious side effects. Note the list below is not exhaustive.

Common side effects of simvastatin include:

• CPK elevation (greater than 3x ULN)
• Constipation
• Upper respiratory infection
• Gas (flatulence)
• Transaminases increased (greater than 3x ULN)
• Headache
• Muscle pain, muscle damage, or muscle weakness
• Eczema
• Spinning sensation (vertigo)
• Abdominal pain

Less common side effects of simvastatin include:

• Muscle weakness
• Joint pain
• Arthritis
• Eosinophilia
• Chills
• Skin swelling
• Muscle wasting
• Abdominal pain

Postmarketing side effects of simvastatin reported include:

• Erectile dysfunction
• Interstitial lung disease
• Rare reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use

Adverse reactions associated with Simvastatin therapy reported since market introduction, that are not listed above, regardless of causality assessment, include the following: anaphylaxis, angioneurotic edema, bullous rashes (including erythema multiforme, and toxic epidermal necrolysis), rhabdomyolysis, myositis, fatigue, tendon rupture, fatal and non-fatal hepatic failure, dizziness, depression, peripheral neuropathy, and pancreatitis.

There have been rare reports of immune-mediated necrotizing myopathy associated with statin use

Contra-indications and Cautions for Simvastatin

Contra-indications

Do not take Zocor if you are allergic to simvastatin or any ingredients contained in this drug.

Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center immediately.

Cautions

Non-serious and reversible cognitive side effects may occur.

Increased blood sugar and glycosylated hemoglobin (HbA1c) levels reported with statin intake.

Heavy alcohol use, history of liver disease, renal failure.

Monitor LFTs before initiating treatment and thereafter when clinically indicated; reports of fatal and nonfatal hepatic failure in people taking statins .

Discontinue if markedly elevated CPK levels occur or myopathy is diagnosed or suspected.

Increases in HbA1c and fasting serum glucose levels reported with simvastatin.

Severe electrolyte, endocrine, or metabolic disorders.

Grapefruit juice increases simvastatin systemic exposure; avoid large quantities of grapefruit juice (i.e., 1 quart/day or more).

Simvastatin and myopathy risk:

• Dose adjustment required when co-administered with niacin, amiodarone, verapamil, diltiazem, amlodipine, and ranolazine
• Predisposing factors for myopathy include advanced age (older than 65 years), uncontrolled hypothyroidism, and renal impairment
• Increased risk for myopathy in Chinese people co-administered niacin greater than 1 g/day; they should not receive simvastatin 80 mg co-administered with lipid-modifying doses of niacin-containing products
• Withhold or discontinue if myopathy, renal failure, or transaminase levels greater than 3x ULN develop
• Risk of myopathy is greater in people taking simvastatin 80 mg/day, especially in the 1st year of treatment
• Rare reports of immune-mediated necrotizing myopathy (IMNM), characterized by increased serum creatine kinase that persists despite discontinuing statin
• Risk for myopathy increased when coadministered with other lipid-lowering drugs (other fibrates, 1 g/day of niacin or more, or, for patients with HoFH, lomitapide), colchicine, amiodarone, dronedarone, verapamil, diltiazem, amlodipine, or ranolazine
• See Contraindications for list of drugs contraindicated because of increased risk for myopathy when co-administered with simvastatin
• See Adult Dosing for dose limitations and modifications

Drug Interactions for Simvastatin

Your pharmacist will be aware of potential interactions between Simvastatin and any other medications you use. It’s wise to double-check with your pharmacist and always read package inserts and check the drugs you currently use for possible interactions. If in doubt, revert to your pharmacist with a list of all your medication. It’s a great idea if you own a smartphone to add all your medications to an app on your phone. This can be a lifesaver.

This drug has severe interactions with at least 32 different drugs.

This drug has serious interactions with at least 79 different drugs.

This drug has moderate interactions with at least 79 different drugs.

Mild Interactions

• aliskiren
• alvimopan
• ambrisentan
• armodafinil
• coenzyme Q10
• colestipol
• fexofenadine
• isradipine
• loratadine
• orlistat
• sacubitril/valsartan
• telmisartan
• trazodone
• valsartan

Contra Indicated

• atazanavir
• clarithromycin
• cobicistat
• cyclosporine
• danazol
• darunavir
• elvitegravir/cobicistat/emtricitabine/tenofovir DF
• erythromycin base
• erythromycin ethylsuccinate
• erythromycin lactobionate
• erythromycin stearate
• fosamprenavir
• gemfibrozil
• idelalisib
• indinavir
• itraconazole
• ketoconazole
• letermovir
• lonafarnib
• lopinavir
• mifepristone
• nefazodone
• nelfinavir
• ombitasvir/paritaprevir/ritonavir & dasabuvir
• posaconazole
• red yeast rice
• ritonavir
• saquinavir
• tipranavir

Serious – Use alternative

• abametapir
• afatinib
• amiodarone
• amlodipine
• apalutamide
• aprepitant
• armodafinil
• artemether/lumefantrine
• bosentan
• bosutinib
• butabarbital
• butalbital
• carbamazepine
• cimetidine
• colchicine
• conivaptan
• darifenacin
• darolutamide
• dasatinib
• dexamethasone
• diltiazem
• eltrombopag
• eluxadoline
• enzalutamide
• etravirine
• fenofibrate
• fenofibrate micronized
• fenofibric acid
• fluconazole
• fosphenytoin
• glecaprevir/pibrentasvir
• grapefruit
• griseofulvin
• hydrocortisone
• isoniazid
• ivosidenib
• lapatinib
• lasmiditan
• lomitapide
• lumefantrine
• marijuana
• mesterolone
• methylprednisolone
• metronidazole
• miconazole vaginal
• modafinil
• nafcillin
• nevirapine
• niacin
• nifedipine
• nilotinib
• oxcarbazepine
• pentobarbital
• pexidartinib
• phenobarbital
• phenytoin
• pomalidomide
• prednisone
• pretomanid
• primidone
• quinupristin/dalfopristin
• ranolazine
• rifabutin
• rifampin
• rifapentine
• riociguat
• rufinamide
• secobarbital
• St John’s Wort
• topiramate
• tucatinib
• verapamil
• voriconazole
• voxelotor
• zafirlukast

Monitor Closely

• amitriptyline
• apalutamide
• atorvastatin
• azithromycin
• bazedoxifene/conjugated estrogens
• bempedoic acid
• budesonide
• carbamazepine
• caspofungin
• cenobamate
• ceritinib
• cholestyramine
• cholic acid
• clobetasone
• clotrimazole
• conjugated estrogens
• conjugated estrogens, vaginal
• cortisone
• crizotinib
• crofelemer
• dabrafenib
• daptomycin
• deferasirox
• deflazacort
• dexamethasone
• digoxin
• docetaxel
• dronedarone
• duvelisib
• efavirenz
• elagolix
• elbasvir/grazoprevir
• eliglustat
• eluxadoline
• encorafenib
• eslicarbazepine acetate
• estradiol
• estropipate
• fedratinib
• fludrocortisone
• fostemsavir
• glyburide
• hydrocortisone
• iloperidone
• irinotecan liposomal
• istradefylline
• itraconazole
• ivacaftor
• ivermectin
• lanthanum carbonate
• levamlodipine
• loperamide
• lorlatinib
• lovastatin
• mestranol
• methylprednisolone
• metyrapone
• mipomersen
• mitotane
• paclitaxel
• paclitaxel protein bound
• paliperidone
• pazopanib
• pioglitazone
• ponatinib
• posaconazole
• prednisolone
• prednisone
• repaglinide
• ribociclib
• rifampin
• risperidone
• rosiglitazone
• sacubitril/valsartan
• sarecycline
• silodosin
• sirolimus
• sofosbuvir/velpatasvir
• stiripentol
• tacrolimus
• tazemetostat
• tecovirimat
• ticagrelor
• tolvaptan
• valsartan
• vinblastine
• vincristine
• vincristine liposomal
• warfarin

Safety in Pregnancy for Simvastatin

Simvastatin is not indicated for use in pregnant or breastfeeding women.

Pregnancy

Contraindicated in women who are or may become pregnant

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 should have little impact on long-term outcomes of primary hypercholesterolemia therapy

There are no adequate and well-controlled studies of use with statins during pregnancy; however, there are rare reports of congenital anomalies in infants exposed to statins in utero

Lactation

Unknown if simvastatin excreted in human milk; because a small amount of another drug in this class is excreted in human milk and because of the potential for serious adverse reactions in nursing infants, women taking simvastatin should not breastfeed

A decision should be made whether to discontinue nursing or discontinue drug, taking into account the importance of the drug to the mother