No

Antilipemic Agent (HMG-CoA Reductase Inhibitor)

Adjunct to dietary therapy to decrease elevated serum total and LDL cholesterol, apolipoprotein B (apo-B), and triglyceride levels, and to increase HDL cholesterol in patients with primary hypercholesterolemia (heterozygous, familial and nonfamilial) and mixed dyslipidemia (Fredrickson types IIa and IIb); treatment of homozygous familial hypercholesterolemia; treatment of isolated hypertriglyceridemia (Fredrickson type IV) and type III hyperlipoproteinemia; to reduce the risk of myocardial infarction, stroke, or TIA

X

Hypersensitivity to simvastatin or any component; acute liver disease; unexplained persistent elevations of serum transaminases; pregnancy

Liver function must be monitored by periodic laboratory assessment. Rhabdomyolysis with acute renal failure has occurred. Risk is increased with concurrent use of clarithromycin, danazol, diltiazem, fluvoxamine, indinavir, nefazodone, nelfinavir, ritonavir, verapamil, troleandomycin, cyclosporine, fibric acid derivatives, erythromycin, niacin, or azole antifungals. Weigh the risk versus benefit when combining any of these drugs with simvastatin. Temporarily discontinue in any patient experiencing an acute or serious condition predisposing to renal failure secondary to rhabdomyolysis.

1% to 10%:

Gastrointestinal: Constipation (2.3%), dyspepsia (1.1%), flatulence (1.9%)

Neuromuscular & skeletal: CPK elevation (>3x normal on one or more occasions - 5%)

Respiratory: Upper respiratory infection (2.1%)

<1%: Thrombocytopenia, dizziness, headache, vertigo, weakness, fatigue, insomnia, nausea, diarrhea, abdominal pain

Case reports: Hypotension, depression, dermatomyositis, lichen planus, photosensitivity

Additional class-related events or case reports (not necessarily reported with simvastatin therapy): Myopathy, increased CPK (>10x normal), rhabdomyolysis, renal failure (secondary to rhabdomyolysis), alteration in taste, impaired extraocular muscle movement, facial paresis, tremor, headache, memory loss, vertigo, paresthesia, peripheral neuropathy, peripheral nerve palsy, anxiety, depression, psychic disturbance, hypersensitivity reaction, angioedema, anaphylaxis, systemic lupus erythematosus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, increased ESR, eosinophilia, arthritis, urticaria, photosensitivity, fever, chills, flushing, malaise, dyspnea, rash, toxic epidermal necrolysis, erythema multiforme, Stevens-Johnson syndrome, pancreatitis, hepatitis, cholestatic jaundice, fatty liver, cirrhosis, fulminant hepatic necrosis, hepatoma, anorexia, vomiting, alopecia, pruritus, nodules, skin discoloration, dryness of skin/mucous membranes, nail changes, gynecomastia, decreased libido, erectile dysfunction/impotence, cataracts, ophthalmoplegia, elevated transaminases, increased alkaline phosphatase, increased GGT, hyperbilirubinemia, thyroid dysfunction

Very few adverse events; treatment is symptomatic

CYP3A3/4 enzyme substrate

Cholestyramine reduces absorption of several HMG-CoA reductase inhibitors. Separate administration times by at least 4 hours.

Cholestyramine and colestipol (bile acid sequestrants): Cholesterol-lowering effects are additive.

Clofibrate and fenofibrate may increase the risk of myopathy and rhabdomyolysis.

Gemfibrozil: Increased risk of myopathy and rhabdomyolysis.

Grapefruit juice may inhibit metabolism of simvastatin via CYP3A3/4; avoid high dietary intakes of grapefruit juice.

Niacin may increase the risk of myopathy and rhabdomyolysis.

Warfarin effects (hypoprothrombinemic response) may be increased; monitor INR closely when simvastatin is initiated or discontinued.

Tablets should be stored in well closed containers at temperatures between 5°C to 30°C (41°F to 86°F)

Simvastatin is a methylated derivative of lovastatin that acts by competitively inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the rate-limiting step in cholesterol biosynthesis

Onset of effect: >3 days; maximal effects after 2 weeks

Absorption: Oral: Although 85% is absorbed following administration, <5% reaches the general circulation due to an extensive first-pass effect

Time to peak concentrations: 1.3-2.4 hours

Protein binding: ~95%

Elimination: 13% excreted in urine and 60% in feces; the elimination half-life is unknown

In patients with severe renal insufficiency, high systemic levels may occur

Oral:

Initial: 20 mg once daily in the evening

Patients who require only a moderate reduction of LDL cholesterol may be started at 10 mg

Patients who require a reduction of >45% in low-density lipoprotein (LDL) cholesterol: 40 mg once daily

Maintenance: Recommended dosage range: 5-80 mg/day as a single dose in the evening; doses should be individualized according to the baseline LDL cholesterol levels, the recommended goal of therapy, and the patient's response.

Adjustments: Should be made at intervals of 4 weeks or more.

Patients with homozygous familial hypercholesteremia: Adults: 40 mg in the evening or 80 mg/day in 3 divided doses of 20 mg, 20 mg, and an evening dose of 40 mg.

Elderly: Maximum reductions in LDL-cholesterol may be achieved with daily dose of less than or equal to 20 mg.

Patients who are concomitantly receiving cyclosporine: Initial: 5 mg, should not exceed 10 mg/day.

Patients receiving concomitant fibrates or niacin: Dose should not exceed 10 mg/day.

Dosing adjustment/comments in renal impairment: Because simvastatin does not undergo significant renal excretion, modification of dose should not be necessary in patients with mild to moderate renal insufficiency.

Severe renal impairment: Cl_cr <10 mL/minute: Initial: 5 mg/day with close monitoring.

Creatine phosphokinase levels due to possibility of myopathy; serum cholesterol (total and fractionated)

HMG-CoA reductase inhibitors are effective in secondary prevention of cardiovascular events in patients with hyperlipidemia. In these situations, the target of therapy is a reduction in LDL cholesterol to <100 mg/dL. HMG-CoA reductase inhibitors have also been shown to be effective in primary prevention of coronary artery disease in individuals without established cardiovascular disease but who have multiple risk factors. Selection of lipid-lowering therapy should be based on the patient's lipid profile, concomitant disease states, and the cost of therapy. The benefits of lipid-lowering are also compelling in women and in the elderly. Important side effects relate to elevated liver enzymes and rhabdomyolysis. LFTs need to be monitored at specified intervals.

May cause drowsiness

None reported

No information available to require special precautions

No effects or complications reported

Take this medication as directed, with meals, 1 hour prior to or after any other medications. You may experience nausea, flatulence, dyspepsia (small frequent meals may help), headache, muscle or joint pain (will probably lessen with continued use), and light sensitivity (use sunblock and wear protective clothing). Report severe and unresolved gastric upset, any vision changes, changes in color of urine or stool, yellowing of skin or eyes, and any unusual bruising. Pregnancy/breast-feeding precautions: Inform prescriber if you are pregnant. Do not get pregnant 1 month before, during, or for 1 month following therapy. Consult prescriber for instruction on appropriate contraceptive measures. This drug may cause severe fetal defects. Do not donate blood during or for 1 month following therapy (same reason). Do not breast-feed.

Liver enzyme elevations may be observed during simvastatin therapy; combination therapy with other hypolipidemic agents may be required to achieve optimal reductions of LDL cholesterol; diet, weight reduction, and exercise should be attempted to control hypercholesterolemia before the institution of simvastatin therapy

Tablet: 5 mg, 10 mg, 20 mg, 40 mg, 80 mg

Bach LA, Cooper ME, O'Brien RC, et al, "The Use of Simvastatin, an HMG-CoA Reductase Inhibitor, in Older Patients With Hypercholesterolemia and Atherosclerosis," J Am Geriatr Soc, 1990, 38(1):10-4.

French J and White H, "Transient Symptomatic Hypotension in Patients on Simvastatin," Lancet, 1989, 2(8666):807-8.

Lintott CJ and Scott RS, "HMG-CoA Reductase Inhibitor Use in the Aged: A Review of Clinical Experience," Drugs Aging, 1992, 2(6):518-29.

Mauro VF and MacDonald JL, "Simvastatin: A Review of Its Pharmacology and Clinical Use," DICP, 1991, 25(3):257-64.

Mol MJ and Stalenhoef AF, "Adrenocortical Function in Patients on Simvastatin," Lancet, 1990, 335(8686):412-3.

"Summary of the Second Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults," JAMA, 1993, 269(23):3015-23.