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Special Alerts
HMG-CoA Reductase Inhibitors and Protease Inhibitors: New Contraindications and Dose Limitations
March 2012
The U.S. Food and Drug Administration (FDA) has notified healthcare professionals of updates to the prescribing information regarding use of HMG-CoA reductase inhibitors with protease inhibitors. Use of some of these medications together may increase the risk of myopathy or the more serious rhabdomyolysis, which can damage the kidneys and lead to kidney failure (sometimes fatal). The updates include new contraindications (lovastatin, simvastatin), warnings (atorvastatin), and maximum dose restrictions for specific HMG-CoA reductase inhibitors (atorvastatin, rosuvastatin) when combined with specific protease inhibitors used for the treatment of human immunodeficiency virus (HIV) or hepatitis C virus (HCV).
Lovastatin, simvastatin: Protease inhibitors (including boceprevir and telaprevir) are contraindicated with either lovastatin or simvastatin
Rosuvastatin: With atazanavir ± ritonavir or lopinavir + ritonavir: Rosuvastatin maximum daily dose of 10 mg
Atorvastatin:
With darunavir + ritonavir or fosamprenavir ± ritonavir or saquinavir + ritonavir: Atorvastatin maximum daily dose of 20 mg
With lopinavir + ritonavir: Use lowest daily atorvastatin dose; monitor closely
With nelfinavir: Atorvastatin maximum daily dose of 40 mg
With telaprevir or tipranavir + ritonavir: Avoid concurrent use
Other HMG-CoA reductase inhibitors were reviewed, but did not have adjustments to dosing.
For additional information, please refer to http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm294294.htm.
HMG-CoA Reductase Inhibitors: Liver Enzyme Monitoring Requirements Removed, Drug Interactions and Warning Updates
February 2012
The U.S. Food and Drug Administration (FDA) has approved important labeling changes for lovastatin.
New drug-drug interactions, contraindications, and new dosing limits based upon the interaction assessment have been added to the lovastatin label. Itraconazole, ketoconazole, posaconazole (new), erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir (new), telaprevir (new) and nefazodone are contraindicated for use with lovastatin. Concomitant use of cyclosporine and gemfibrozil should be avoided. In addition to danazol, a maximum daily lovastatin dose of 20 mg is now recommended for concomitant use with diltiazem or verapamil. A lovastatin dose limit of 40 mg remains for concomitant use with amiodarone.
Routine monitoring of liver enzymes has been removed from the drug labeling. The incidence of serious liver injury associated with the currently marketed HMG-CoA Reductase Inhibitors is very low and routine periodic monitoring of serum alanine aminotransferase (ALT) does not appear to detect or prevent serious liver injury but may cause interruptions in therapy for patients with isolated increases in ALT levels, placing them at risk for cardiovascular events. Baseline liver function tests are still recommended prior to initiation of HMG-CoA Reductase Inhibitor therapy.
Based upon review of postmarketing events through the AERS database and clinical trials, updated details regarding cognitive adverse events and glycemic regulation have been added to the labels. Although rare, reversible memory impairment (including confusion, forgetfulness, amnesia, and memory loss) can occur with HMG-CoA reductase inhibitors. These cognitive symptoms have been reported at variable times during therapy (1 day to years after initiation) and are reversible with discontinuation; resolution usually occurs within ~3 weeks. Cases have not been associated with fixed or progressive dementia; nor have they been associated with age, specific HMG CoA reductase inhibitor, dose or concomitant medication use.
Additionally, HMG-CoA Reductase Inhibitors have been associated with increases in glycosylated hemoglobin and fasting plasma glucose. Subgroup analyses of randomized controlled clinical trials, an observational study, and meta-analyses have observed an association between new onset diabetes and the use of an HMG CoA reductase inhibitor.
For additional information, please refer to http://www.fda.gov/Drugs/DrugSafety/ucm293101.htm.
Pronunciation
(LOE va sta tin)
Generic Available (U.S.)
Yes: Excludes extended release tablet
Index Terms
Brand Names: U.S.
Brand Names: Canada
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Adjunct to dietary therapy to decrease elevated serum total and LDL-cholesterol concentrations in primary hypercholesterolemia
Primary prevention of coronary artery disease (patients without symptomatic disease with average to moderately elevated total and LDL-cholesterol and below average HDL-cholesterol); slow progression of coronary atherosclerosis in patients with coronary heart disease and reduce the risk of myocardial infarction, unstable angina, and coronary revascularization procedures.
Adjunct to dietary therapy in adolescent patients (10-17 years of age, females >1 year postmenarche) with heterozygous familial hypercholesterolemia having LDL >189 mg/dL, or LDL >160 mg/dL with positive family history of premature cardiovascular disease (CVD), or LDL >160 mg/dL with the presence of at least two other CVD risk factors
Pregnancy Risk Factor
X
Pregnancy Considerations
Cholesterol biosynthesis may be important in fetal development. Contraindicated in pregnancy. Administer to women of childbearing potential only when conception is highly unlikely and patients have been informed of potential hazards.
Lactation
Excretion in breast milk unknown/contraindicated
Contraindications
Hypersensitivity to lovastatin or any component of the formulation; active liver disease; unexplained persistent elevations of serum transaminases; concomitant use of strong CYP3A4 inhibitors (eg, clarithromycin, erythromycin, itraconazole, ketoconazole, nefazodone, posaconazole, protease inhibitors [including boceprevir and telaprevir], telithromycin); pregnancy; breast-feeding
Warnings/Precautions
Concerns related to adverse effects:
• Diabetes mellitus: Increases in Hb A1c and fasting blood glucose have been reported with HMG-CoA reductase inhibitors; however, the benefits of statin therapy far outweigh the risk of dysglycemia.
• Hepatotoxicity: Postmarketing reports of fatal and nonfatal hepatic failure are rare. If serious hepatotoxicity with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment, interrupt therapy. If an alternate etiology is not identified, do not restart lovastatin. Liver enzyme tests should be obtained at baseline and as clinically indicated; routine periodic monitoring of liver enzymes is not necessary.
• Myopathy/rhabdomyolysis: Patients receiving HMG-CoA reductase inhibitors have developed rhabdomyolysis with acute renal failure and/or myopathy; patients should be monitored closely. This risk is dose-related and is increased with concurrent use of other lipid-lowering medications (eg, fibric acid derivatives, or niacin at doses ≥1 g/day) or during concurrent use with potent CYP3A4 inhibitors. The manufacturer recommends temporary discontinuation for elective major surgery, acute medical or surgical conditions, or in any patient experiencing an acute or serious condition predisposing to renal failure (eg, sepsis, hypotension, trauma, uncontrolled seizures). However, based upon current evidence, HMG-CoA reductase inhibitor therapy should be continued in the perioperative period unless risk outweighs cardioprotective benefit. Use caution in patients with renal impairment, inadequately treated hypothyroidism, and those taking other drugs associated with myopathy (eg, colchicine); these patients are predisposed to myopathy. Patients should be instructed to report unexplained muscle pain, tenderness, weakness, or brown urine.
Disease-related concerns:
• Hepatic impairment and/or ethanol use: Use with caution in patients who consume large amounts of ethanol or have a history of liver disease. Use is contraindicated in patients with active liver disease or unexplained transaminase elevations.
Concurrent drug therapy issues:
• High potential for interactions: Concomitant use of lovastatin with some drugs may require cautious use, may not be recommended, may require dosage adjustments, or may be contraindicated.
Special populations:
• Elderly: Use with caution in patients with advanced age, these patients are predisposed to myopathy.
Other warnings/precautions:
• Hyperlipidemia: Secondary causes of hyperlipidemia should be ruled out prior to therapy.
Adverse Reactions
Percentages as reported with immediate release tablets; similar adverse reactions seen with extended release tablets.
>10%: Neuromuscular & skeletal: CPK increased (>2x normal) (11%)
1% to 10%:
Central nervous system: Headache (2% to 3%), dizziness (≤1%)
Dermatologic: Rash (≤1%)
Gastrointestinal: Flatulence (4% to 5%), constipation (2% to 4%), abdominal pain (2% to 3%), diarrhea (2% to 3%), nausea (2% to 3%), dyspepsia (1% to 2%)
Neuromuscular & skeletal: Myalgia (2% to 3%), weakness (1% to 2%), muscle cramps (≤1%)
Ocular: Blurred vision (≤1%)
<1%, postmarketing, and/or case reports (limited to important or life-threatening): Acid regurgitation, alopecia, amnesia (reversible), arthralgia, blood glucose increased, chest pain, cognitive impairment (reversible), confusion (reversible), dermatomyositis, diabetes mellitus (new onset), eye irritation, glycosylated hemoglobin (Hb A1c) increased, insomnia, leg pain, memory disturbance (reversible), memory impairment (reversible), paresthesia, pruritus, vomiting, xerostomia
Additional class-related events or case reports (not necessarily reported with lovastatin therapy): Alkaline phosphatase increased, alteration in taste, anaphylaxis, angioedema, anorexia, anxiety, arthritis, cataracts, chills, cholestatic jaundice, cirrhosis, depression, dryness of skin/mucous membranes, dyspnea, eosinophilia, erectile dysfunction, erythema multiforme, ESR increased, facial paresis, fatty liver, fever, flushing, fulminant hepatic necrosis, GGT increased, gynecomastia, hemolytic anemia, hepatitis, hepatoma, hyperbilirubinemia, hypersensitivity reaction, impaired extraocular muscle movement, impotence, interstitial lung disease, leukopenia, libido decreased, malaise, myopathy, nail changes, nodules, ophthalmoplegia, pancreatitis, peripheral nerve palsy, peripheral neuropathy, photosensitivity, polymyalgia rheumatica, positive ANA, psychic disturbance, purpura, renal failure (secondary to rhabdomyolysis), rhabdomyolysis, skin discoloration, Stevens-Johnson syndrome, systemic lupus erythematosus-like syndrome, thrombocytopenia, thyroid dysfunction, toxic epidermal necrolysis, transaminases increased, tremor, urticaria, vasculitis, vertigo
Metabolism/Transport Effects
Substrate of CYP3A4 (major), P-glycoprotein; Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP2C9 (weak), CYP3A4 (weak)
Drug Interactions
Amiodarone: May decrease the metabolism of HMG-CoA Reductase Inhibitors. Management: Dose of HMG-CoA reductase inhibitor may need to be reduced (limit simvastatin adult maximum dose to 20 mg/day, limit immediate-release lovastatin to 40 mg/day, limit extended-release lovastatin to 20 mg/day). Risk D: Consider therapy modification
Antacids: May decrease the serum concentration of HMG-CoA Reductase Inhibitors. Risk C: Monitor therapy
Antifungal Agents (Azole Derivatives, Systemic): May decrease the metabolism of HMG-CoA Reductase Inhibitors. Management: Consider use of HMG-CoA reductase inhibitors posing the least rhabdomyolysis risk (e.g. fluva- or pravastatin), and monitor for signs/symptoms of rhabdomyolysis. Do not use keto- or itraconazole with lova- or simvastatin, or posaconazole with simvastatin. Risk D: Consider therapy modification
ARIPiprazole: CYP3A4 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole systemic exposure/affects with concomitant use of a weak CYP3A4 inhibitor. Decrease aripiprazole dose to 25% of the usual dose in patients receiving both a CYP3A4 and a CYP2D6 inhibitor (regardless of potencies). Risk C: Monitor therapy
Boceprevir: May increase the serum concentration of Lovastatin. Risk X: Avoid combination
Bosentan: May increase the metabolism of HMG-CoA Reductase Inhibitors. Risk C: Monitor therapy
Colchicine: May enhance the myopathic (rhabdomyolysis) effect of HMG-CoA Reductase Inhibitors. Colchicine may increase the serum concentration of HMG-CoA Reductase Inhibitors. Risk D: Consider therapy modification
CycloSPORINE: May increase the serum concentration of Lovastatin. Risk X: Avoid combination
CycloSPORINE (Systemic): May increase the serum concentration of Lovastatin. Risk X: Avoid combination
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Lovastatin. Risk X: Avoid combination
Cyproterone: May increase the serum concentration of HMG-CoA Reductase Inhibitors. Management: Avoid use of statins metabolized by CYP3A4 (eg, simvastatin) and consider avoiding fluvastatin as well in patients receiving high dose cyproterone (300 mg/day). Consider use of pravastatin, rosuvastatin, or pitavastatin if statin therapy is needed. Risk D: Consider therapy modification
Danazol: May increase the serum concentration of HMG-CoA Reductase Inhibitors. Management: Concurrent use of simvastatin with danazol is contraindicated. Initiate lovastatin at an adult maximum dose of 10 mg/day, and do not 20 mg/day, when danazol is given concomitantly. Fluvastatin, pravastatin and rosuvastatin may pose lower risk. Risk D: Consider therapy modification
DAPTOmycin: HMG-CoA Reductase Inhibitors may enhance the adverse/toxic effect of DAPTOmycin. Specifically, the risk of skeletal muscle toxicity may be increased. Management: Consider temporarily stopping HMG-CoA reductase inhibitor therapy prior to daptomycin. If used together, regular (i.e., at least weekly) monitoring of CPK concentrations is recommended. Risk D: Consider therapy modification
Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Diltiazem: May increase the serum concentration of Lovastatin. Lovastatin may increase the serum concentration of Diltiazem. Management: Initiate lovastatin at a maximum adult dose of 10 mg/day, and do not exceed 20 mg/day, in patients receiving diltiazem. Monitor closely for signs of HMG-CoA reductase inhibitor toxicity (e.g., myositis, rhabdomyolysis). Risk D: Consider therapy modification
Dronedarone: May increase the serum concentration of Lovastatin. Management: Consider using lower lovastatin doses; consider limiting lovastatin to a max of 40 mg/day (in adults). Increase monitoring for signs of lovastatin toxicity (e.g., myositis, rhabdomyolysis). Risk D: Consider therapy modification
Efavirenz: May decrease the serum concentration of Lovastatin. Risk C: Monitor therapy
Erythromycin: May increase the serum concentration of Lovastatin. Risk X: Avoid combination
Etravirine: May decrease the serum concentration of HMG-CoA Reductase Inhibitors. This applies to atorvastatin, lovastatin and simvastatin. Conversely, levels of fluvastatin may be increased. Management: Dose adjustment of the HMG-CoA reductase inhibitor may be warranted. No interaction is expected with rosuvastatin, pravastatin, or pitavastatin. Risk C: Monitor therapy
Fenofibrate: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors. Risk C: Monitor therapy
Fenofibric Acid: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors. Risk C: Monitor therapy
Fluconazole: May decrease the metabolism of HMG-CoA Reductase Inhibitors. Risk D: Consider therapy modification
Fosphenytoin: May decrease the serum concentration of HMG-CoA Reductase Inhibitors. Risk D: Consider therapy modification
Gemfibrozil: May enhance the myopathic (rhabdomyolysis) effect of Lovastatin. Gemfibrozil may increase the serum concentration of Lovastatin. More specifically, gemfibrozil may increase the serum concentrations of lovastatin acid (active form of parent drug). Risk X: Avoid combination
Grapefruit Juice: May increase the serum concentration of HMG-CoA Reductase Inhibitors. Management: Consider avoiding concurrent use of GFJ (especially larger amounts) with lovastatin, simvastatin, or atorvastatin. Consider using a lower statin dose or a statin that is less likely to interact when possible. Risk D: Consider therapy modification
Lanthanum: HMG-CoA Reductase Inhibitors may decrease the serum concentration of Lanthanum. Management: Administer HMG-CoA reductase inhibitors at least two hours before or after lanthanum. Risk D: Consider therapy modification
Macrolide Antibiotics: May decrease the metabolism of HMG-CoA Reductase Inhibitors. Management: Avoid lovastatin or simvastatin with erythro-, clarithro-, or telithromycin. Limit pitavastatin to a 1 mg/day maximum adult dose with erythromycin. Atorvastatin dose adjustments may be required. Increase monitoring for toxicity with any such combination. Exceptions: Azithromycin; Azithromycin (Systemic); Fidaxomicin; Spiramycin. Risk D: Consider therapy modification
Mifepristone: May increase the serum concentration of Lovastatin. Management: Avoid lovastatin during and 2 weeks following mifepristone for treatment of hyperglycemia in Cushing's syndrome. The interaction magnitude could be lower with single doses used to terminate pregnancy, but neither effect has been studied clinically. Risk X: Avoid combination
Niacin: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors. Management: This is of greatest concern with niacin doses of 1 g or greater daily. Avoid simvastatin 80 mg in combination with niacin 1 g or greater in Chinese patients. Canadian labeling contraindicates use of niacin with rosuvastatin 40 mg. Risk D: Consider therapy modification
Niacinamide: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors. Risk C: Monitor therapy
P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
Phenytoin: May decrease the serum concentration of HMG-CoA Reductase Inhibitors. Risk D: Consider therapy modification
Pimozide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Pimozide. Risk X: Avoid combination
Protease Inhibitors: May increase the serum concentration of Lovastatin. Risk X: Avoid combination
QuiNINE: May increase the serum concentration of HMG-CoA Reductase Inhibitors. Management: Consider using a lower starting dose and lower maintenance/maximum doses of atorvastatin, simvastatin, or lovastatin when used together with quinine. Risk D: Consider therapy modification
Ranolazine: May enhance the myopathic (rhabdomyolysis) effect of Lovastatin. Ranolazine may increase the serum concentration of Lovastatin. Ranolazine may also enhance the distribution of lovastatin to specific cells/tissues/organs where P-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
Red Yeast Rice: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors. Risk X: Avoid combination
Rifamycin Derivatives: May decrease the serum concentration of HMG-CoA Reductase Inhibitors. Management: Consider use of noninteracting antilipemic agents (note: pitavastatin concentrations may increase with rifamycin treatment). Monitor for altered HMG-CoA reductase inhibitor effects. Rifabutin and fluvastatin, or possibly pravastatin, may pose lower risk. Risk D: Consider therapy modification
Sildenafil: May decrease the metabolism of HMG-CoA Reductase Inhibitors. Risk D: Consider therapy modification
St Johns Wort: May increase the metabolism of HMG-CoA Reductase Inhibitors. Risk C: Monitor therapy
Telaprevir: May increase the serum concentration of Lovastatin. Risk X: Avoid combination
Ticagrelor: May increase the serum concentration of Lovastatin. Management: Avoid using doses of lovastatin greater than 40 mg/day with ticagrelor. This specific recommendation is found in the U.S. prescribing information but not in the Canadian product monograph. Risk D: Consider therapy modification
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Trabectedin: HMG-CoA Reductase Inhibitors may enhance the myopathic (rhabdomyolysis) effect of Trabectedin. Risk C: Monitor therapy
Verapamil: May increase the serum concentration of Lovastatin. Management: Initiate lovastatin at a maximum adult dose of 10 mg/day, and do not exceed 20 mg/day, in patients receiving verapamil. Monitor closely for signs of HMG-CoA reductase inhibitor toxicity (e.g., myositis, rhabdomyolysis). Risk D: Consider therapy modification
Vitamin K Antagonists (eg, warfarin): HMG-CoA Reductase Inhibitors may enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Ethanol: Excessive ethanol consumption may have harmful hepatic effects. Management: Avoid excessive ethanol consumption.
Food: Food decreases the bioavailability of lovastatin extended release tablets and increases the bioavailability of lovastatin immediate release tablets. Lovastatin serum concentrations may be increased if taken with grapefruit juice. Management: Avoid concurrent intake of large quantities (>1 quart/day) of grapefruit juice. Red yeast rice contains an estimated 2.4 mg lovastatin per 600 mg rice.
Herb/Nutraceutical: St John's wort may decrease lovastatin levels.
Storage
Tablet, immediate release: Store at 20°C to 25°C (68°F to 77°F). Protect from light
Tablet, extended release: Store between 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). Avoid excessive heat and humidity.
Mechanism of Action
Lovastatin acts by competitively inhibiting 3-hydroxyl-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the rate-limiting step in cholesterol biosynthesis
Pharmacodynamics/Kinetics
Onset of action: LDL-cholesterol reductions: 3 days
Absorption: 30%; increased with extended release tablets when taken in the fasting state
Protein binding: >95%
Metabolism: Hepatic; extensive first-pass effect; hydrolyzed to β-hydroxyacid (active)
Bioavailability: Increased with extended release tablets
Half-life elimination: 1.1-1.7 hours
Time to peak, serum: Immediate release: 2-4 hours; extended release: 12-14 hours
Excretion: Feces (~80% to 85%); urine (10%)
Dosage
Oral:
Adolescents 10-17 years: Immediate release tablet:
LDL reduction <20%: Initial: 10 mg/day with evening meal
LDL reduction ≥20%: Initial: 20 mg/day with evening meal
Usual range: 10-40 mg with evening meal, then adjust dose at 4-week intervals; maximum dose per manufacturer: 40 mg/day
Adults: Initial: 20 mg with evening meal, then adjust at 4-week intervals; maximum dose: 80 mg/day immediate release tablet or 60 mg/day extended release tablet
Note: Doses should be individualized according to the baseline LDL-cholesterol levels, the recommended goal of therapy, and patient response.
Lovastatin dose limits based on concurrent therapy:
Amiodarone: Maximum recommended lovastatin dose: 40 mg/day (immediate release) or 20 mg/day (extended release)
Danazol or diltiazem: Initial lovastatin (immediate release) dose: 10 mg/day; Maximum recommended lovastatin (immediate release) dose: 20 mg/day
Verapamil: Initial lovastatin (immediate release) dose: 10 mg/day; Maximum recommended lovastatin (extended release and immediate release) dose: 20 mg/day
Dosage adjustment in renal impairment: Clcr <30 mL/minute: Use doses >20 mg/day with caution.
Administration: Oral
Administer immediate release tablet with the evening meal. Administer extended release tablet at bedtime; do not crush or chew.
Monitoring Parameters
Obtain baseline LFTs (repeat during therapy if clinically indicated) and total cholesterol profile; baseline CPK (recheck CPK in any patient with symptoms suggestive of myopathy)
Reference Range
NCEP classification of pediatric patients with familial history of hypercholesterolemia or premature CVD: Acceptable total cholesterol: <170 mg/dL, LDL: <110 mg/dL
Test Interactions
Altered thyroid function tests
Dietary Considerations
Before initiation of therapy, patients should be placed on a standard cholesterol-lowering diet for 6 weeks and the diet should be continued during drug therapy. Avoid intake of large quantities of grapefruit juice (≥1 quart/day); may increase toxicity. Red yeast rice contains an estimated 2.4 mg lovastatin per 600 mg rice. Immediate release tablet should be taken with the evening meal.
Patient Education
Take with food at evening meal. Follow prescribed diet and exercise regimen. You will have periodic blood tests to assess effectiveness. Avoid excessive alcohol. Report unusual muscle cramping or weakness, yellowing of skin or eyes, easy bruising or bleeding, or unusual fatigue.
Geriatric Considerations
The definition of and, therefore, when to treat hyperlipidemia in the elderly is a controversial issue. The National Cholesterol Education Program recommends that all adults maintain a plasma cholesterol <160 mg/dL. For elderly patients with one additional risk factor, goal LDL would be <130 mg/dL. It is the authors' belief that pharmacologic treatment be reserved for those who are unable to obtain a desirable plasma cholesterol concentration by diet alone and for whom the benefits of treatment are believed to outweigh the potential adverse effects, drug interactions, and cost of treatment. Age ≥65 years is a risk factor for myopathy.
Anesthesia and Critical Care Concerns/Other Considerations
Clinical Pearls/Comments: Based on current research and clinical guidelines (Fleisher, 2009), HMG-CoA reductase inhibitors should be continued in the perioperative period. Postoperative discontinuation of statin therapy is associated with an increased risk of cardiac morbidity and mortality.
Cardiovascular Considerations
Primary Prevention: HMG-CoA reductase inhibitors are effective in primary and secondary prevention of cardiovascular events in patients with hyperlipidemia. For primary prevention, a patient's major risk factors (cigarette smoking, hypertension or currently taking antihypertensives, low HDL-C, family history, age, gender) should be evaluated. Patients with multiple risk factors (≥2) require more intensive therapy guided by the calculation of a 10-year absolute CHD risk (eg, the percent probability of having a CHD event in next 10 years). An individual's 10-year absolute CHD risk can be calculated at www.med-decisions.com/cvtool/phys/phys.html. LDL cholesterol goals, therapeutic lifestyle changes, and drug therapy are determined based upon a patient's risk factor profile.
Primary prevention trials show that cholesterol-lowering drugs reduce the risk of major coronary events, coronary death, and cerebrovascular events even in the first 6-12 months of use. The WOSCOP trial suggested a trend towards enhanced survival using pravastatin in their patients (mean LDL-cholesterol of 192 mg/dL and no history of MI). In a recent trial (Sever, 2003), patients with HTN and at least three other risk factors were randomized to 10 mg daily of atorvastatin or placebo. These patients had a total nonfasting cholesterol <250 mg/dL before treatment. LDL-C levels were 132 mg/dL before treatment and fell to an average of 90 mg/dL in the atorvastatin-treated group. There was a significant reduction in stroke, cardiovascular events, and coronary events in the atorvastatin-treated group as compared to the placebo group. There was no difference in mortality between the groups.
HMG-CoA reductase inhibitors decrease C-reactive protein (CRP), an inflammatory marker and an acute phase reactant. Elevated levels of high sensitive CRP (hsCRP), which detects CRP levels as low as 0.175 mg/L, have been shown to be associated with an increased risk of cardiovascular events. Recently, the JUPITER trial demonstrated that the use of rosuvastatin in healthy patients (men ≥50 years and women ≥60 years) without a history of cardiovascular disease with LDL <130 mg/dL and a hsCRP level ≥2 mg/L reduced the risk of major cardiovascular events (eg, nonfatal MI, stroke, death from cardiovascular causes), The number needed to treat over 5 years to prevent 1 cardiovascular event is 25. Current guidelines do not recommend drug treatment for patients with an LDL <130 mg/dL. However, identification of the patient at higher risk of cardiovascular events within this subgroup using hsCRP is now important given that statins may prevent the occurrence of these serious cardiovascular events (Ridker, 2008).
Secondary Prevention: Secondary prevention trials indicate that “statin” therapy reduces mortality, major coronary events, coronary artery procedures, and stroke. The Heart Protection Study proved that lowering serum cholesterol levels reduces the rate of major vascular events among high-risk individuals with documented vascular disease (CHD, cerebrovascular, peripheral vascular) or diabetes regardless of initial cholesterol concentrations. PROVE IT is a randomized, double-blind trial evaluating hospitalized patients with acute coronary syndrome to determine the effects of intense LDL-C lowering therapy. Four thousand patients with an LDL-C levels of 106 mg/dL were randomized to pravastatin 40 mg daily or atorvastatin 80 mg daily. After 2 years, the combined cardiovascular endpoint (death, MI, unstable angina requiring hospitalization, revascularization and stroke) was ~26% in the pravastatin patients (median LDL-C 95 mg/dL) and ~22% in the atorvastatin treated patients (median LDL-C 62 mg/dL).
LaRosa and colleagues assessed the efficacy and safety of lowering LDL cholesterol <100 mg/dL in patients with stable coronary heart disease (LaRosa, 2005). Ten thousand and one patients with baseline LDL levels <130 mg/dL were randomized to atorvastatin 10 mg or 80 mg daily and followed for a median of 4.9 years. The primary endpoint was the occurrence of the first major cardiovascular event (death from CVD, MI, resuscitation after cardiac arrest, or stroke). A primary event occurred in 434 patients (8.7%) receiving 80 mg daily (mean LDL 77 mg/dL) and 548 patients (10.9%) receiving 10 mg dose (mean LDL 101 mg/dL) (95% CI, 0.69-0.89; p <0.001). There was no mortality difference between the two treatment groups.
In addition to the ability of HMG-CoA reductase inhibitors to decrease levels of high-sensitivity C-reactive protein (hsCRP), they also possess pleiotropic properties including improved endothelial function, reduced inflammation at the site of the coronary plaque, inhibition of platelet aggregation, and anticoagulant effects. These nonlipid effects may be beneficial when HMG-CoA reductase inhibitors are introduced early in the management of acute coronary syndromes (de Denus, 2002).
Myopathy: Currently-marketed HMG-CoA reductase inhibitors appear to have a similar potential for causing myopathy. Incidence of severe myopathy is about 0.08% to 0.09%. The factors that increase risk include advanced age (especially >80 years of age), women more frequently than men, small body frame, frailty, multisystem disease (eg, chronic renal insufficiency especially due to diabetes), multiple medications, drug interactions (use with caution or avoid). The combination of a HMG-CoA reductase inhibitor plus nicotinic acid seems to carry a lower risk of myopathy than does a HMG-CoA reductase inhibitor plus a fibrate. Other medications, when used concurrently, may enhance the risk of myopathy associated with statins; these include drugs that inhibit CYP3A4 isoenzymes (lovastatin, simvastatin, atorvastatin) or CYP2C9 isoenzymes (fluvastatin). HMG-CoA reductase inhibitors may exacerbate exercise-induced skeletal muscle injury. Many experts favor getting a baseline creatine kinase (CK) measurement before initiating therapy (asymptomatic CK elevations are common). Obtain a CK measurement if patient complains of muscle soreness, tenderness, or pain.
Dental Health: Effects on Dental Treatment
No significant effects or complications reported
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May cause dizziness
Mental Health: Effects on Psychiatric Treatment
None reported
Nursing: Physical Assessment/Monitoring
Use caution with history of hepatic disease. Assess risk potential for interactions with other prescriptions or herbal products patient may be taking that may increase risk of myopathy or rhabdomyolysis. Evaluate LFTs (repeat during therapy if clinically indicated) and lipid profile prior to treatment; periodic lipid profile assessment. Teach proper diet and exercise program.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, oral: 10 mg, 20 mg, 40 mg
Mevacor®: 20 mg, 40 mg
Tablet, extended release, oral:
Altoprev®: 20 mg, 40 mg, 60 mg
Pricing: U.S. (www.drugstore.com)
Tablet, 24-hour (Altoprev)
20 mg (30): $399.98
60 mg (30): $374.98
Tablets (Lovastatin)
10 mg (45): $47.99
20 mg (30): $22.99
40 mg (30): $35.99
Tablets (Mevacor)
40 mg (30): $146.00
References
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International Brand Names
Lexi-Comp.com
Last full review/revision April 2012
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