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Lovastatin

Pronunciation

(LOE va sta tin)

Index Terms

  • Mevinolin
  • Monacolin K

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Tablet, Oral:

Mevacor: 20 mg [DSC], 40 mg [DSC]

Generic: 10 mg, 20 mg, 40 mg

Tablet Extended Release 24 Hour, Oral:

Altoprev: 20 mg, 40 mg, 60 mg [contains corn starch, fd&c yellow #6 (sunset yellow)]

Brand Names: U.S.

  • Altoprev
  • Mevacor [DSC]

Pharmacologic Category

  • Antilipemic Agent, HMG-CoA Reductase Inhibitor

Pharmacology

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. 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 (de Denus 2002; Ray 2005).

Absorption

30% absorbed but less than 5% reaches the systemic circulation due to an extensive first-pass effect; increased with extended release tablets when taken in the fasting state

Metabolism

Hepatic; extensive first-pass effect; hydrolyzed to β-hydroxyacid (active)

Excretion

Feces (~80% to 85%); urine (10%)

Onset of Action

LDL-cholesterol reductions: 3 days

Time to Peak

Serum: Immediate release: 2-4 hours; extended release: 12-14 hours

Half-Life Elimination

1.1-1.7 hours

Protein Binding

>95%

Special Populations: Renal Function Impairment

Plasma concentrations of total inhibitors are increased 2-fold in severe renal insufficiency (CrCl <30 mL/minute).

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 to 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

Guideline recommendations: Primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD) to reduce the risk of ASCVD in select adult patients (ACC/AHA [Stone 2013]; ADA 2017a; NLA [Jacobson 2015]; USPSTF 2016). Refer to respective guideline for specific recommendations.

Off Label Uses

Cardiac risk reduction for noncardiac surgery (perioperative therapy)

Based on the 2014 American College of Cardiology/American Heart Association (ACC/AHA) guidelines on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery, perioperative initiation of statins is reasonable for patients undergoing vascular surgery and may be considered in patients with clinical indications according to guideline-directed medical therapy who are undergoing elevated risk procedures. In patients undergoing non-cardiac surgery who are currently receiving a statin, the statin should be continued.

Noncardioembolic stroke/TIA (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, 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).

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, voriconazole, protease inhibitors [including boceprevir and telaprevir], telithromycin, cobicistat-containing products); pregnancy; breastfeeding

Canadian labeling: Additional contraindications (not in US labeling): Concomitant use of cyclosporine

Dosing: Adult

Dyslipidemia and primary prevention of CAD: Oral:

Immediate release: Initial: 20 mg once daily with evening meal, then adjust at 4-week intervals; maximum dose: 80 mg daily

Extended release: Initial: 20, 40, or 60 mg once daily at bedtime, then adjust at 4-week intervals; maximum dose: 60 mg daily

Note: Doses should be individualized according to the baseline LDL-cholesterol levels, the recommended goal of therapy, and patient response. For patients requiring smaller reductions in cholesterol, the use of the extended release tablet is not recommended; consider use of immediate release formulation.

Prevention of cardiovascular disease/reduce the risk of ASCVD:

ACC/AHA Blood Cholesterol Guideline recommendations (ACC/AHA [Stone 2013]): Adults ≥21 years:

Primary prevention:

LDL-C ≥190 mg/dL: High intensity therapy necessary; use alternate statin therapy (eg, atorvastatin or rosuvastatin)

Type 1 or 2 diabetes and age 40-75 years: Moderate intensity therapy: Immediate release: 40 mg once daily

Type 1 or 2 diabetes, age 40-75 years, and an estimated 10-year ASCVD risk ≥7.5%: High intensity therapy necessary; use alternate statin therapy (eg, atorvastatin or rosuvastatin)

Age 40-75 years and an estimated 10-year ASCVD risk ≥7.5%: Moderate to high intensity therapy: Immediate release: 40 mg once daily or consider using high intensity statin therapy (eg, atorvastatin or rosuvastatin)

Secondary prevention:

Patient has clinical ASCVD (eg, coronary heart disease, stroke/TIA, or peripheral arterial disease presumed to be of atherosclerotic origin) or is post-CABG (AHA [Kulik 2015]) and:

Age ≤75 years: High intensity therapy necessary; use alternate statin therapy (eg, atorvastatin or rosuvastatin)

Age >75 years or not a candidate for high intensity therapy: Moderate intensity therapy: Immediate release: 40 mg once daily

NLA Dyslipidemia Guideline recommendations (NLA [Jacobson 2015]): Adults ≥20 years:

Primary or secondary prevention: Note: Treatment initiation using either moderate- or high-intensity statin therapy is recommended in qualifying patients based on ASCVD risk assessment criteria and baseline non-HDL-C and LDL-C values. Dosage should be individualized based on patient characteristics, tolerance to therapy and with consideration for non-HDL-C and LDL-C treatment goals.

Moderate-intensity therapy (30 to 50% reduction of LDL-C generally): Immediate release: 40 mg once daily

High-intensity therapy (≥50% reduction of LDL-C generally): Use alternate statin therapy (eg, atorvastatin, rosuvastatin)

US Preventive Services Task Force Recommendations (USPSTF 2016):

Primary prevention: Age 40 to 75 years, no history of CVD, with ≥1 CVD risk factor (dyslipidemia, diabetes, hypertension, or smoking), and calculated 10-year CVD event risk of ≥10%:

Low to moderate intensity therapy: 20 to 40 mg once daily

Note: These recommendations do not pertain to patients with very high CVD risk factors (eg, LDL >190 mg/dL, familial hypercholesterolemia) (were excluded from primary prevention trials); use clinical judgment in the treatment of these patients. In patients with a calculated 10-year CVD event risk of 7.5% to 10%, may consider use of a statin based on patient characteristics.

Dosage adjustment for lovastatin with concomitant medications:

Amiodarone: Maximum recommended lovastatin dose (extended release and immediate release): 40 mg daily

Danazol, diltiazem, dronedarone, or verapamil: Initial lovastatin (immediate release) dose: 10 mg daily; Maximum recommended lovastatin (extended release and immediate release) dose: 20 mg daily

Lomitapide: Consider lovastatin dose reduction (per lomitapide manufacturer).

Ranolazine: Consider lovastatin dose reduction.

Dosing: Geriatric

Immediate release: Refer to adult dosing; Extended release: Initial: 20 mg once daily at bedtime

Dosing: Pediatric

Heterozygous familial hypercholesterolemia: Oral (immediate release tablet): Adolescents 10 to 17 years:

LDL reduction <20%: Initial: 10 mg daily with evening meal

LDL reduction ≥20%: Initial: 20 mg daily with evening meal

Usual range: 10 to 40 mg once daily with evening meal, then adjust dose at 4-week intervals; maximum dose per manufacturer: 40 mg daily

Dosage adjustment for lovastatin with concomitant medications (amiodarone, danazol, diltiazem, dronedarone, lomitapide, ranolazine, or verapamil): Refer to adult dosing.

Dosing: Renal Impairment

CrCl <30 mL/minute: Use with caution and carefully consider doses >20 mg/day.

Dosing: Hepatic Impairment

No dosage adjustment provided in manufacturer’s labeling (has not been studied).

Dosing: Adjustment for Toxicity

Severe muscle symptoms or fatigue: Promptly discontinue use; evaluate CPK, creatinine, and urinalysis for myoglobinuria (Stone 2013).

Mild to moderate muscle symptoms: Discontinue use until symptoms can be evaluated; evaluate patient for conditions that may increase the risk for muscle symptoms (eg, hypothyroidism, reduced renal or hepatic function, rheumatologic disorders such as polymyalgia rheumatica, steroid myopathy, vitamin D deficiency, or primary muscle diseases). Upon resolution, resume the original or lower dose of lovastatin. If muscle symptoms recur, discontinue lovastatin use. After muscle symptom resolution, may then use a low dose of a different statin; gradually increase if tolerated. In the absence of continued statin use, if muscle symptoms or elevated CPK continues after 2 months, consider other causes of muscle symptoms. If determined to be due to another condition aside from statin use, may resume statin therapy at the original dose (Stone 2013).

Administration

Administer immediate release tablet with the evening meal. Administer extended release tablet at bedtime; do not crush or chew.

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 grapefruit juice; may increase toxicity. Immediate release tablet should be taken with the evening meal.

Red yeast rice contains variable amounts of several compounds that are structurally similar to HMG-CoA reductase inhibitors, primarily monacolin K (or mevinolin) which is structurally identical to lovastatin; concurrent use of red yeast rice with HMG-CoA reductase inhibitors may increase the incidence of adverse and toxic effects (Lapi 2008; Smith 2003).

Storage

Tablet, immediate release: Store at 20°C to 25°C (68°F to 77°F). Protect from light

Tablet, extended release: Store at 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.

Drug Interactions

Acipimox: May enhance the myopathic (rhabdomyolysis) effect of HMG-CoA Reductase Inhibitors (Statins). Monitor therapy

Amiodarone: May increase the serum concentration of Lovastatin. Management: Consider using a non-interacting statin (pravastatin) in patients on amiodarone. If combined, limit the lovastatin dose to 40 mg daily and monitor for evidence of lovastatin toxicities (eg, myalgia, liver function test elevations, rhabdomyolysis). Consider therapy modification

Antacids: May decrease the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Monitor therapy

Aprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Asunaprevir: May increase the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Monitor therapy

Azithromycin (Systemic): May enhance the myopathic (rhabdomyolysis) effect of Lovastatin. Monitor therapy

Bezafibrate: May enhance the myopathic (rhabdomyolysis) effect of HMG-CoA Reductase Inhibitors (Statins). Bezafibrate may increase the serum concentration of HMG-CoA Reductase Inhibitors (Statins). More specifically, bezafibrate may increase the serum concentration of fluvastatin Management: Monitor patients closely for myopathy with concomitant use of bezafibrate and HMG-CoA reductase inhibitors. Concomitant use is contraindicated in patients predisposed to myopathy and alternative therapy should be considered. Consider therapy modification

Boceprevir: May increase the serum concentration of Lovastatin. Avoid combination

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Ciprofibrate: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors (Statins). Management: Avoid the use of HMG-CoA reductase inhibitors and ciprofibrate if possible. If concomitant therapy is considered, benefits should be carefully weighed against the risks, and patients should be monitored closely for signs/symptoms of muscle toxicity. Consider therapy modification

Clarithromycin: May increase the serum concentration of Lovastatin. Avoid combination

Colchicine: May enhance the myopathic (rhabdomyolysis) effect of HMG-CoA Reductase Inhibitors (Statins). Colchicine may increase the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Consider therapy modification

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

CycloSPORINE (Systemic): May increase the serum concentration of Lovastatin. Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Lovastatin. Avoid combination

Cyproterone: May increase the serum concentration of HMG-CoA Reductase Inhibitors (Statins). 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. Consider therapy modification

Dabigatran Etexilate: Lovastatin may enhance the anticoagulant effect of Dabigatran Etexilate. Management: Consider an alternative HMG-CoA reductase inhibitor (statin) in patients taking dabigatran who require statin therapy. If used together, monitor patients closely for signs and symptoms of bleeding. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Daclatasvir: May increase the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Monitor therapy

Danazol: May increase the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Management: Concurrent use of simvastatin with danazol is contraindicated. Initiate lovastatin at an adult maximum dose of 10 mg/day, and do not exceed 20 mg/day, when danazol is given concomitantly. Fluvastatin, pravastatin and rosuvastatin may pose lower risk. Consider therapy modification

DAPTOmycin: HMG-CoA Reductase Inhibitors (Statins) 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. Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

DilTIAZem: Lovastatin may increase the serum concentration of DilTIAZem. DilTIAZem 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 diltiazem. Monitor closely for signs of HMG-CoA reductase inhibitor toxicity (e.g., myositis, rhabdomyolysis). Consider therapy modification

Dronedarone: May increase the serum concentration of Lovastatin. Management: Limit lovastatin to a maximum of 20 mg/day (in adults). Increase monitoring for signs of lovastatin toxicity (e.g., myopathy, rhabdomyolysis). Consider therapy modification

Efavirenz: May decrease the serum concentration of Lovastatin. Monitor therapy

Elbasvir: May increase the serum concentration of Lovastatin. Monitor therapy

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Erythromycin (Systemic): May increase the serum concentration of Lovastatin. Avoid combination

Etravirine: May decrease the serum concentration of HMG-CoA Reductase Inhibitors (Statins). 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. Monitor therapy

Fenofibrate and Derivatives: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors (Statins). Monitor therapy

Fluconazole: May increase the serum concentration of Lovastatin. Monitor therapy

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fosphenytoin: May decrease the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Consider therapy modification

Fusidic Acid (Systemic): May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors (Statins). Specifically, the risk for muscle toxicities, including rhabdomyolysis may be significantly increased. Management: Avoid concurrent use whenever possible. Use is listed as contraindicated in product characteristic summaries in several countries, although UK labeling suggests that use could be considered under exceptional circumstances and with close supervision. Avoid combination

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

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). Avoid combination

Glecaprevir and Pibrentasvir: May increase the serum concentration of Lovastatin. Avoid combination

Grapefruit Juice: May increase the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Management: Avoid concurrent use of GFJ with lovastatin or simvastatin. Avoid high quantities of GFJ with atorvastatin. Consider using a lower statin dose or a statin that is less likely to interact when possible. Consider therapy modification

Grazoprevir: May increase the serum concentration of Lovastatin. Monitor therapy

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Lanthanum: HMG-CoA Reductase Inhibitors (Statins) may decrease the serum concentration of Lanthanum. Management: Administer HMG-CoA reductase inhibitors at least two hours before or after lanthanum. Consider therapy modification

Lomitapide: May increase the serum concentration of Lovastatin. Management: Consider reducing lovastatin doses during concomitant treatment with lomitapide, and monitor for signs and symptoms of muscle toxicity. Specific dosing recommendations are not presently available. 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. Avoid combination

Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Niacin: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors (Statins). Monitor therapy

Niacinamide: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors (Statins). Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

PAZOPanib: HMG-CoA Reductase Inhibitors (Statins) may enhance the hepatotoxic effect of PAZOPanib. Specifically, the risk for increased serum transaminase concentrations may be increased. Management: Simvastatin is specifically implicated in the interaction. There is a lack of data regarding risk with other statins, but caution appears warranted with any statins. Atorvastatin should be avoided due to P-gp inhibition. 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.). Monitor therapy

Phenytoin: May decrease the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Consider therapy modification

Pitolisant: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Combined use of pitolisant with a CYP3A4 substrate that has a narrow therapeutic index should be avoided. Other CYP3A4 substrates should be monitored more closely when used with pitolisant. Consider therapy modification

Protease Inhibitors: May increase the serum concentration of Lovastatin. Avoid combination

QuiNINE: May increase the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Management: Consider using a lower starting dose and lower maintenance/maximum doses of atorvastatin, simvastatin, or lovastatin when used together with quinine. Consider therapy modification

Raltegravir: May enhance the myopathic (rhabdomyolysis) effect of HMG-CoA Reductase Inhibitors (Statins). Monitor therapy

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.). Monitor therapy

Red Yeast Rice: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors (Statins). Avoid combination

Repaglinide: HMG-CoA Reductase Inhibitors (Statins) may increase the serum concentration of Repaglinide. Monitor therapy

Rifamycin Derivatives: May decrease the serum concentration of HMG-CoA Reductase Inhibitors (Statins). 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. Consider therapy modification

Rupatadine: May enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors (Statins). Specifically, the risk for increased CPK and/or other muscle toxicities may be increased. Monitor therapy

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Simeprevir: May increase the serum concentration of Lovastatin. Monitor therapy

St John's Wort: May increase the metabolism of HMG-CoA Reductase Inhibitors (Statins). Management: Consider avoiding the concomitant administration of St Johns Wort with interacting HMG-CoA reductase inhibitors in order to avoid the potential for decreased antilipemic effects. Monitor for decreased effects during concomitant therapy. Consider therapy modification

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Telaprevir: May increase the serum concentration of Lovastatin. Avoid combination

Telithromycin: May increase the serum concentration of Lovastatin. 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. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Trabectedin: HMG-CoA Reductase Inhibitors (Statins) may enhance the myopathic (rhabdomyolysis) effect of Trabectedin. 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). Consider therapy modification

Vitamin K Antagonists (eg, warfarin): HMG-CoA Reductase Inhibitors (Statins) may enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Voxilaprevir: May increase the serum concentration of HMG-CoA Reductase Inhibitors (Statins). Management: Use the lowest statin dose possible if combined with voxilaprevir and monitor patients for increased statin effects/toxicities. Avoid concomitant use of voxilaprevir with rosuvastatin or pitavastatin, and limit pravastatin doses to 40 mg daily. Consider therapy modification

Adverse Reactions

Percentages as reported with immediate release tablets; similar adverse reactions seen with extended release tablets.

>10%: Neuromuscular & skeletal: Increased creatine phosphokinase (>2x normal) (11%)

1% to 10%:

Central nervous system: Headache (2% to 3%), dizziness (≤1%)

Dermatologic: Skin 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%)

Ophthalmic: Blurred vision (≤1%)

Frequency not defined: Genitourinary: Cystitis (interstitial; Huang 2015)

<1% (Limited to important or life-threatening): Acid regurgitation, alopecia, amnesia (reversible), arthralgia, chest pain, cognitive dysfunction (reversible), dermatomyositis, diabetes mellitus (new-onset), elevated glycosylated hemoglobin (HbA1c), eye irritation, increased blood glucose, insomnia, interstitial pulmonary disease, leg pain, memory impairment (reversible), paresthesia, pruritus, reversible confusional state, vomiting, xerostomia

Warnings/Precautions

Concerns related to adverse effects:

• Diabetes mellitus: Increases in HbA1c 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. Ethanol may enhance the potential of adverse hepatic effects; instruct patients to avoid excessive ethanol consumption.

• Immune-mediated necrotizing myopathy (IMNM): IMNM, an autoimmune-mediated myopathy, has been reported (rarely) with HMG-CoA reductase inhibitor therapy. IMNM presents as proximal muscle weakness with elevated CPK levels, which persists despite discontinuation of HMG-CoA reductase inhibitor therapy; additionally, muscle biopsy may show necrotizing myopathy with limited inflammation. Immunosuppressive therapy (eg, corticosteroids, azathioprine) may be used for treatment.

• 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. 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.

• Renal impairment: Use with caution in patients with renal impairment; risk of myopathy is increased.

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.

• Surgical patients: 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). Based on current research and clinical guidelines, HMG-CoA reductase inhibitors should be continued in the perioperative period for noncardiac and cardiac surgery (ACC/AHA [Fleisher 2014]; ACC/AHA [Hillis 2011]). Perioperative discontinuation of statin therapy is associated with an increased risk of cardiac morbidity and mortality.

Other warnings/precautions:

• Hyperlipidemia: Secondary causes of hyperlipidemia should be ruled out prior to therapy.

Monitoring Parameters

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

Lipid panel (total cholesterol, HDL, LDL, triglycerides): Baseline lipid panel; fasting lipid profile within 4-12 weeks after initiation or dose adjustment and every 3-12 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: Liver enzyme tests at baseline and repeated when clinically indicated. Measure CPK when myopathy is being considered or may measure CPK periodically in patients starting therapy or when dosage increase is necessary. Analyze lipid panel at intervals of 4 weeks or more.

Pregnancy Risk Factor

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Pregnancy Considerations

Adverse events were observed in animal reproduction studies. There are reports of congenital anomalies following maternal use of HMG-CoA reductase inhibitors in pregnancy; however, maternal disease, differences in specific agents used, and the low rates of exposure limit the interpretation of the available data (Godfrey 2012; Lecarpentier 2012). Cholesterol biosynthesis may be important in fetal development; serum cholesterol and triglycerides increase normally during pregnancy. The discontinuation of lipid lowering medications temporarily during pregnancy is not expected to have significant impact on the long term outcomes of primary hypercholesterolemia treatment.

Use of lovastatin is contraindicated in pregnancy. The ADA Diabetes guidelines recommends avoiding use of HMG-CoA reductase inhibitors (because they are potentially teratogenic), in sexually active women of childbearing age who are not using reliable contraception (ADA 2017b). If treatment of dyslipidemias is needed in pregnant women or in women of reproductive age, other agents are preferred (Berglund 2012; Stone 2013). The manufacturer recommends administration to women of childbearing potential only when conception is highly unlikely and patients have been informed of potential hazards.

Patient Education

• 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, back pain, or flu-like symptoms. 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), urinary retention, change in amount of urine passed, 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.

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