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Ezetimibe and Atorvastatin

Pronunciation

(ez ET i mibe & a TORE va sta tin)

Index Terms

  • Atorvastatin and Ezetimibe

Dosage Forms

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

Tablet, oral:

Liptruzet 10/10: Ezetimibe 10 mg and atorvastatin 10 mg [DSC]

Liptruzet 10/20: Ezetimibe 10 mg and atorvastatin 20 mg [DSC]

Liptruzet 10/40: Ezetimibe 10 mg and atorvastatin 40 mg [DSC]

Liptruzet 10/80: Ezetimibe 10 mg and atorvastatin 80 mg [DSC]

Brand Names: U.S.

  • Liptruzet [DSC]

Pharmacologic Category

  • Antilipemic Agent, 2-Azetidinone
  • Antilipemic Agent, HMG-CoA Reductase Inhibitor

Pharmacology

Ezetimibe: Inhibits absorption of cholesterol at the brush border of the small intestine via the sterol transporter, Niemann-Pick C1-Like1 (NPC1L1). This leads to a decreased delivery of cholesterol to the liver, reduction of hepatic cholesterol stores and an increased clearance of cholesterol from the blood.

Atorvastatin: Inhibits 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol synthesis (reduces the production of mevalonic acid from HMG-CoA); this then results in a compensatory increase in the expression of LDL receptors on hepatocyte membranes and a stimulation of LDL catabolism. 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).

Use: Labeled Indications

Homozygous familial hypercholesterolemia: As an adjunct to diet for the reduction of elevated total cholesterol, and low-density lipoprotein cholesterol (LDL-C) in patients with homozygous familial hypercholesterolemia, as an adjunct to other lipid-lowering treatments (eg, LDL apheresis) or if such treatments are unavailable.

Primary hyperlipidemia: As an adjunct to diet for the reduction of elevated total cholesterol, LDL-C, apolipoprotein B (apo B), triglycerides, and non-high-density lipoprotein cholesterol (non-HDL-C), and to increase HDL-C in patients with primary (heterozygous familial and nonfamilial) hyperlipidemia or mixed hyperlipidemia.

Guideline recommendations:

Ezetimibe: The National Lipid Association (NLA) recommends ezetimibe in combination with a statin to reduce the risk of atherosclerotic cardiovascular disease (ASCVD) events for at-risk patients not at non-HDL-C and/or LDL-C goals despite receiving maximally tolerated statin therapy or for those who cannot tolerate higher statin doses (eg, the elderly) (NLA [Jacobson 2015]). The American Diabetes Association (ADA) recommends ezetimibe in combination with moderate-intensity statin therapy be considered for patients with diabetes and a history of ASCVD who cannot tolerate high-intensity statin therapy (ADA 2017).

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

Contraindications

Hypersensitivity to ezetimibe, atorvastatin, or any component of the formulation; active liver disease; unexplained persistent elevations of serum transaminases; pregnancy or women who may become pregnant; breastfeeding

Dosing: Adult

Note: Doses should be individualized according to the baseline LDL-cholesterol concentrations and patient response; adjustments should be made at intervals of ≥2 weeks.

Homozygous familial hypercholesterolemia: Oral: Ezetimibe 10 mg/atorvastatin 40 mg or ezetimibe 10 mg/atorvastatin 80 mg once daily

Primary hyperlipidemia: Oral: Initial: Ezetimibe 10 mg/atorvastatin 10 mg or ezetimibe 10 mg/atorvastatin 20 mg once daily; patients requiring >55% reduction in LDL-C may be started on ezetimibe 10 mg/atorvastatin 40 mg once daily; dosing range: Ezetimibe 10 mg/atorvastatin 10 to 80 mg once daily

Dosage adjustment with concomitant medications:

Clarithromycin, fosamprenavir, hepatitis C antivirals containing elbasvir and grazoprevir, itraconazole, ritonavir (plus darunavir, fosamprenavir or saquinavir): Maximum dose: Ezetimibe 10 mg/atorvastatin 20 mg once daily

Boceprevir, nelfinavir: Maximum dose: Ezetimibe 10 mg/atorvastatin 40 mg once daily

Lomitapide: Consider atorvastatin dose reduction (per lomitapide manufacturer)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

No dosage adjustment necessary.

Dosing: Hepatic Impairment

Contraindicated in active liver disease or in patients with unexplained persistent elevations of serum transaminases.

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 atorvastatin. If muscle symptoms recur, discontinue atorvastatin 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 without regard to meals. Swallow tablets whole; do not crush, dissolve, or chew. Administer ≥2 hours before or ≥4 hours after bile acid sequestrants.

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 (NCEP 2002).

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).

Atorvastatin serum concentration may be increased when taken with grapefruit juice; avoid concurrent intake of large quantities (>1.2 L/day).

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Drug Interactions

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

Aliskiren: AtorvaSTATin may increase the serum concentration of Aliskiren. Monitor therapy

Amiodarone: May increase the serum concentration of AtorvaSTATin. Monitor therapy

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

Antihepaciviral Combination Products: May increase the serum concentration of AtorvaSTATin. Avoid combination

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

ARIPiprazole: CYP3A4 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. 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 AtorvaSTATin. Monitor therapy

Bexarotene (Systemic): May decrease the serum concentration of AtorvaSTATin. Monitor therapy

Bezafibrate: May enhance the adverse/toxic effect of Ezetimibe. Specifically, the risk of myopathy and cholelithiasis may be increased. Avoid combination

Bile Acid Sequestrants: May decrease the absorption of Ezetimibe. Management: Administer ezetimibe at least 2 hours before or 4 hours after any bile acid sequestrant. Consider therapy modification

Boceprevir: May increase the serum concentration of AtorvaSTATin. Management: Limit the atorvastatin maximum adult dose to 40 mg daily in patients receiving boceprevir. Monitor clinical response to ensure that the lowest necessary atorvastatin dose is used. Consider therapy modification

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

Cimetidine: AtorvaSTATin may enhance the adverse/toxic effect of Cimetidine. Specifically, there is a theoretical potential for enhanced effects on reducing endogenous steroid activity. 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 AtorvaSTATin. Management: Limit atorvastatin to a maximum dose of 20 mg/day (for adults) when used with clarithromycin. If this combination is used, monitor patients more closely for evidence of atorvastatin toxicity. Consider therapy modification

Cobicistat: May increase the serum concentration of AtorvaSTATin. Management: Initiate atorvastatin at the lowest recommended dose and titrate slowly as needed while monitoring closely for evidence of atorvastatin toxicity. Atorvastatin dose should not exceed 20 mg/day with concurrent use of darunavir and cobicistat. Consider therapy modification

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 AtorvaSTATin. 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 decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Consider therapy modification

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: AtorvaSTATin may decrease the serum concentration of Dabigatran Etexilate. Monitor therapy

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

Digoxin: AtorvaSTATin may increase the serum concentration of Digoxin. Monitor therapy

DilTIAZem: AtorvaSTATin may increase the serum concentration of DilTIAZem. DilTIAZem may increase the serum concentration of AtorvaSTATin. Management: Consider using lower atorvastatin doses when used together with diltiazem. Consider therapy modification

Dofetilide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Dofetilide. Monitor therapy

Dronedarone: May increase the serum concentration of AtorvaSTATin. Monitor therapy

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

Elbasvir: May increase the serum concentration of AtorvaSTATin. Management: Limit the dose of atorvastatin to a maximum of 20 mg/day when used together with elbasvir and grazoprevir. Monitor closely for evidence of statin-related toxicities such as myalgia or myopathy. Consider therapy modification

Eltrombopag: May increase the serum concentration of OATP1B1/SLCO1B1 Substrates. 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 AtorvaSTATin. Monitor therapy

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 Ezetimibe. Specifically, the risk of myopathy and cholelithiasis may be increased. Monitor therapy

Flibanserin: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Flibanserin. Monitor therapy

Fluconazole: May increase the serum concentration of AtorvaSTATin. 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 AtorvaSTATin. Gemfibrozil may increase the serum concentration of AtorvaSTATin. Avoid combination

Gemfibrozil: May enhance the adverse/toxic effect of Ezetimibe. Specifically, the risk of myopathy and cholelithiasis may be increased. Gemfibrozil may increase the serum concentration of Ezetimibe. Avoid combination

Glecaprevir and Pibrentasvir: May increase the serum concentration of AtorvaSTATin. 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 AtorvaSTATin. Management: Limit the dose of atorvastatin to a maximum of 20 mg/day when used together with elbasvir and grazoprevir. Monitor closely for evidence of statin-related toxicities such as myalgia or myopathy. Consider therapy modification

HYDROcodone: CYP3A4 Inhibitors (Weak) may increase the serum concentration of HYDROcodone. Monitor therapy

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

Itraconazole: May increase the serum concentration of AtorvaSTATin. Management: Limit atorvastatin to a maximum adult dose of 20 mg/day in patients receiving itraconazole. Assess clinical response to ensure that the lowest necessary dose of atorvastatin is used. Consider use of fluva-, rosuva-, pitava-, or pravastatin when possible. Consider therapy modification

Ketoconazole (Systemic): AtorvaSTATin may enhance the adverse/toxic effect of Ketoconazole (Systemic). Specifically, there is a theoretical potential for additive effects on reducing endogenous steroid concentrations. Ketoconazole (Systemic) may increase the serum concentration of AtorvaSTATin. Management: Administer ketoconazole with atorvastatin cautiously, and monitor for toxic effects of atorvastatin (e.g., myalgia, rhabdomyolysis, liver function test abnormalities). Consider use of fluva-, rosuva-, pitava-, or pravastatin when possible. Consider therapy modification

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

Letermovir: May increase the serum concentration of AtorvaSTATin. Management: Limit the atorvastatin dose to 20 mg daily when combined with letermovir. When letermovir is coadministered with cyclosporine, the use of atorvastatin (at any dose) is not recommended. Consider therapy modification

Lomitapide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lomitapide. Management: Patients on lomitapide 5 mg/day may continue that dose. Patients taking lomitapide 10 mg/day or more should decrease the lomitapide dose by half. The lomitapide dose may then be titrated up to a max adult dose of 30 mg/day. Consider therapy modification

Midazolam: AtorvaSTATin may increase the serum concentration of Midazolam. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

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

NiMODipine: CYP3A4 Inhibitors (Weak) may increase the serum concentration of NiMODipine. Monitor therapy

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

PAZOPanib: AtorvaSTATin may enhance the hepatotoxic effect of PAZOPanib. AtorvaSTATin may increase the serum concentration of PAZOPanib. Avoid combination

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

Pimozide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Pimozide. Avoid combination

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

Posaconazole: May increase the serum concentration of AtorvaSTATin. Avoid combination

Protease Inhibitors: May increase the serum concentration of AtorvaSTATin. Management: See full monograph for recommended dose limits. Avoid atorvastatin with tipranavir/ritonavir. Consider therapy modification

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 increase the serum concentration of AtorvaSTATin. 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 AtorvaSTATin. Management: The maximum atorvastatin dose should not exceed 40 mg/day with concurrent use of simeprevir, and use of the lowest necessary atorvastatin dose is recommended. Consider therapy modification

Spironolactone: AtorvaSTATin may enhance the adverse/toxic effect of Spironolactone. Specifically, there is a theoretical potential for enhanced effects on reducing endogenous steroid activity. 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 AtorvaSTATin. Avoid combination

Telithromycin: May increase the serum concentration of AtorvaSTATin. Management: Consider limiting atorvastatin to a max (adult) dose of 20 mg/day when used with telithromycin. Although not a specific recommendation in atorvastatin labeling, this is consistent with dosing for other strong CYP3A4 inhibitors, including clarithromycin. Consider therapy modification

Teriflunomide: May increase the serum concentration of OATP1B1/SLCO1B1 Substrates. Monitor therapy

Ticagrelor: May increase the serum concentration of AtorvaSTATin. Monitor therapy

Tipranavir: May increase the serum concentration of AtorvaSTATin. Avoid combination

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

Velpatasvir: May increase the serum concentration of AtorvaSTATin. Monitor therapy

Verapamil: AtorvaSTATin may increase the serum concentration of Verapamil. Verapamil may increase the serum concentration of AtorvaSTATin. Management: Consider using lower atorvastatin doses when used together with verapamil. Consider therapy modification

Voriconazole: May increase the serum concentration of AtorvaSTATin. Management: Monitor for toxic effects of atorvastatin (e.g., myalgia, rhabdomyolysis, liver function test abnormalities) during concomitant treatment, and reduce atorvastatin dose when possible. Consider use of fluva-, rosuva-, pitava-, or pravastatin when possible. Consider therapy modification

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 refer to combination Liptruzet™. Also see individual agents.

1% to 10%:

Central nervous system: Dizziness (2%), myasthenia (2%)

Endocrine & metabolic: Hot flash (2%), hyperkalemia (2%)

Gastrointestinal: Abdominal pain (3%), nausea (3%)

Hepatic: Increased serum ALT (5%), increased serum AST (4%)

Neuromuscular & skeletal: Musculoskeletal pain (4%), arthralgia (3%)

Respiratory: Bronchitis (2%), cough (2%), sinusitis (2%)

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: Persistent elevations in serum transaminases have been reported; upon dose reduction, drug interruption, or discontinuation, transaminase levels returned to or near pretreatment levels. Postmarketing reports of fatal and nonfatal hepatic failure have been reported and are rare. If serious hepatotoxicity with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment, interrupt therapy promptly. If an alternate etiology is not identified, do not restart. Liver enzyme tests should be obtained at baseline and as clinically indicated and if signs/symptoms of liver injury occur. Ethanol may enhance the potential of adverse hepatic effects; instruct patients to avoid excessive ethanol consumption.

• Myopathy/rhabdomyolysis: Rhabdomyolysis with acute renal failure secondary to myoglobinuria and/or myopathy has been reported; patients should be monitored closely. This risk is dose-related and is increased with use of strong CYP3A4 inhibitors (eg, clarithromycin, itraconazole, elbasvir plus grazoprevir, protease inhibitors), cyclosporine, fibric acid derivatives (eg, gemfibrozil), or niacin (doses ≥1 g/day), age ≥ 65 years, uncontrolled hypothyroidism, and renal dysfunction; if concurrent use is warranted, consider dose adjustment. Immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy associated with HMG-CoA reductase inhibitors use, has also been reported (rarely). Use caution in patients with 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, particularly if accompanied by malaise or fever. Discontinue therapy if markedly elevated CPK levels occur or myopathy is diagnosed/suspected.

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 persistent elevations of serum transaminases.

• Renal impairment: Use with caution in patients with renal impairment; these patients are predisposed to myopathy.

• Stroke: Patients with recent stroke or TIA receiving long-term therapy with high-dose (ie, 80 mg/day) atorvastatin may be at increased risk for hemorrhagic stroke (SPARCL Investigators, 2006). A subsequent post-hoc analysis demonstrated that patients with lacunar or hemorrhagic stroke may be at higher risk of hemorrhagic stroke; however, this finding was determined to be hypothesis generating. The overall benefit of treatment with atorvastatin (ie, reduced risk of stroke and cardiovascular events) in this population seems to outweigh the increased risk of hemorrhagic stroke if one truly exists (Goldstein, 2008).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

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, serious condition suggestive of a myopathy or having a risk factor predisposing to the development of renal failure secondary to rhabdomyolysis (eg, sepsis, hypotension, trauma, uncontrolled seizures, severe metabolic, endocrine, or electrolyte disorders). 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]). Postoperative discontinuation of statin therapy is associated with an increased risk of cardiac morbidity and mortality.

Other warnings/precautions:

• Appropriate use: No incremental benefit of ezetimibe/atorvastatin on cardiovascular morbidity and mortality over and above that demonstrated for atorvastatin has been established. Ezetimibe/atorvastatin has not been studied in Fredrickson type I, III, IV, and V dyslipidemias.

• 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 to 12 weeks after initiation or dose adjustment and every 3 to 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: Baseline liver function tests and repeat when clinically indicated thereafter. Upon initiation or titration, lipid panel should be analyzed within 2 to 4 weeks.

Pregnancy Risk Factor

X

Pregnancy Considerations

Use is contraindicated in women who are or may become pregnant. See individual agents.

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 joint pain, rhinitis, pharyngitis, or diarrhea. Have patient report immediately to prescriber signs of a urinary tract infection (hematuria, burning or painful urination, polyuria, fever, lower abdominal pain, or pelvic pain), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), muscle pain, muscle weakness, muscle tenderness, confusion, memory impairment, depression, urinary retention, change in amount of urine passed, difficulty swallowing, severe loss of strength and energy, severe nausea, or vomiting (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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