Optimizing Statin Therapy by Avoiding Clinically Relevant Drug Interactions

This article was sponsored by Kowa Pharmaceuticals America, Inc.

Please see Important Safety Information below and full Prescribing Information.

For decades, statins have been used for the treatment of hyperlipidemia and prevention of primary and secondary cardiovascular events.¹ Nearly one-third (31.8%) of individuals 55 to 64 years of age use prescription cholesterol-lowering medications, most commonly statins. Many of these individuals are also being treated for other conditions.^2,3 As such, there is widespread use of statins in patients taking multiple medications, and it is therefore important to consider the possible risks involved in polypharmacy, including the potential for clinically relevant drug interactions between statins and concomitant medications.

Pharmacologic Basis for Statin-Related Interactions

Of all medications metabolized, approximately 3 out of every 4 rely on the cytochrome P450 isoenzymes for metabolism, and approximately half of these rely on CYP3A4/5 isoenzymes.^4,5 Because many commonly used statins rely on this same metabolic pathway,^4,6 use of a statin with medications that inhibit isoenzymes such as CYP3A4 may lead to supratherapeutic statin levels and may increase the risk of statin-related adverse events, such as myalgia, myositis, and, in rare cases, rhabdomyolysis.^7,8

The FDA released a public safety announcement highlighting this risk for those statins that are sensitive in vivo cytochrome P450 3A4 (CYP3A4) substrates. Regarding other medications metabolized, strong CYP3A4 inhibitors are predicted to significantly increase overall exposures to certain statins. For example, itraconazole, a strong CYP3A4 inhibitor, increases maximal concentrations of simvastatin up to 13-fold and lovastatin exposure up to 20-fold, with the potential interaction to result in rhabdomyolysis.⁹ Hence, other CYP3A4 inhibitors may significantly increase lovastatin and simvastatin exposures based on metabolic dependency on the CYP450 system. Statins may also inhibit CYP3A4, exposing patients to supratherapeutic levels of other medications.^4,7

Key Statin-Related Interactions

Pursuant to an FDA safety advisory communication released in 2011, restrictions, limitations, and contraindications were added to the labeling of simvastatin and simvastatin-containing agents. A later FDA communication, released in 2012, advised against use of statins in combination with human immunodeficiency virus or hepatitis C protease inhibitors (Table 1⁹). Following these communications, the FDA added several contraindications and dose restrictions to the labeling of many statins (Table 2¹⁰).^9-11 Additionally, for patients taking commonly prescribed antihypertensive medications, the dose of simvastatin must be limited. Patients taking verapamil or diltiazem should take no more than 10 mg of simvastatin daily, and in patients taking amlodipine, simvastatin should not be administered at a dosage greater than 20 mg daily.¹¹ Use of simvastatin or rosuvastatin with warfarin may affect coagulation parameters, such as prothrombin time (PT) and international normalized ratio (INR), further complicating therapy.^11,12

Unlike most other statins, pitavastatin (Livalo) is only minimally metabolized by the CYP450 system, has no clinically relevant interactions with strong CYP3A4 inhibitors, has no contraindication, restriction or limitation in patients taking protease inhibitors, and does not significantly affect coagulation parameters (ie, PT/ INR) in patients taking warfarin.^4,13 It has no dose-limitation restriction when used with calcium channel blockers. Key clinically relevant drug interactions with pitavastatin include a contraindication for use with cyclosporine and limitation of the pitavastatin dose to 1 mg daily in patients taking erythromycin. As with other statins, due to classwide effects, fibrates, niacin (≥1 gram daily), and colchicine should be used with caution, and gemfibrozil should be avoided.¹³

Assessing Statin-Related Interactions

In the largest Internet-based survey to date on statin use, of more than 10,000 individuals, which included 1220 former statin users and 8919 current statin users, drug interactions that involved statins occurred in more than 8 of every 10 respondents (84%). For each participant with an interaction, an average of 3 other products interacted with the statin, including prescription medications, OTC products, and dietary supplements. Nearly three-fourths (74%) of these respondents never spoke with their physician about the possibility of these drug interactions.⁶

Although a causal relationship between drug interactions and adverse events (AEs) leading to treatment discontinuation was not evaluated in this survey, in this population of patients with unaddressed drug interactions, 1 of 4 current statin users and more than half (60%) of former users reported experiencing muscle-related AEs. In former statin users, AEs, including muscle pain and weakness, were responsible for nearly two-thirds (62%) of statin discontinuations.⁶

Considering that patients prescribed statins who do not take them have nearly 3 times greater mortality risk than patients who take statins as prescribed, treatment discontinuation may have important clinical consequences.¹⁴ In the modern treatment era, statins with fewer drug interactions are available; they are worth consideration because their interaction burden is lower than other medications in this class while still providing potent efficacy.⁴

Role of the Pharmacist

In addition to advising and counseling patients about the importance of adherence to statin therapy to reduce the risk of negative cardiovascular outcomes, pharmacists are instrumental in recognizing and managing drug interactions to achieve treatment regimen harmonization for patients. To achieve this desirable end, pharmacists should not only alert prescribers to drug interactions, but also provide recommendations for alternative therapy to help resolve these drug interactions whenever possible.

In discussing these interactions with prescribers, rather than focusing only on the increased risk of rhabdomyolysis with statins and interacting medications, pharmacists should emphasize the risk of drug interactions leading to statin-related AEs and statin discontinuation. Approximately 8 in 10 patients taking statins are using an average of 3 interacting medications. These interactions may increase the risk of AEs such as myalgia, weakness, myositis, and myopathy.^6,7 Harmonizing treatment regimens may help patients continue taking statins. By applying their specialized knowledge about the subtle but clinically significant differences between individual statins, pharmacists can help align patients with the most appropriate statin and associated dose to help achieve improved long-term outcomes.

INDICATIONS AND USAGE

Drug therapy should be one component of multiple-risk-factor intervention in individuals who require modifications of their lipid profile. Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol only when the response to diet and other nonpharmacological measures has been inadequate.

PRIMARY HYPERLIPIDEMIA AND MIXED DYSLIPIDEMIA

LIVALO (pitavastatin) is indicated as an adjunctive therapy to diet to reduce elevated total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), triglycerides (TG), and to increase high-density lipoprotein cholesterol (HDL-C) in adult patients with primary hyperlipidemia or mixed dyslipidemia.

LIMITATIONS OF USE

• Doses of LIVALO greater than 4 mg once daily were associated with an increased risk for severe myopathy in premarketing clinical studies. Do not exceed 4-mg, once-daily dosing of LIVALO
• The effect of LIVALO on cardiovascular morbidity and mortality has not been determined
• LIVALO has not been studied in Fredrickson Type I, III, and V dyslipidemias

IMPORTANT SAFETY INFORMATION FOR LIVALO^® (pitavastatin) tablets

CONTRAINDICATIONS

LIVALO is contraindicated in patients with a known hypersensitivity to product components, in patients with active liver disease (which may include unexplained persistent elevations in hepatic transaminase levels), in women who are pregnant or may become pregnant, in nursing mothers, or in co-administration with cyclosporine.

WARNINGS AND PRECAUTIONS

Skeletal Muscle Effects

Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with HMG-CoA reductase inhibitors, including LIVALO. These risks can occur at any dose level, but increase in a dose-dependent manner.

• LIVALO should be prescribed with caution in patients with predisposing factors for myopathy.
• The risk of skeletal muscle effects (e.g., myopathy and rhabdomyolysis) increases in a dose-dependent manner with advanced age (≥65 years), renal impairment, inadequately treated hypothyroidism, and in combination use with fibrates or lipid-modifying doses of niacin (≥1 g/day).
• LIVALO should be administered with caution in patients with impaired renal function, in elderly patients, or when used concomitantly with fibrates or lipid-modifying doses of niacin.
• Concomitant administration of LIVALO with gemfibrozil should be avoided.
• LIVALO therapy should be discontinued if markedly elevated CK levels occur or myopathy is diagnosed or suspected. LIVALO therapy should also be temporarily withheld in any patient with an acute, serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., sepsis; hypotension; dehydration; major surgery; trauma; severe metabolic, endocrine, and electrolyte disorders; or uncontrolled seizures).
• Advise patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever, and to discontinue LIVALO if these signs or symptoms appear.
• Cases of myopathy, including rhabdomyolysis, have been reported with HMG-CoA reductase inhibitors coadministered with colchicine, and caution should be exercised when prescribing LIVALO with colchicine
• There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents. IMNM has not been reported with LIVALO therapy.
• Advise patients to promptly report if muscle signs and symptoms persist after discontinuing LIVALO as this may be a sign of IMNM requiring immediate medical attention.

Liver Enzyme Abnormalities

Increases in serum transaminases have been reported with HMG-CoA reductase inhibitors, including LIVALO.

• It is recommended that liver enzyme tests be performed before the initiation of LIVALO and if signs or symptoms of liver injury occur.
• There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including pitavastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with LIVALO, promptly interrupt therapy. If an alternate etiology is not found do not restart LIVALO.
• Advise patients to promptly report any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice.
• LIVALO should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of chronic liver disease.

Endocrine Function

Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including LIVALO.

ADVERSE REACTIONS

In short-term controlled studies, the most frequent adverse reactions reported by ≥2% of patients treated with LIVALO 1 mg, 2 mg, and 4 mg, respectively, and at a rate ≥ placebo were back pain (3.9%, 1.8%, 1.4% vs 2.9%), constipation (3.6%, 1.5%, 2.2% vs 1.9%), diarrhea (2.6%, 1.5%, 1.9% vs 1.9%), myalgia (1.9%, 2.8%, 3.1% vs 1.4%), and pain in extremity (2.3%, 0.6%, 0.9% vs 1.9%). This is not a complete listing of all reported adverse events.

References

• Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(25)(suppl 2):S1-S45. doi: 10.1161/01.cir.0000437738.63853.7a.
• National Health and Nutrition Examination Survey (NHANES). Health, United States, 2014: With Special Feature on Adults Aged 55-64. Hyattsville, MD: National Center for Health Statistics; 2015. DHHS publication 2015-1232. CDC website. http://www.cdc.gov/nchs/data/hus/hus14.pdf. Accessed December 30, 2015.
• Gu Q, Paulose-Ram R, Burt VL, Kit BK. Prescription cholesterol-lowering medication use in adults aged 40 and over: Unites States, 2003-2012. CDC website. http://www.cdc.gov/nchs/data/databriefs/db177.pdf. Published December 2014. Accessed December 16, 2015.
• Falko JM. Balancing efficacy and tolerability issues with statin therapy—considerations for the use of pitavastatin in special patient populations. US Endocrinol. 2011;7(1):30-39. doi: 10.17925/USE.2011.07.01.30.
• Guengerich FP. Cytochrome p450 and chemical toxicology. Chem Res Toxicol. 2008;21(1):70-83.
• Cohen JD, Brinton EA, Ito MK, Jacobson TA. Understanding Statin Use in America and Gaps in Patient Education (USAGE): an internet-based survey of 10,138 current and former statin users. J Clin Lipidol. 2012;6(3):208-215. doi: 10.1016/j.jacl.2012.03.003.
• Causevic-Ramosevac A, Semiz S. Drug interactions with statins. Acta Pharm. 2013;63(3):277-293. doi: 10.2478/acph-2013-0022.
• Williams D, Feely J. Pharmacokineticpharmacodynamic drug interactions with HMGCoA reductase inhibitors. Clin Pharmacokinet. 2002; 41(5):343-370.
• FDA. Drug Safety Communication: Interactions between certain HIV or hepatitis C drugs and cholesterol-lowering statin drugs can increase the risk of muscle injury. FDA website. http://www.fda.gov/Drugs/DrugSafety/ucm293877.htm. Published March 1, 2012. Accessed February 10, 2016.
• FDA. Drug Safety Communication: New restrictions, contraindications, and dose limitations for Zocor (simvastatin) to reduce the risk of muscle injury. FDA website. http://www.fda.gov/Drugs/DrugSafety/ucm256581.htm. Published June 8, 2011. Updated December 15, 2011. Accessed February 10, 2016.
• Zocor [package insert]. Whitehouse Station, NJ: Merck Sharp & Dohme Corp; 2015.
• Crestor [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2015.
• Livalo [package insert]. Montgomery, AL: Kowa Pharmaceuticals America, Inc; 2013.
• Allonen J, Nieminen MS, Lokki M, et al. Mortality rate increases steeply with nonadherence to statin therapy in patients with acute coronary syndrome. Clin Cardiol. 2012;35(11):E22-E27. doi: 10.1002/clc.22056.

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