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Criteria for Outpatient Use Guidelines

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3-Hydroxy-3-Methylglutaryl Coenzyme A (HMG-CoA) Reductase Inhibitors

[Developed, November 1994; Revised, October 1996; September 1997; September 1998; October 1999; November 1999; August 2000; September 2000; September 2001; March 2008; July 2008; September 2008; November 2008; March 2011; April 2011]

Dietary control of hyperlipidemias with counseling by a registered dietician, physician, or other health care provider should precede and be an essential adjunct of any intervention effort involving prescribing and dispensing of  HMG-CoA reductase inhibitors. Additionally, periodic monitoring of hepatic function should occur with HMG-CoA reductase inhibitor administration.  Hepatic function should also be reviewed following any dosage increase or medication addition which may potentiate a drug interaction.

Information on indications for use or diagnosis is assumed to be unavailable.All criteria may be applied retrospectively; prospective application is indicated with [*].

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1.*Dosage

Adults
HMG-CoA reductase inhibitors are lipid-lowering agents that competitively inhibit HMG-CoA reductase, the enzyme that catalyzes cholesterol biosynthesis.   Inhibition of this enzyme results in decreases in total cholesterol, low density lipoprotein cholesterol (LDL-C), triglycerides (TG) and apoprotein B (Apo B), increases in high density lipoprotein cholesterol (HDL-C), as well as increases in the number of LDL receptors on hepatic and extrahepatic tissues.    Clinical and epidemiologic studies have documented that low HDL-C, high LDL-C and elevated TG augment atherosclerosis development and are risk factors for cardiovascular disease, while higher HDL-C levels and lower LDL-C concentrations are associated with reduced cardiovascular risk. 

HMG-CoA reductase inhibitors are FDA-approved to manage hyperlipidemia (including hypercholesterolemia, mixed dyslipidemia, hypertriglyceridemia, and primary dysbetalipoproteinemia) in adults, treat homozygous familial hypercholesterolemia in adults, reduce the risk of coronary heart disease mortality and cardiovascular events in patients at high risk for coronary events, slow the progression of coronary atherosclerosis in patients with coronary artery disease by reducing total cholesterol and LDL-C levels, provide primary prevention of coronary artery disease in patients with risk factors for coronary artery disease but without symptomatic cardiovascular disease, promote secondary prevention of coronary events in patients with cardiovascular disease, and treat adolescents with heterozygous familial hypercholesterolemia unresponsive to diet therapy. 

HMG-CoA reductase inhibitor combination therapies are FDA-approved for use in managing hyperlipidemia (including hypercholesterolemia, mixed lipidemia, and hypertriglyceridemia) when monotherapy is considered inadequate (Simcor®) as well as primary hyperlipidemia/mixed dyslipidemia and homozygous familial hypercholesterolemia (Vytorin®).  Advicor® is FDA-approved for use in patients requiring both niacin and lovastatin, while Caduet® is FDA-approved in those patients requiring both amlodipine and atorvastatin.

Higher HMG-CoA reductase inhibitor doses may be necessary in patients who respond poorly to initial prescribed amounts.  Doses may be escalated incrementally at a minimum of every four weeks based on need and tolerance of each patient to the maximum recommended dose.  Recommended adult maintenance doses of HMG-CoA reductase inhibitors as mono- and combination therapy should not exceed the maximum doses listed in Tables 1 and 2.

Table 1
HMG-CoA Reductase Inhibitor Monotherapy - Maximum Recommended Adult Dosages
DRUG MAXIMUM RECOMMENDED DOSAGE
Atorvastatin (Lipitor®) 10 mg, 20 mg, 40 mg, 80 mg tablets 80 mg once daily concurrent administration with cyclosporine: 10 mg once daily
Fluvastatin (Lescol®, Lescol® XL) 20 mg, 40 mg capsules; 80 mg extended-release tablets 80 mg once daily, as single evening dose or in two divided doses
Lovastatin (Mevacor®) 20 mg, 40 mg tablets 80 mg once daily with evening meal concurrent administration with cyclosporine, danazol, gemfibrozil, other fibrates, or lipid-lowering doses of niacin: 20 mg once daily with evening meal concurrent administration with amiodarone or verapamil: 40 mg once daily with evening meal
Lovastatin (Altaprev®) [20 mg, 40 mg, 60 mg extended-release tablets] 60 mg once daily at bedtime
concurrent administration with gemfibrozil, other fibrates,  lipid-lowering doses of niacin, amiodarone, or verapamil: 20 mg once daily at bedtime
pitavastatin (Livalo®) [1 mg, 2 mg, 4 mg tablets] 4 mg once daily
Pravastatin (Pravachol®) 10 mg, 20 mg 40 mg, 80 mg tablets 80 mg once daily; concurrent administration with immunosuppressives:  20 mg once daily
Rosuvastatin (Crestor®) 5 mg, 10 mg, 20 mg, 40 mg tablets 40 mg once daily
concurrent administration with gemfibrozil, lopinavir/ritonavir, or atazanavir/ritonavir: 10 mg once daily
concurrent administration with cyclosporine: 5 mg once daily
Simvastatin (Zocor®, generic)
5 mg, 10 mg, 20 mg, 40 mg, 80 mg tablets 		80 mg once daily in evening
concurrent administration with cyclosporine, danazol or gemfibrozil:
10 mg once daily in evening
concurrent administration with amiodarone or verapamil:
20 mg once daily in evening
concurrent administration with diltiazem: 40 mg once daily in evening

Table 2
HMG-CoA Reductase Inhibitor Combination Therapy – Maximum Recommended Adult Dosages
DRUG MAXIMUM RECOMMENDED DOSAGE
Amlodipine/atorvastatin (Caduet®) 2.5 mg/10 mg, 2.5 mg/20 mg, 2.5 mg/40 mg, 5 mg/10 mg,5 mg/20 mg, 5 mg/40 mg, 5 mg/80 mg, 10 mg/10 mg, 10 mg/20 mg, 10 mg/40 mg, 10 mg/80 mg tablets 10 mg amlodipine/80 mg atorvastatin per day
Lovastatin/niacin extended-release (Advicor®) 20 mg/500 mg, 20 mg/1000 mg, 40 mg/1000 mg tablets 40 mg lovastatin/1000 mg niacin extended-release per day
Simvastatin/niacin extended-release (Simcor®) 20 mg/500 mg, 20 mg/750 mg, 20 mg/1000 mg tablets 40 mg simvastatin/2000 mg niacin extended-release per day

concurrent administration with amiodarone or verapamil: 20 mg simvastatin once daily
Ezetimibe/simvastatin (Vytorin®) 10 mg/10 mg, 10 mg/20 mg, 10 mg/40 mg, 10 mg/80 mg tablets 10 mg/80 mg once daily in evening
concurrent administration with cyclosporine, danazol or fibrates:
10 mg ezetimibe/10 mg simvastatin once daily in evening
concurrent administration with amiodarone or verapamil:
10 mg ezetimibe/20 mg simvastatin once daily in evening
concurrent administration with diltiazem: 10 mg ezetimibe/40 mg simvastatin once daily in evening

Pediatrics
With the exception of pitavastatin, HMG-CoA reductase inhibitors are FDA-approved for use as a dietary adjunct to reduce total cholesterol, LDL-C, TG, and Apo B in adolescent boys, and girls who are at least one year post-menarche, (for pravastatin, children and adolescents 8-18 years of age regardless of menarchal status) with elevated LDL-C due to heterozygous familial hypercholesterolemia.  Safety and efficacy of pitavastatin in pediatric patients have not been established.  Safety and effectiveness of HMG-CoA reductase inhibitors in pre-menarchal girls or children younger than 10 years of age (for pravastatin, younger than 8 years of age regardless of menarchal status) have not been well established.  Maximum recommended doses for HMG-CoA reductase inhibitors in pediatric patients are summarized in Table 3.

Table 3
Maximum Recommended HMG CoA Reductase Inhibitor Pediatric Dosagesfor Heterozygous Familial Hypercholesterolemia
DRUG MAXIMUM RECOMMENDED DOSE
Atorvastatin 10-17 years of age: 20 mg once daily
Fluvastatin 10-16 years of age: 80 mg daily, as single evening dose or two divided doses
Lovastatin 10-17 years of age: 40 mg once daily with evening meal
Pravastatin 8 years to 13 years of age: 20 mg once daily; 14 years to 18 years of age: 40 mg once daily
Rosuvastatin 10-17 years of age: 20 mg once daily
Simvastatin 10-17 years of age: 40 mg once daily in evening

2. Duration of Therapy

There is no basis for limiting duration of therapy for HMG-CoA reductase inhibitors as control of
cholesterol and other coronary heart disease risk factors is a life-long process.

3.*Duplicative Therapy

The use of two or more HMG-CoA reductase inhibitors in combination is not justified.  Additional therapeutic benefit is not realized when HMG-CoA reductase inhibitors are used concomitantly, and may result in increased adverse reactions such as myopathy and rhabdomyolysis.  Patients receiving multiple HMG-CoA reductase inhibitors concurrently will be reviewed.

4.*Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens which may result in clinically significant drug-drug interactions.

Drug-drug interactions considered most significant for HMG-CoA reductase inhibitors are summarized in Table 4.  Only those drug-drug interactions classified as clinical significance level 1 or those considered life-threatening which have not yet been classified will be reviewed:

Table 4
Significant Drug-Drug Interactions for HMG-CoA Reductase Inhibitors
TARGET DRUG INTERACTING DRUG INTERACTION RECOMMENDATION CLINICAL SIGNIFICANCE*+
HMG-CoA reductase inhibitors (HMG) amiodarone combined administration may increase risk of  HMG adverse effects [e.g., myopathy (MYO), rhabdomyolysis (RHAB)] most likely due to inhibition of HMG metabolism (CYP3A4, CYP2C9) by amiodarone (CYP3A4, CYP2C9 inhibitor) monitor for MYO, RHAB; use lowest recommended HMG doses; consider using HMG not metabolized by CYP3A4 or CYP2C9, such as pravastatin, if drug combination necessary major, moderate (DrugReax)
2-major, 3-moderate (CP)
1 (DIF)
HMG azole antifungals combined administration may lead to increased HMG concentrations and potential for enhanced pharmacologic/adverse effects (e.g., MYO, RHAB) due to inhibition of HMG metabolism (CYP3A4) by azole antifungals  (CYP3A4 inhibitor); fluvastatin with increased risk of adverse effects when prescribed with fluconazole, voriconazole (CYP2C9 inhibitors) avoid adjunctive therapy, if possible; if combined therapy necessary, monitor for signs/symptoms of MYO, RHAB; may consider using HMG not metabolized by CYP3A4, CYP2C9 such as pravastatin contraindicated, major (DrugReax)
1-severe, 2-major, 3-moderate (CP)
1 (DIF)
HMG cyclosporine combined administration may lead to increased HMG concentrations and potential for enhanced pharmacologic/adverse effects (e.g., MYO, RHAB) due to inhibition of HMG metabolism (CYP3A4; OATP1B1) by cyclosporine  (CYP3A4, OATP1B1 inhibitor) avoid adjunctive therapy, if possible; if combined therapy necessary, monitor for signs/symptoms of MYO, RHAB; use lowest recommended HMG doses; fluvastatin may be alternative as  metabolized by CYP2C9 and not affected by OATP1B1 major, moderate (DrugReax)
2-major (CP)
1 (DIF)
HMG fibric acid derivatives (e.g., fenofibrate, gemfibrozil) adjunctive administration may elevate HMG serum levels, with increased risk of severe MYO, RHAB, due to inhibition of HMG metabolism (CYP2C8; OATP1B1) by gemfibrozil  (CYP2C8, OATP1B1 inhibitor), or additive myopathy risk (fibrates) avoid combination, if possible, if concurrent therapy necessary, use cautiously, closely monitor creatine kinase and observe for MYO, RHAB; use lowest recommended HMG doses major (DrugReax)
2-major (CP)
1 (DIF)
 Select HMGs macrolide antibiotics macrolides (CYP3A4, OATP1B1 inhibitors) prescribed with HMGs metabolized by CYP3A4 or OATP1B1 may increase HMG serum levels and elevate potential for enhanced pharmacologic/adverse effects (e.g., MYO, RHAB) avoid macrolides with HMGs metabolized by CYP3A4, OATP1B1, if possible; pravastatin, rosuvastatin not metabolized by CYP3A4 and may be alternative HMGs; if combination necessary, monitor for MYO, RHAB major (DrugReax)
1-severe, 2-major (CP)
1 (DIF)
Select HMGs other CYP3A4 inhibitors (e.g., diltiazem, imatinib, nefazodone, verapamil) CYP3A4 inhibitors administered with HMGs metabolized by CYP3A4  may increase HMG serum levels and elevate potential for enhanced pharmacologic/adverse effects (e.g., MYO, RHAB) avoid CYP3A4 inhibitors with HMGs metabolized by CYP3A4, if possible; pravastatin, rosuvastatin not metabolized by CYP3A4 and may be alternative HMGs; if combination necessary, use lowest recommended dose and monitor for MYO, RHAB contraindicated, major, moderate (DrugReax)
1-severe, 2-major, 3-moderate (CP)
1, 2 (DIF)
HMGs protease inhibitors adjunctive administration may increase HMG serum levels and elevate potential for enhanced pharmacologic/adverse effects (e.g., MYO, RHAB) due to CYP3A4 inhibition and other unknown mechanisms avoid combination therapy, if possible; if combined therapy necessary, monitor for increased adverse effects (e.g., MYO, RHAB) and use lowest recommended HMG dose; may consider pravastatin, an HMG not metabolized by CYP3A4 contraindicated, major, moderate (DrugReax)
1-severe, 2-major, 3-moderate (CP)
1 (DIF)
Select HMGs select NNRT inhibitors (delavirdine, efavirenz) combined administration of delavirdine (CYP3A4 inhibitor) with HMGs metabolized by CYP3A4 may increase HMG serum levels and elevate potential for enhanced pharmacologic/adverse effects (e.g., MYO, RHAB); alternately, concurrent administration of efavirenz (CYP3A4 inducer) with HMGs metabolized by CYP3A4 may decrease HMG serum levels and potentially decrease therapeutic efficacy monitor for increased adverse effects (e.g., MYO, RHAB) or decreased HMG efficacy; may alter HMG dose or add other lipid-lowering therapy; consider alternative HMGs not metabolized by CYP3A4 major, moderate (DrugReax)
1-severe, 2-major, 3-moderate (CP)
1 (DIF)

*CP = Clinical Pharmacology                               
+Drug Interaction Facts

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Prepared by: Drug Information Service, The University of Texas Health Science Center at San Antonio, and the College of Pharmacy, The University of Texas at Austin.