A clinician's guide to statin drug-drug interactions

Kenneth A. Kellick; Michael Bottorff; Peter P. Toth

doi:10.1016/j.jacl.2014.02.010

Original Contribution| Volume 8, ISSUE 3, SUPPLEMENT , S30-S46, May 2014

A clinician's guide to statin drug-drug interactions

Kenneth A. Kellick, PharmD, FNLA
Kenneth A. Kellick
Correspondence
Corresponding author.
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Affiliations
Veterans Administration Western New York Healthcare System, State University of New York at Buffalo, Buffalo, NY 14215, USA
Department of Pharmacy, State University of New York at Buffalo, Buffalo, NY, USA
Department of Medicine, State University of New York at Buffalo, Buffalo, NY, USA
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Michael Bottorff, PharmD, FNLA
Michael Bottorff
Affiliations
Department of Pharmacy Practice, South College School of Pharmacy, Knoxville, TN, USA
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Peter P. Toth, MD, PhD, FNLA
Peter P. Toth
Affiliations
Medical Center, Sterling, IL, USA
University of Illinois School of Medicine-Peoria, Peoria, IL, USA
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DOI:https://doi.org/10.1016/j.jacl.2014.02.010

Highlights

After reading the article, the practitioner will:
►
Better understand the different enzyme systems involved in statin metabolism and intrapatient differences.
►
Be able to predict potential drug interactions based on changes in the area under the curve for statin concentrations.
►
Be able to better interpret package labeling with respect to drug-drug interactions.
►
Identify common prescription and nonprescription medications that interact with statins.
►
Identify special populations that may be at risk for statin drug-drug interactions.

Abstract

The statins are widely used worldwide to reduce risk for cardiovascular events in both the primary and secondary prevention settings. Although generally quite safe, the statins can be associated with a variety of serious side adverse effects, including myalgia, myopathy, and changes in plasma enzymes of hepatic origin. Although rare, the most serious of these is rhabdomyolysis. Several drugs can interfere with the metabolism and disposal of the statins, thereby increasing risk for adverse events. It is important that clinicians treating patients with statins be aware of the potential for drug-drug interactions between each statin and specific other drugs and take measures to prevent them. The prediction of potential drug-drug interactions derives from basic pharmacokinetic principles. Certain drug interactions are predicted by measuring the effect of interacting drugs on blood plasma concentrations of the statin. Individual patient variations resulting in part from polymorphisms in the metabolizing enzymes confound some of these predictions. Based on these known effects, a new classification for predicting statin drug interactions is proposed. This report discusses likely prescription and nonprescription interactions as well as potential alternatives for special populations.

Keywords

The metabolism of statins is described by basic pharmacokinetic principles. Pharmacokinetic measures involve the rate of absorption, distribution, metabolism, and excretion for these molecules. With the exception of lovastatin and simvastatin, which are given as prodrugs, all statins are administered in the active hydroxyl acid form (Fig. 1). Once ingested, various other factors affect their absorption, distribution, metabolism, and excretion. Statins are moderately to well absorbed, with the time to reach peak plasma concentration averaging about 4 hours. When consumed with food, lovastatin is more efficiently absorbed. Rosuvastatin, pitavastatin, and simvastatin are not affected by food, whereas fluvastatin, pravastatin, and atorvastatin have a reduced absorption with food. Once absorbed into the portal venous system, while all statins undergo extensive first-pass metabolism, the rate of this first-pass hepatic uptake inversely relates to the systemic bioavailability. Therefore, the lower systemic bioavailability of fluvastatin (19%–29%) may suggest a more efficient first-pass metabolism. Pravastatin is the only statin not protein bound, which imparts a low systemic exposure to the medication.

¹

Gazzerro P.
Proto M.C.
Gangemi G.
et al.

Pharmacological actions of statins: a critical appraisal in the management of cancer.

Figure thumbnail gr1 — Figure 1Chemical structures of statins. Type I naphthalene statins (lovastatin, pravastatin, simvastatin); type II non-naphthalene (atorvastatin, pitavastatin, rosuvastatin, fluvastatin). Lovastatin and simvastatin are prodrugs.
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Statins undergo a complex metabolic fate, beginning with absorption, followed by hepatic uptake, metabolism, and eventually elimination from the liver into either the systemic circulation or the biliary tract (Fig. 2).

²

Niemi M.
Pasanen M.K.
Neuvonen P.J.

Organic anion transporting polypeptide 1B1: a genetically polymorphic transporter of major importance for hepatic drug uptake.

During the absorption process, most statins are substrates for the P-glycoprotein (P-gp) efflux transporter, which reduces absorption into the portal circulation. Enterocyte cytochrome P450 (CYP) may metabolize some statins before eventual absorption into the portal circulation. Hepatic uptake is mediated by several transporters, including organic anion transporting polypeptide 1B1 (OATP1B1), which facilitates metabolism by additional CYP enzymes (phase I metabolism) and glucuronidation (phase II metabolism). Additional efflux transporters on the canalicular membranes of hepatocytes facilitate biliary excretion.

Figure thumbnail gr2 — Figure 2Metabolic fate of statins. BCRP, breast cancer–resistant protein, encoded by gene ABCG2; MDR1, multidrug-resistant protein 1; MRP2, multidrug-resistant–associated protein 2, encoded by gene ABCC2; OATP1B1, organic anion transporter protein 1B1, formerly known as OATP2, encoded by SLCO1B1 gene; OATP1B3, organic anion transporter protein 1B3, encoded by the SLCO1B3 gene; P-glycoprotein, P-gp, encoded by the ABCB1 gene.
Adapted from Niemi et al.
²
Niemi M.
Pasanen M.K.
Neuvonen P.J.
Organic anion transporting polypeptide 1B1: a genetically polymorphic transporter of major importance for hepatic drug uptake.
*Pharmacol Rev.* 2011; 63: 157-181
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Some interacting drugs, such as cyclosporine, inhibit multiple sites of statin disposition (Table 1),

³

Harper C.R.
Jacobson T.A.

Avoiding statin myopathy: understanding key drug interactions.

resulting in larger increases in serum concentrations and subsequent risk for myopathy. Cyclosporine is an inhibitor of OATP1B1, OATP1B3, P-gp, and adenosine triphosphate cassette transporter subfamily G, member 2 (ABCG2 or breast cancer–resistant protein [BCRP]). Transporters are membrane proteins that move drugs (and other chemicals) in and out of cells (Table 2).

⁴

Giacomini K.M.
Huang S.M.
Tweedie D.J.
et al.

International Transporter Consortium
Membrane transporters in drug development.

As such, transporters are an important determinant of statin disposition and a source of drug interactions when transporter inhibitors are coadministered with a statin. All statins are substrates for OATP1B1, which provides statin access into the hepatocyte both for pharmacologic activity and subsequent metabolism and elimination. In addition, genetic polymorphisms in the solute carrier organic anion transporter family member 1B1 gene (SLCO1B1) have been associated with a higher statin exposure and increased risk for myopathy.

²

Niemi M.
Pasanen M.K.
Neuvonen P.J.

Organic anion transporting polypeptide 1B1: a genetically polymorphic transporter of major importance for hepatic drug uptake.

^,

⁵

Niemi M.

Transporter pharmacogenetics and statin toxicity.

^,

⁶

Golomb B.A.
Evans M.A.

Statin adverse effects: a review of the literature and evidence for a mitochondrial mechanism.

^,

⁷

Ho K.M.
Walker S.W.

Statins and their interactions with other lipid-modifying medications.

^,

⁸

Elsby R.
Hilgendorf C.
Fenner K.

Understanding the critical disposition pathways of statins to assess drug-drug interaction risk during drug development: it's not just about OATP1B1.

Table 1Transporters and enzymes involved in statin metabolism

Adapted from Harper et al.

³

Harper C.R.
Jacobson T.A.

Avoiding statin myopathy: understanding key drug interactions.

Statin	Transporters and enzymes affecting metabolism
Simvastatin	CYP3A4 (intestinal and hepatic)
Lovastatin	OAT1B1
	P-gp
	MDR1
	BCRP
Atorvastatin	BCRP (intestinal)
	CYP3A4 (intestinal and hepatic)
	OAT1B1 and OAT2B1
	P-gp
Rosuvastatin	BCRP (intestinal)
	CYP2C9 (minor)
	OAT1B1 and OAT1B3
	NTCP
	OAT2B1
Pravastatin	BCRP (intestinal)
	OAT1B1 and OAT1B3
	OAT2B1
Fluvastatin	BCRP (intestinal)
	OATP1B1
	OAT1B3
	OAT2B1
	CYP2C9
	CYP3A4
Pitavastatin	BCRP (intestinal)
	MDR1
	OAT1B1 andOAT1B3
	OATP2B1
	CYP2C9 (minor)

BCRP, breast cancer–resistant protein; CYP, cytochrome P450; MDR1, multidrug-resistant protein; OAT, organic anion transporters; OATP, organic anion transporting polypeptides; P-gp, p-glycoprotein.

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Table 2Membrane transporters

Adapted from Giacomini et al.

⁴

Giacomini K.M.
Huang S.M.
Tweedie D.J.
et al.

International Transporter Consortium
Membrane transporters in drug development.

Transporter/alias (gene)	Organ or cells	Comment
P-gp/MDR1 (ABCB1)	Intestinal enterocyte	Drug absorption, distribution, and excretion
	Hepatocyte (canalicular)	Source of drug interaction
	Kidney proximal tubule
BCRP (ABCB2)	Intestinal enterocyte	Drug absorption, distribution, and excretion
	Hepatocyte (canalicular)	Genetic polymorphisms
	Kidney proximal tubule	Source of drug interaction
OATP1B1/OATP2 (SLCO1B1)	Hepatocyte (sinusoidal)	Drug distribution, excretion
		Genetic polymorphisms
		Source of drug interaction
OATP1A2/OATP-A (SLCO1A2)	Cholangiocyte	Drug distribution, excretion
OATP1A2/OATP-A (SLCO1A2)	Distal nephron
OATP2B1/OATP-B (SLCO2B1)	Hepatocytes (sinusoidal)	Drug distribution, excretion
OATP2B1/OATP-B (SLCO2B1)	Hepatocytes (sinusoidal)	Source of drug interaction

ABCRP, breast cancer–resistant protein; CYP, cytochrome P450; MDR1, multidrug-resistant protein; OAT, organic anion transporters; OATP, organic anion transporting polypeptides; P-gp, p-glycoprotein; SLCO2B1, gene for solute carrier organic anion transporter family member 2B1.

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Individual variation in enzyme induction, inhibition, and patient response

Although traditional models attribute statin metabolism to the cytochrome hepatic systems, more contemporary theories involve classification of potential pathways as follows:

a
lipophilic lactone prodrugs such as simvastatin are predominantly CYP metabolized;
b
polar statins such as rosuvastatin and pravastatin are substrates of transporters including the hepatic OATPs, sodium/taurocholate cotransporting peptides (NTCP), and the renal OATPs; and
c
statins such as fluvastatin that are metabolized by CYP and access the hepatocyte by active transport.

In addition, all statins have affinity to the multi-drug-resistance protein (MRP2), P-gp, the bile salt export pump, and the BCRP. The latter transporters may have a minor role in statin drug interactions. Finally, there appears to be a delicate balance between these transporter proteins and CYP metabolism.

²

Niemi M.
Pasanen M.K.
Neuvonen P.J.

Organic anion transporting polypeptide 1B1: a genetically polymorphic transporter of major importance for hepatic drug uptake.

^,

⁵

Niemi M.

Transporter pharmacogenetics and statin toxicity.

^,

⁶

Golomb B.A.
Evans M.A.

Statin adverse effects: a review of the literature and evidence for a mitochondrial mechanism.

^,

⁷

Ho K.M.
Walker S.W.

Statins and their interactions with other lipid-modifying medications.

P-gp is a member of the ATP binding cassette-subfamily B. P-gp is the 170-kD protein product of the multidrug resistance gene ABCB1 (MDR1). Many compounds can alter the function and/or expression of P-gp, providing mechanisms for several clinically important drug-drug interactions (DDIs), which were unexplained or attributed solely to inhibition of CYP. Verapamil, cyclosporine, erythromycin, ketoconazole, and tamoxifen are examples of agents that have demonstrated either in vitro or in vivo inhibition of P-gp function. An interesting feature of P-gp is the interaction with drug-metabolizing enzymes, specifically the 3A4 isozyme of CYP (CYP3A4). P-gp and CYP3A4 share many substrates and inhibitors and have a common tissue distribution. After entering the enterocyte, a compound with affinity for P-gp or as a substrate for CYP3A4 may be absorbed directly into the systemic circulation, metabolized by CYP3A4 in the enterocyte, or secreted back into the intestinal lumen by P-gp. Drugs pumped back into the lumen may be reabsorbed at a distal site and exposed again to any of the 3 fates previously described. This may create a cycling effect (enteroenteric recycling) and increase the mean residence time in the intestinal lumen and interaction, in the case of statins, with 3-hyroxy-3-methyglutaryl coenzyme A reductase. Fluvastatin and pravastatin consistently demonstrate no significant inhibition of P-gp transport. Rosuvastatin acid or its lactone do not appear to be substrates for P-gp, leaving the effect of P-gp largely with lovastatin, simvastatin, and atorvastatin.

⁹

Holtzman C.W.
Wiggins B.S.
Spinler S.A.

Role of P-glycoprotein in statin drug interactions.

What appears to be the conundrum in understanding variations in statin tolerance are single-nucleotide polymorphisms in individuals and specific patient populations. The OATP1B1 (SLBO1B1) and BCRP (ABC2) genes have been studied most extensively.

⁸

Elsby R.
Hilgendorf C.
Fenner K.

Understanding the critical disposition pathways of statins to assess drug-drug interaction risk during drug development: it's not just about OATP1B1.

^,

¹⁰

Link E.
Parish S.
Armitage J.
et al.

SEARCH Collaborative Group
SLCO1B1 variants and statin-induced myopathy–a genomewide study.

In diploid carriers of the OAT1B1 521T > single-nucleotide polymorphism (174Val > Ala variant rs4149056), therapeutic doses of 5 statins showed altered pharmacokinetics (Table 3A, Table 3BA, B ).

⁸

Elsby R.
Hilgendorf C.
Fenner K.

Understanding the critical disposition pathways of statins to assess drug-drug interaction risk during drug development: it's not just about OATP1B1.

Fluvastatin has no apparent association with variations in implied OATP1B1 function from studies in different genetic groups. The results in Table 3A, Table 3B, however, only partially translate into day-to-day clinical scenarios with regard to muscle side effects. It may apply most often to simvastatin and atorvastatin.

Table 3AComparison of peripheral blood plasma concentrations of different statins in individuals with homozygous (OATP1B1) 521CC (dysfunctional) compared with those with fully functional homozygous (OATP1B1) 521 TT (fold AUC changes are based on group mean AUC 0–∞)

^∗

Heterozygous individuals with the c.521 TC genotype generally show smaller AUC value increases than individuals with the c.521CC genotype.

Adapted with permission from Elsby et al.

⁸

Elsby R.
Hilgendorf C.
Fenner K.

Understanding the critical disposition pathways of statins to assess drug-drug interaction risk during drug development: it's not just about OATP1B1.

Statin	AUC change
Simvastatin acid	3.21-fold ↑ (+221%)
Pitavastatin	3.08-fold ↑ (+208%)
Atorvastatin	2.45-fold ↑ (+145%)
Pravastatin	1.91-fold ↑ (+91%)
Rosuvastatin	1.62-fold ↑ (+61%)
Fluvastatin	1.19-fold ↑ (+19%, ns)

AUC, area under the curve; ns, not significant; OATP, organic anion transporting polypeptide.

∗ Heterozygous individuals with the c.521 TC genotype generally show smaller AUC value increases than individuals with the c.521CC genotype.

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Table 3BComparison of postdosing plasma concentrations of different statins in homozygous BCRP 421AA individuals compared with homozygous BCRP 421CC individuals (fold AUC changes are based on group mean AUC 0–∞)∗

Adapted with permission from Elsby et al.

⁸

Elsby R.
Hilgendorf C.
Fenner K.

Understanding the critical disposition pathways of statins to assess drug-drug interaction risk during drug development: it's not just about OATP1B1.

Drug	AUC change
Rosuvastatin	2.44-fold ↑ (+144%)
Simvastatin acid	1.22-fold ↑ (+22%)
Simvastatin lactone	2.11-fold ↑ (+111%)
Atorvastatin lactone	1.94-fold ↑ (+94%)
Atorvastatin acid	1.72-fold ↑ (+72%)
Fluvastatin	1.72-fold ↑ (+72%)
Pravastatin	1.13-fold ↓ (ns)
Pitavastatin	1.05-fold ↑ (+5%, ns)

AUC, area under the curve; BCRP, breast cancer–resistant protein; ns, not significant.

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Differences in the ABC2 gene may explain some ethnic differences. It has been suggested that 1% to 4% of African Americans, 5% to 10% Caucasians, and 35% to 45% of Asians carry variations in the ABCG2 (BCRP) gene. These changes suggest differences in the absorption of rosuvastatin, simvastatin-lactone, fluvastatin, and atorvastatin, but not simvastatin acid (active moiety) or pravastatin (Table 4).

⁸

Elsby R.
Hilgendorf C.
Fenner K.

Understanding the critical disposition pathways of statins to assess drug-drug interaction risk during drug development: it's not just about OATP1B1.

^,

⁹

Holtzman C.W.
Wiggins B.S.
Spinler S.A.

Role of P-glycoprotein in statin drug interactions.

^,

¹⁰

Link E.
Parish S.
Armitage J.
et al.

SEARCH Collaborative Group
SLCO1B1 variants and statin-induced myopathy–a genomewide study.

^,

¹¹

Neuvonen P.J.
Niemi M.
Backman J.T.

Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance.

^,

¹²

Joy T.R.
Hegele R.A.

Narrative review: statin-related myopathy.

^,

¹³

Corsini A.
Bellosta S.
Baetta R.
Fumagalli R.
Paoletti R.
Bernini F.

New insights into the pharmacodynamic and pharmacokinetic properties of statins.

^,

¹⁴

Cohen D.E.
Anania F.A.
Chalasani N.

National Lipid Association Statin Safety Task Force Liver Expert Panel. An assessment of statin safety by hepatologists.

^,

¹⁵

Chasman D.I.
Posada D.
Subrahmanyan L.
Cook N.R.
Stanton Jr., V.P.
Ridker P.M.

Pharmacogenetic study of statin therapy and cholesterol reduction.

^,

¹⁶

Bellosta S.
Paoletti R.
Corsini A.

Safety of statins: focus on clinical pharmacokinetics and drug interactions.

Table 4Predicted vs observed fold increases in various statins and enzyme systems

^∗

(number), ratio of inlet max, unbound/IC50 or Ki (>0.1 indicates potential for interaction); [number], ratio of [I2]/IC50 or Ki (>10 indicates potential for interaction).

Adapted with permission from Elsby et al.

⁸

Elsby R.
Hilgendorf C.
Fenner K.

Understanding the critical disposition pathways of statins to assess drug-drug interaction risk during drug development: it's not just about OATP1B1.

		Predicted fold increase in AUC from inhibition of composite pathways			CYP3A4 hepatic	Clinically predicted fold increase in AUC
Statin	Perpetrator drug	BCRP (intestine)	CYP3A4 (intestine)	OAT1B1	CYP3A4 hepatic	Clinically predicted fold increase in AUC
Simvastatin	Cyclosporine		1.67	4.5 (56)	1.0 (0.09)	7.5
	Telithromycin		1.67	1.2 (0.2)	2.0 (1.6)	4.0
	Posaconazole		1.67	NI	1.7 (0.9)	4.0
Atorvastatin	Cyclosporine	1.72 (174)	1.45	3.2 (103)	NA	8.0
	Lopinavir/ritonavir	NA, low solubility	1.45	1.9 (2.3) 1.1 (0.14)	1.0 (0.16)	2.9
	Clarithromycin	NI	1.45	2.0 (2.7)	1.1 (0.4)	3.2
	Itraconazole	NI	1.45	NI	1.0 (0.4)	1.45
		BCRP (intestine)		OAT1B3	CYP2C9
Fluvastatin	Cyclosporine	1.72 (100)		1.8 (19)	NI	3.2
	Fluconazole	NI		NI	1.7 (9.9)	1.7
Statin	Precipitating drug	BCRP (intestine)	Active uptake (OATP1B1:NTCP:OATP1B3) (f_e = 0.38:0.21:0.11 = 0.7)	OAT3	Overall predicted fold increase in AUC	Clinically observed fold increase in AUC
Rosuvastatin	Cyclosporine	2.0 (100)	3.2 (56)	NI	6.4	7.1
	Gemfibrozil	NI	1.5 (OATP1B) (2.0)	1.2 (2.1)	1.8	1.9
	Lopinavir/ritonavir	No effect-low solubility	1.5 (OATP1B) (1.9 if all inhibited) (2.3)	NA	1.5 (1.9)	2.1
	Atazanavir/ritonavir	2.0 (25)	1.6 (OATP1B) (3.5)	NA	3.2	3.1
		Efflux (intestine)	OATP1B1	OAT3
Pravastatin	Cyclosporine	2.9	2.0 (103)	NI	5.8	3.82
	Clarithromycin	NI	1.6 (2.7)	NI	1.6	2.1
	Gemfibrozil	NI	1.3 (0.9)	1.4 (2.6)	2.1	2.0
			OAT
Pitavastatin	Cyclosporine		4.2 (39)		4.2	4.55
	Erythromycin		1.5 (0.7)		1.5	2.8
	Gemfibrozil		1.5 (0.8)		1.5	1.45

AUC, area under the curve; BCRP, breast cancer–resistant protein; CYP3A4, cytochrome P450 isozyme 3A4; DDI, drug-drug interaction; IC50, half maximal inhibitory concentration; Ki, reversible inhibition constant; NA, not applicable; NI, not an inhibitor; OAT, organic anion transporter; OATP, organic anion transporting polypeptide.

∗ (number), ratio of _{inlet max, unbound}/IC₅₀ or Ki (>0.1 indicates potential for interaction); [number], ratio of [I₂]/IC₅₀ or Ki (>10 indicates potential for interaction).

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Focus on drugs that have the highest potential to interact with statins

Although multiple pathways have been shown to play a role in statin DDIs, the CYP3A4 and CYP2C9 pathways have been most commonly described. Focusing on simvastatin, the potential for DDIs involves complete inhibition of intestinal CYP3A4-mediated metabolism in addition to OATP1B1-mediated uptake of the statin acid. Based on this mechanism, cyclosporine, telithromycin, and posaconazole are also likely to produce similar multiple-fold increases in areas under the curve (AUCs). Although a critical interaction, the combination of gemfibrozil and simvastatin perhaps is less daunting because gemfibrozil only inhibits OATP1B1 in turn because neither gemfibrozil, nor its glucuronide, are CYP3A4 inhibitors.

Atorvastatin may be more complex because of the passive absorption of atorvastatin acid. Cyclosporine enterocyte concentrations and BCRP intestinal inhibition would result in full inhibition of CYP3A4, causing the interaction. Yet for the other atorvastatin interactions, there is less involvement of BCRP and a greater involvement of combined OATP1/CYP3A4 interaction. Fluvastatin interactions are predominately related to complete inhibition of CYP2C9. The AUC changes for fluvastatin involve OAT1B3 and BCRP. There is a strong likelihood that pharmacogenetic differences in intestinal BCRP are the cause of the fluvastatin/cyclosporine interaction. Pitavastatin is largely eliminated through OATP1B1. Although this is a common pathway for erythromycin and gemfibrozil, the AUC changes in these drug combinations with pitavastatin are less than predicted. The cause may be only partial inhibition of OATP1B1.

Multiple mechanisms including complete inhibition of various OATPs (1B1 and OAT3 enzyme systems, inhibition of intestinal efflux, and intestinal BCRP and possibly other proteins) may be responsible for increased blood levels of statins (Table 4).

⁸

Elsby R.
Hilgendorf C.
Fenner K.

Understanding the critical disposition pathways of statins to assess drug-drug interaction risk during drug development: it's not just about OATP1B1.

These cannot always be accurately predicted by pharmacokinetic modeling. Pravastatin and gemfibrozil theoretically would produce a DDI by completely inhibiting OAT1B1; however, gemfibrozil is also able to inhibit the renal transporter OAT3. This suggests the possibility that the drug interaction involves mediation of both the hepatic and renal pathways. Similarly, the interaction of cyclosporine and pravastatin cannot be attributed solely to OAT1B1 inhibition. Therefore, other potential mechanisms of intestinal efflux may be responsible.

The cyclosporine induced changes in rosuvastatin AUC are likely related to inhibition of all active uptake (OATP1B1, NTCP, and OATP1B3) in addition to intestinal BCRP. The gemfibrozil/rosuvastatin DDI could be related to inhibition of both OATP1B1/3 and OAT3. There may be issues with this theory in day-to-day clinical practice, where many patients may not present with the DDI.

Following the previous discussion, it is important to know how the statins and their potential interactants affect intestinal, hepatic, and possibly renal efflux pumps. There are likely pharmacogenetic differences among various cohorts involving differing hepatic uptake (via OATP1B1/3 and NTCP), first-pass metabolism via CYP3A4, absorption via BCRP, and renal elimination by OAT3. Understanding more definitively how these drugs affect or are affected by these enzyme and transport systems can be useful in DDI prediction. Although not fully recognized until studying cerivastatin interactions, glucuronidation is now identified as a common metabolic pathway for the conversion of active open acid forms of several statins (including atorvastatin and rosuvastatin) to their lactone form. Catabolism of lactone forms of statins is common to CYP3A4 enzyme activity.

Suggested nomenclature for classifying statin drug interaction

There appears to be a concentration-dependent relationship between the risk of myopathy/myonecrosis (clinical rhabdomyolysis) and the serum concentration of a statin. As such, we propose adopting the system shown in Figure 3 for the clinician to apply drug interaction studies with the relative risk to an exposed patient.

¹⁷

Rodriques A.D.

Prioritization of clinical drug interaction studies using in vitro cytochrome P450 data: proposed refinement and expansion of the “rank order” approach.

An interaction resulting in less than a 2-fold increase in statin AUC, a marker for systemic exposure, would be classified as “mild” risk. Interactions producing more than a 2- but less than 5-fold increase in systemic exposure would be classified as “moderate.” A strong interaction would result in a 5-fold or higher increase in statin exposure. This system should only be used as a guide, because an individual patient's response may be dictated by other clinical features, such as inherent susceptibility to statin-related myopathy, unidentified genetic predisposition, and history or presence of other predictors of statin muscle side effects (eg, hypothyroidism, vitamin D deficiency, electrolyte disturbances, low baseline muscle mass).

¹¹

Neuvonen P.J.
Niemi M.
Backman J.T.

Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance.

Figure thumbnail gr3 — Figure 3A proposed ranking of significance with respect to area under the curve (AUC) changes and drug-drug interaction possibilities. AUC, area under the curve; CYP, cytochrome P450.
Adapted from Rodrigues et al.
¹⁷
Rodriques A.D.
Prioritization of clinical drug interaction studies using in vitro cytochrome P450 data: proposed refinement and expansion of the “rank order” approach.
*Drug Metabolism Letters.* 2007; 1: 31-35
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PubMed

Scopus (19)

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Understanding package labeling

The US Food and Drug Administration (FDA) label repository maintains copies of all statin labeling.

¹⁸

US Food and Drug Administration. FDA Online Label Repository. Available at: http://labels.fda.gov/. Accessed February 9, 2014.

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The repository first used the portable document format and then transitioned to the new technology called the “structured product label” for use in the National Library of Medicine. Changes up until 2008 were minor, adding only new indications, drug interactions, or adverse reactions. With the possible exception of the 2001 cerivastatin (Baycol) recall, warning information was sparse. Starting with its review of ezetimibe/simvastatin (Vytorin) in the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression study, the FDA began issuing study review communications and commenced major labeling changes for the various statins. In 2011, dosing limits on simvastatin were established and the labeling for both lovastatin and simvastatin was revised. Subsequent labeling changes included obviating the need for routine liver transaminase monitoring, suggested dosing limits on concomitant statin prescription with either niacin, amiodarone, or calcium channel blockers, and warnings regarding statin-induced cognitive impairment and diabetes mellitus. The FDA is assuming a greater role in postmarketing surveillance and keeping package labeling current with contemporary literature.

¹⁹

US Food and Drug Administration. FDA Drug Safety Communication: New restrictions, contraindications, and dose limitations for Zocor (simvastatin) to reduce the risk of muscle injury. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm256581.htm. Accessed February 8, 2014.

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^,

²⁰

US Food and Drug Administration. FDA Drug Safety Communication: Revised dose limitation for Zocor (simvastatin) when taken with amiodarone. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm283137.htm. Accessed February 8, 2014.

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^,

²¹

US Food and Drug Administration. FDA Drug Safety Communication: FDA announces safety changes in labeling for some cholesterol-lowering drugs. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm293101.htm. Accessed February 8, 2014.

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Using the concepts presented here, the 2012 simvastatin (Zocor) package insert can be examined as an example.

²²

Merck & Co. Inc. ZOCOR (simvastatin) tablets prescribing information. Available at: http://www.merck.com/product/usa/pi_circulars/z/zocor/zocor_pi.pdf. Accessed February 8, 2014.

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The values of the geometric mean ratio, AUC, and maximum concentration are determined separately. Each dose is compared with the reference dose on a pairwise basis. The geometric mean ratios for each dose level are compared with the reference dose. If the confidence intervals include unity, it is implied that the relationship between the test dose and the reference dose is proportional. If the lower confidence interval lies just less than 1.0, this may be an indication that the true response at this level is slightly more than dose-proportional compared with the reference dose level. This concept may be confusing to the understanding of the true potential for clinically significant DDIs.

More recent package inserts for statins (Lipitor, Crestor, Livalo) provide greater clarity.

²³

Parke-Davis-Pfizer. Lipitor (atorvastatin calcium) tablets for oral administration prescribing information. Available at: http://labeling.pfizer.com/ShowLabeling.aspx?id=587. Accessed February 8, 2014.

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^,

²⁴

AstraZeneca. Crestor (rosuvastatin calcium) tablets prescribing information. Available at: http://www1.astrazeneca-us.com/pi/crestor.pdf. Accessed February 8, 2014.

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^,

²⁵

Kowa Pharmaceuticals America I. LIVALO (pitavastatin) tablet 1 mg, 2 mg, and 4 mg package insert - product labeling. Available at: http://www.kowapharma.com/documents/LIVALO_PI_CURRENT.pdf. Accessed February 8, 2014.

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The statin AUC, when coadministered with the reference drug, is expressed as an x-fold change and represents a simple ratio between coadministration and statin alone (ie, 1-fold = no change). This concept appears simpler and provides information similar to that in package inserts of other drug classes as well as many clinical prediction models. The modified package inserts for drug coadministered interactions are shown in Table 5, Table 6, Table 7, Table 8, Table 9, Table 10, Table 11.

²²

Merck & Co. Inc. ZOCOR (simvastatin) tablets prescribing information. Available at: http://www.merck.com/product/usa/pi_circulars/z/zocor/zocor_pi.pdf. Accessed February 8, 2014.

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^,

²³

Parke-Davis-Pfizer. Lipitor (atorvastatin calcium) tablets for oral administration prescribing information. Available at: http://labeling.pfizer.com/ShowLabeling.aspx?id=587. Accessed February 8, 2014.

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^,

²⁴

AstraZeneca. Crestor (rosuvastatin calcium) tablets prescribing information. Available at: http://www1.astrazeneca-us.com/pi/crestor.pdf. Accessed February 8, 2014.

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^,

²⁵

Kowa Pharmaceuticals America I. LIVALO (pitavastatin) tablet 1 mg, 2 mg, and 4 mg package insert - product labeling. Available at: http://www.kowapharma.com/documents/LIVALO_PI_CURRENT.pdf. Accessed February 8, 2014.

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^,

²⁶

Merck & Co. Inc. MEVACOR (lovastatin) tablets. Available at: http://www.merck.com/product/usa/pi_circulars/m/mevacor/mevacor_pi.pdf. Accessed February 9, 2014.

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^,

²⁷

Novartis Pharmaceuticals Corporation. Lescol (fluvastatin sodium) capsules/Lescol XL (fluvastatin sodium) extended-release tablets for oral use prescribing information. Available at: https://www.pharma.us.novartis.com/product/pi/pdf/Lescol.pdf. Accessed February 9, 2014.

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^,

²⁸

Company B-MS. PRAVACHOL (pravastatin sodium) tablets. Available at: http://packageinserts.bms.com/pi/pi_pravachol.pdf. Accessed February 9, 2014.

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These tables are by no means complete, hence current reference sources, such as Table 12

²⁹

Elsevier/Gold Standard Inc. Clinical Pharmacology [database online]. Available at: http://www.goldstandard.com/product/gold-standard-drug-database. Accessed November, 2013.

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and other contemporary drug interaction references should be consulted before prescribing interacting drugs.

Table 5Simvastatin drug interactions

²²

Merck & Co. Inc. ZOCOR (simvastatin) tablets prescribing information. Available at: http://www.merck.com/product/usa/pi_circulars/z/zocor/zocor_pi.pdf. Accessed February 8, 2014.

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Coadministered drug and dosing regimen	Simvastatin (mg)	Simvastatin form	Geometric mean ratio (ratio ∗ Results based on a chemical assay except results with propranolol as indicated. with/without coadministered drug) No effect = 1.00 AUC
Contraindicated with simvastatin
Telithromycin ^† Results could be representative of the following cytochrome P450 3A4 isozyme inhibitors: ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, and nefazodone. 200 mg QD for 4 d	80 mg	Simvastatin acid ^‡ Simvastatin acid refers to the β-hydroxyacid of simvastatin. Simvastatin	12 8.9
Nelfinavir ^† Results could be representative of the following cytochrome P450 3A4 isozyme inhibitors: ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, and nefazodone. 1250 mg BID for 14 d	20 mg QD for 28 d	Simvastatin acid ^‡ Simvastatin acid refers to the β-hydroxyacid of simvastatin. Simvastatin	6.2
Itraconazole ^† Results could be representative of the following cytochrome P450 3A4 isozyme inhibitors: ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, and nefazodone. 200 mg QD for 4 d	80 mg	Simvastatin acid ^‡ Simvastatin acid refers to the β-hydroxyacid of simvastatin. Simvastatin	AUC not reported C_max 13.1
Posaconazole
100 mg (oral suspension) QD for 13 d	40 mg	Simvastatin acid Simvastatin	7.3 10.3
200 mg (oral suspension) QD for 13 d	40 mg	Simvastatin acid Simvastatin	8.5 10.6
Avoid >1 quart of grapefruit juice with simvastatin
Grapefruit juice ^§ The effect of amounts of grapefruit juice between those used in these 2 studies on simvastatin pharmacokinetics has not been studied. (high dose)	60 mg single dose	Simvastatin acid Simvastatin	7 16
200 mL of double-strength TID Double strength: 1 can of frozen concentrate diluted with 1 can of water. Grapefruit juice was administered TID for 2 d, and 200 mL together with single-dose simvastatin and 30 and 90 min after single-dose simvastatin on day 3.
Grapefruit juice ^§ The effect of amounts of grapefruit juice between those used in these 2 studies on simvastatin pharmacokinetics has not been studied. (low dose)	20 mg single dose	Simvastatin acid Simvastatin	1.3 1.9
8 oz (about 237 mL) of single-strength ^¶ Single strength: 1 can of frozen concentrate diluted with 3 cans of water. Grapefruit juice was administered with breakfast for 3 d; simvastatin was administered in the evening on day 3.
Avoid taking with >10 mg simvastatin, based on clinical and/or postmarketing experience
Verapamil SR 240 mg QD days 1-7 then 240 mg BID on days 8-10	80 mg on day 10	Simvastatin acid Simvastatin	2.3 2.5
Diltiazem 120 mg BID for 10 d	80 mg on day 10	Simvastatin acid Simvastatin	2.69 3.10
Diltiazem 120 mg BID for 14 d	20 mg on day 14	Simvastatin	4.6
Avoid taking with >20 mg simvastatin, based on clinical and/or post-marketing experience
Amiodarone 400 mg QD for 3 d	40 mg on day 3	Simvastatin acid Simvastatin	1.75 1.76
Amlodipine 10 mg QD x 10 d	80 mg on day 10	Simvastatin acid Simvastatin	1.58 1.77
Ranolazine SR 1000 mg BID for 7 d	80 mg on day 1 and days 6-9	Simvastatin acid Simvastatin	2.26 1.86
No dosing adjustments required for the following
Fenofibrate 160 mg QD × 14 d	80 mg QD on days 8-14	Simvastatin acid Simvastatin	0.64 0.89
Niacin extended-release Chinese patients have an increased risk for myopathy with simvastatin coadministered with lipid-modifying doses (≥1 g/day niacin) of niacin-containing products. Because the risk is dose-related, it is recommended that Chinese patients not receive simvastatin 80 mg coadministered with lipid-modifying doses of niacin-containing products. 2 g single dose	20 mg single dose	Simvastatin acid Simvastatin	1.6 1.4
Propranolol 80 mg single dose	80 mg single dose	Total inhibitor Active inhibitor	0.79 0.79

AUC, area under the curve; BID, twice a day; C_max, maximum concentration; TID, 3 times a day; QD, every day; SR, slow release.

∗ Results based on a chemical assay except results with propranolol as indicated.

† Results could be representative of the following cytochrome P450 3A4 isozyme inhibitors: ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, and nefazodone.

‡ Simvastatin acid refers to the β-hydroxyacid of simvastatin.

§ The effect of amounts of grapefruit juice between those used in these 2 studies on simvastatin pharmacokinetics has not been studied.

|| Double strength: 1 can of frozen concentrate diluted with 1 can of water. Grapefruit juice was administered TID for 2 d, and 200 mL together with single-dose simvastatin and 30 and 90 min after single-dose simvastatin on day 3.

¶ Single strength: 1 can of frozen concentrate diluted with 3 cans of water. Grapefruit juice was administered with breakfast for 3 d; simvastatin was administered in the evening on day 3.

∗∗ Chinese patients have an increased risk for myopathy with simvastatin coadministered with lipid-modifying doses (≥1 g/day niacin) of niacin-containing products. Because the risk is dose-related, it is recommended that Chinese patients not receive simvastatin 80 mg coadministered with lipid-modifying doses of niacin-containing products.

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Table 6Lovastatin drug interactions

²⁶

Merck & Co. Inc. MEVACOR (lovastatin) tablets. Available at: http://www.merck.com/product/usa/pi_circulars/m/mevacor/mevacor_pi.pdf. Accessed February 9, 2014.

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Coadministered drug and dosing regimen	Lovastatin (mg)	Geometric mean ratio (ratio ^∗ Results based on a chemical assay. with/without coadministered drug)
		No effect = 1.00 AUC
		Lovastatin	Lovastatin acid
Gemfibrozil 600 mg BID for 3 d	40 mg	0.96	2.80
Itraconazole 200 mg QD for 4 d	40 mg on day 4	>36 ^† Estimated minimum change.	22
Itraconazole 100 mg QD for 4 d	40 mg on day 4	>14.8 ^† Estimated minimum change.	15.4
Grapefruit juice (high dose) 200 mL of double strength	80 mg single dose	15.3	5.0
Grapefruit juice (low dose) about 250 mL of single strength for 4 d	40 mg single dose	1.94	1.57
Cyclosporine (dose NA)	10 mg daily for 10 d	5- to 8-fold	ND
			Total lovastatin acid
Diltiazem 120 mg BID for 14 d	20 mg		3.57

AUC, area under the curve; BID, twice a day; NA, not applicable; ND, not determined; QD, every day.

∗ Results based on a chemical assay.

† Estimated minimum change.

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Table 7Atorvastatin drug interactions

²³

Parke-Davis-Pfizer. Lipitor (atorvastatin calcium) tablets for oral administration prescribing information. Available at: http://labeling.pfizer.com/ShowLabeling.aspx?id=587. Accessed February 8, 2014.

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Coadministered drug and dosing regimen	Atorvastatin dose (mg)	Atorvastatin change in AUC ^∗ Results based on a chemical assay.
Cyclosporine 5.2 mg/kg/d, stable dose	10 mg QD for 28 d	↑ 8-fold ^‡ Clinically significant.
Tipranavir 500 mg BID/ritonavir 200 mg BID for 7 d	10 mg SD	↑ 9.4-fold ^‡ Clinically significant.
Telaprevir 750 mg every 8 h for 10 d	20 mg SD	↑ 7.88-fold ^‡ Clinically significant.
Saquinavir 400 mg BID/ritonavir 400 mg BID for 15 d ^† Because of the dual interaction mechanism of rifampin, simultaneous coadministration of atorvastatin with rifampin is recommended, because delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations.	40 mg QD for 4 d	↑ 3.9-fold ^‡ Clinically significant.
Clarithromycin 500 mg BID for 9 days	80 mg QD for 8 d	↑ 4.4-fold ^‡ Clinically significant.
Darunavir 300 mg BID/ritonavir 100 mg BID for 9 d	10 mg QD for 4 d	↑ 3.9-fold ^‡ Clinically significant.
Itraconazole 200 mg QD for 4 d	40 mg SD	↑ 3.3-fold ^‡ Clinically significant.
Fosamprenavir 700 mg BID/ritonavir 100 mg BID for 14 d	10 mg QD for 4 d	↑ 2.53-fold ^‡ Clinically significant.
Fosamprenavir 1400 mg BID for 14 d	10 mg QD for 4 d	↑ 2.3-fold ^‡ Clinically significant.
Nelfinavir 1250 mg BID for 14 d	10 mg QD for 28 d	↑ 74% ^‡ Clinically significant.
Grapefruit juice 240 mL QD	40 mg SD	↑ 37%
Diltiazem 240 mg QD for 28 d	40 mg SD	↑ 51%
Erythromycin 500 mg QID for 7 d	10 mg SD	↑ 51%
Amlodipine 10 mg, single dose	80 mg	↑ 15%
Cimetidine 300 mg QD for 4 wk	10 mg QD for 2 wk	↓ Less than 1%
Colestipol 10 mg BID for 28 wk	40 mg QD for 28 wk	Not determined
Maalox TC 30 mL QD for 17 d	10 mg QD for 5 d	↓ 33%
Efavirenz 600 mg QD for 14 d	10 mg QD for 3 d	↓ 41%
Rifampin 600 mg QD, 7 d (coadministered) ^† Because of the dual interaction mechanism of rifampin, simultaneous coadministration of atorvastatin with rifampin is recommended, because delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations.	40 mg SD	↑ 30% ^‡ Clinically significant.
Rifampin 600 mg QD, 5 d (doses separated) ^† Because of the dual interaction mechanism of rifampin, simultaneous coadministration of atorvastatin with rifampin is recommended, because delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations.	40 mg SD	↓ 80%
Gemfibrozil 600 mg BID 7 d	40 mg SD	↑ 35%
Fenofibrate 160 mg QD 7 d	40 mg SD	↑ 3%

AUC, area under the curve; BID, twice a day; QD, every day; QID, 4 times a day; SD, single dose.

∗ Results based on a chemical assay.

† Because of the dual interaction mechanism of rifampin, simultaneous coadministration of atorvastatin with rifampin is recommended, because delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations.

‡ Clinically significant.

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Table 8Rosuvastatin drug interactions

²⁴

AstraZeneca. Crestor (rosuvastatin calcium) tablets prescribing information. Available at: http://www1.astrazeneca-us.com/pi/crestor.pdf. Accessed February 8, 2014.

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Coadministered drug and dosing regimen	Rosuvastatin dose (mg) ^∗ Single dose unless otherwise noted.	Rosuvastatin change in AUC
Cyclosporine (stable dose required 75-200 mg BID)	10 mg/d for 10 d	↑ 10-fold ^‡ Clinically significant.
Gemfibrozil 600 mg BID × 7 d	80 mg	↑ 1.9-fold ^‡ Clinically significant.
Lopinavir/ritonavir combination 400 mg/100 mg BID for 10 d	20 mg/day for 7 d	↑ 2-fold ^‡ Clinically significant.
Atazanavir/ritonavir combination 300 mg/100 mg QD for 7 d	10 mg	↑ 3.1-fold ^‡ Clinically significant.
Eltrombopag 75 mg QD for 5 d	10 mg	↑ 3.1-fold
Tipranavir/ritonavir combination 500 mg/200 mg BID for 11 d	10 mg	↑ 26%
Dronedarone 400 mg BID	10 mg	↑ 1.4-fold
Itraconazole 200 mg QD for 5 d	10 mg or 80 mg	↑ 39% ↑ 28%
Ezetimibe 10 mg daily for 14 d	10 mg daily for 14 d	↑ 1.2-fold
Fosamprenavir/ritonavir 700 mg/100 mg BID for 7 d	10 mg	↑ 8%
Fenofibrate 67 mg TID for 7 d	10 mg	↑ 7%
Aluminum and magnesium hydroxide combination antacid administered simultaneously; administered 2 h apart	40 mg 40 mg	↓ 54% ^‡ Clinically significant. ↓ 22%
Erythromycin 500 mg QID for 7 d	80 mg	↓ 20%
Ketoconazole 200 mg BID for 7 d	80 mg	↑ 2%
Itraconazole 200 mg QD for 5 d	10 mg 80 mg	↑ 39% ↑ 28%
Fluconazole 200 mg QD for 11 d	80 mg	↑ 14%

AUC, area under the curve; BID, twice a day; QD, every day; QID, 4 times a day, TID, 3 times a day.

^†Mean ratio (with/without coadministered drug and no change = 1-fold) or % change (with/without coadministered drug and no change = 0%); symbols of ↑ and ↓ indicate the exposure increase and decrease, respectively.

∗ Single dose unless otherwise noted.

‡ Clinically significant.

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Table 9Fluvastatin drug interactions

²⁷

Novartis Pharmaceuticals Corporation. Lescol (fluvastatin sodium) capsules/Lescol XL (fluvastatin sodium) extended-release tablets for oral use prescribing information. Available at: https://www.pharma.us.novartis.com/product/pi/pdf/Lescol.pdf. Accessed February 9, 2014.

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Coadministered drug and dosing regimen	Fluvastatin dose (mg) ^∗ Single dose, unless otherwise noted.	Fluvastatin change in AUC ^† Mean ratio (with/without coadministered drug and no change = 1-fold) or % change (with/without coadministered drug and no change = 0%); symbols of ↑ and ↓ indicate the exposure increase and decrease, respectively.
Cyclosporine – stable dose BID ^‡ Considered clinically significant.	20 mg QD for 14 wk	↑ 90%
Fluconazole 400 mg QD d 1200 mg BID d 2-4 ^‡ Considered clinically significant.	40 mg QD	↑ 84%
Cholestyramine 8 g QD	20 mg QD administered 4 h after a meal plus cholestyramine	↓ 51%
Rifampicin 600 mg QD for 6 d	20 mg QD	↓ 53%
Cimetidine 400 mg BID for 5 d, QD on day 6	20 mg QD	↑ 30%
Ranitidine 150 mg BID for 5 d, QD on day 6	20 mg QD	↑ 10%
Omeprazole 40 mg QD for 6 d	20 mg QD	↑ 20%
Phenytoin 300 mg QD	40 mg BID for 5 d	↑ 40%
Propranolol 40 mg BID for 3.5 d	40 mg QD	↓ 5%
Digoxin 0.1-0.5 mg QD for 3 wk	40 mg QD	No change
Diclofenac 25 mg QD	40 mg QD for 8 days	↑ 50%
Glyburide 5-20 mg QD for 22 d	40 mg BID for 14 d	↑ 51%
Warfarin 30 mg QD	40 mg QD for 8 d	↑ 30%
Clopidogrel 300 mg loading dose on day 10, 75 mg dose on days 11-19	80 mg XL QD for 19 d	↓ 2%

AUC, area under the curve; BID, twice a day; QD, every day.

∗ Single dose, unless otherwise noted.

† Mean ratio (with/without coadministered drug and no change = 1-fold) or % change (with/without coadministered drug and no change = 0%); symbols of ↑ and ↓ indicate the exposure increase and decrease, respectively.

‡ Considered clinically significant.

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Table 10Pravastatin drug interactions

²⁸

Company B-MS. PRAVACHOL (pravastatin sodium) tablets. Available at: http://packageinserts.bms.com/pi/pi_pravachol.pdf. Accessed February 9, 2014.

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Coadministered drug and dosing regimen	Pravastatin dose (mg)	Pravastatin change in AUC
Cyclosporine 5 mg/kg single dose	40 mg single dose	↑ 282%
Clarithromycin 500 mg BID for 9 d	40 mg QD × 8 d	↑ 110%
Boceprevir 800 mg TID for 6 d	40 mg single dose	↑ 63%
Darunavir 600 mg BID/Ritonavir 100 mg BID for 7 d	40 mg single dose	↑ 81%
Colestipol 10 g single dose	20 mg single dose	↓ 47%
Cholestyramine 4 g single dose	20 mg single dose
Cholestyramine 4 g single dose		↓ 47%
Administered simultaneously		↓ 47%
Administered simultaneously		↑ 12%
Administered 1 h before cholestyramine		↑ 12%
Administered 1 h before cholestyramine		↓ 12%
Administered 4 h after cholestyramine		↓ 12%
Cholestyramine 24 g daily for 4 wk	20 mg BID for 8 wk	↓ 51%
	5 mg BID for 8 wk	↓ 38%
	10 mg BID for 8 wk	↓ 18%
Fluconazole
200 mg IV for 6 d	20 mg PO + 10 mg IV	↓ 34%
200 mg PO for 6 d	20 mg PO + 10 mg IV	↓ 16%
Kaletra 400 mg/100 mg BID for 14 d	20 mg daily for 4 d	↑ 33%
Verapamil IR 120 mg for 1 d and verapamil ER 480 mg for 3 d	40 mg single dose	↑ 31%
Cimetidine 300 mg QID for 3 d	20 mg single dose	↑ 30%
Antacids 15 mL QID for 3 d	20 mg single dose	↓ 28%
Digoxin 0.2 mg daily for 9 d	20 mg daily for 9 d	↑ 23%
Probucol 500 mg single dose	20 mg single dose	↑ 14%
Warfarin 5 mg daily for 6 d	20 mg BID for 6 d	↓ 13%
Itraconazole 200 mg daily for 30 d	40 mg daily for 30 d	↑ 11% (compared with day 1)
Gemfibrozil 600 mg single dose	20 mg single dose	↓ 7.0%
Aspirin 324 mg single dose	20 mg single dose	↑ 4.7%
Niacin 1 g single dose	20 mg single dose	↓ 3.6%
Diltiazem	20 mg single dose	↑ 2.7%
Grapefruit juice	40 mg single dose	↓ 1.8%

AUC, area under the curve; BID, twice a day; ER, extended release; IR, immediate release; IV, intravenous; PO, orally; QD, every day; QID, 4 times a day; TID, 3 times a day.

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Table 11Pitavastatin drug interactions

²⁵

Kowa Pharmaceuticals America I. LIVALO (pitavastatin) tablet 1 mg, 2 mg, and 4 mg package insert - product labeling. Available at: http://www.kowapharma.com/documents/LIVALO_PI_CURRENT.pdf. Accessed February 8, 2014.

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Coadministered drug and dosing regimen	Dose regimen	Pitavastatin change in AUC ^∗ Data presented as x-fold change represent the ratio between coadministration and pitavastatin alone (ie, 1-fold = no change). Data presented as % change represent % difference relative to pitavastatin alone (ie, 0% = no change).
Cyclosporine 2 mg/kg/d on day 6	Pitavastatin 2 mg QD	↑ 4.6-fold ^† Considered clinically significant.
Erythromycin 500 mg 4 times daily for 5 d	Pitavastatin 4 mg single dose on day 4	↑ 2.8-fold ^† Considered clinically significant.
Rifampin 600 mg QD for 5 d	Pitavastatin 4 mg QD	↑ 29%
Atazanavir 300 mg daily for 5 d	Pitavastatin 4 mg QD	↑ 31%
Darunavir/ritonavir 800 mg/100 mg QD on days 6-16	Pitavastatin 4 mg QD on days 1-5 and 12-16	↓ 26%
Lopinavir/ritonavir 400 mg/100 mg BID on days 9-24	Pitavastatin 4 mg QD on days 1-5 and 20-24	↓ 20%
Gemfibrozil 600 mg BID for 7 d	Pitavastatin 4 mg QD	↑ 45%
Fenofibrate 160 mg daily for 7 d	Pitavastatin 4 mg QD	↑ 18%
Ezetimibe 10 mg daily for 7 d	Pitavastatin 2 mg QD	↓ 2%
Enalapril 20 mg daily for 5 d	Pitavastatin 4 mg QD	↑ 6%
Digoxin 0.25 mg daily for 7 d	Pitavastatin 4 mg QD	↑ 4%
Diltiazem LA 240 mg on days 6-15	Pitavastatin 4 mg QD on days 1-5 and 11-15	↑ 10%
Grapefruit juice for 4 d (quantity not specified)	Pitavastatin 2 mg single dose on day 3	↑ 15%
Itraconazole 200 mg daily for 5 d	Pitavastatin 4 mg single dose on day 4	↓ 23%

BID, twice daily; QD, once daily; LA, long acting.

∗ Data presented as x-fold change represent the ratio between coadministration and pitavastatin alone (ie, 1-fold = no change). Data presented as % change represent % difference relative to pitavastatin alone (ie, 0% = no change).

† Considered clinically significant.

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Table 12Comparison of drug-drug interactions across all statins

Adapted with permission from Clinical Pharmacology [database online]. Tampa, FL: Elsevier/Gold Standard, Inc.; 2013.

²⁹

Elsevier/Gold Standard Inc. Clinical Pharmacology [database online]. Available at: http://www.goldstandard.com/product/gold-standard-drug-database. Accessed November, 2013.

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	Level 1 (severe) Do not use	Level 2 (major) Use with caution	Level 3 (moderate) Less likely to cause severe drug interaction	Level 4 (mild) Unlikely to cause drug interaction
Simvastatin/lovastatin	Protease inhibitors	Amiodarone	Afatinib	Barbiturates
	Boceprevir	Amlodipine	Aprepitant	Carbamazepine
	Clarithromycin	Conivaptan	Fosaprepitant	Clopidogrel
	Cobicistat Elvitegravir Emtricitabine Tenofovir	Diltiazem	Bosentan	Nevirapine
	Cyclosporine	Dronedarone	Colchicine	Oxcarbazepine
	Danazol	Efavirenz	Dalfopristin/quinupristin	Rifabutin
	Delavirdine	Other fibrates	Daptomycin	Rifapentine
	Erythromycin	Fluconazole	Digoxin
	Gemfibrozil	Grapefruit juice	Esomeprazole
	Itraconazole	Imatinib	Fluvoxamine
	Ketoconazole	Lomitapide	Fosphenytoin
	Nefazodone	Ranolazine Simeprivir	Lansoprazole
	Posaconazole	Ticagrelor	Niacin, niacinamide
	Red yeast Rice	Troleandomycin	Omeprazole
	Telaprevir	Verapamil	Pantoprazole
	Telithromycin		Phenytoin
	Voriconazole		Quinine
			Repaglinide
			Rifampin
			St. John's wort
			Warfarin
Atorvastatin	Posaconazole	Boceprevir	Amiodarone	Barbiturates
	Red yeast rice	Clarithromycin	Antacids	Carbamazepine
	Telithromycin	Conivaptan	Aprepitant	Cimetidine
	Voriconazole	Cyclosporine	Fosaprepitant	Clopidogrel
		Darunavir	Atazanavir	Miconazole
		Delavirdine	Bosentan	Nevirapine
		Digoxin	Colchicine	Oral contraceptives
		Diltiazem	Colestipol	Oxcarbazepine
		Erythromycin	Dalfopristin/quinupristin	Pioglitazone
		Fluconazole	Danazol	Rifabutin
		Fosamprenavir	Daptomycin	Rifapentine
		Gemfibrozil	Efavirenz	Spironolactone
		Grapefruit juice
		Imatinib	Esomeprazole
		Itraconazole	Fosphenytoin
		Ketoconazole	Indinavir
		Lopinavir/ritonavir	Lansoprazole
		Nefazodone	Mifepristone
		Nelfinavir	Niacin, niacinamide
		Other fibrates	Nilotinib
		Saquinavir Simeprivir	Omeprazole
		Telaprevir	Pantoprazole
		Tipranavir	Phenytoin
		Troleandomycin	Quinine
		Verapamil	Ranolazine
			Rifampin
			St. John's wort
			Warfarin
Rosuvastatin	Red yeast rice	Antacids	Colchicine	Erythromycin
		Atazanavir	Daptomycin	Oral contraceptives
		Clarithromycin	Darunavir
		Cyclosporine	Indinavir
		Fosamprenavir	Itraconazole
		Gemfibrozil and other fibrates	Niacin, niacinamide
		Lopinavir/Ritonavir	Warfarin
		Nelfinavir
		Ritonavir
		Saquinavir Simeprivir
		Telithromycin
Pravastatin	Red yeast rice	Bile acid resins	Boceprevir
		Clarithromycin	Colchicine
		Cyclosporine	Daptomycin
		Darunavir	Itraconazole
		Erythromycin	Niacin, niacinamide
		Gemfibrozil and other fibrates Simeprivir	Orlistat
		Telithromycin	Warfarin
Fluvastatin	Red yeast rice	Cyclosporine	Amiodarone	Clopidogrel
		Erythromycin	Antiretroviral protease inhibitors	Irbesartan
		Gemfibrozil and other fibrates	Cholestyramine	Rifabutin
		Telithromycin	Cimetidine	Rifapentine
			Colchicine	Zafirlukast
			Daptomycin
			Delavirdine
			Diclofenac
			Digoxin
			Efavirenz
			Ethanol
			Fluconazole
			Fluoxetine
			Fluvoxamine
			Glyburide
			Imatinib
			Niacin, niacinamide
			Nilotinib
			Omeprazole
			Phenytoin
			Ranitidine
			Rifampin
			Sulfinpyrazone
			Sulfonamides
			Voriconazole
			Warfarin
Pitavastatin	Cyclosporine	Atazanavir	Colchicine	Warfarin
	Red yeast rice	Darunavir	Niacin, niacinamide
		Erythromycin	Raltegravir
		Fosamprenavir
		Gemfibrozil and other fibrates
		Lopinavir; Ritonavir
		Rifampin
		Ritonavir
		Saquinavir Simeprivir
		Telithromycin
		Tipranavir

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Table 13 suggests dose limits for various drugs based on FDA package labeling. As new drugs are approved, the FDA does not always update the statin package inserts, even if a suspected dose limit may occur. It is often best to consult proprietary drug databases that reference these limits for the most up to date information.

Table 13Dose limits of various statins with respect to various interacting medications

²¹

US Food and Drug Administration. FDA Drug Safety Communication: FDA announces safety changes in labeling for some cholesterol-lowering drugs. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm293101.htm. Accessed February 8, 2014.

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Merck & Co. Inc. ZOCOR (simvastatin) tablets prescribing information. Available at: http://www.merck.com/product/usa/pi_circulars/z/zocor/zocor_pi.pdf. Accessed February 8, 2014.

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Parke-Davis-Pfizer. Lipitor (atorvastatin calcium) tablets for oral administration prescribing information. Available at: http://labeling.pfizer.com/ShowLabeling.aspx?id=587. Accessed February 8, 2014.

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AstraZeneca. Crestor (rosuvastatin calcium) tablets prescribing information. Available at: http://www1.astrazeneca-us.com/pi/crestor.pdf. Accessed February 8, 2014.

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Kowa Pharmaceuticals America I. LIVALO (pitavastatin) tablet 1 mg, 2 mg, and 4 mg package insert - product labeling. Available at: http://www.kowapharma.com/documents/LIVALO_PI_CURRENT.pdf. Accessed February 8, 2014.

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²⁶

Merck & Co. Inc. MEVACOR (lovastatin) tablets. Available at: http://www.merck.com/product/usa/pi_circulars/m/mevacor/mevacor_pi.pdf. Accessed February 9, 2014.

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Novartis Pharmaceuticals Corporation. Lescol (fluvastatin sodium) capsules/Lescol XL (fluvastatin sodium) extended-release tablets for oral use prescribing information. Available at: https://www.pharma.us.novartis.com/product/pi/pdf/Lescol.pdf. Accessed February 9, 2014.

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Company B-MS. PRAVACHOL (pravastatin sodium) tablets. Available at: http://packageinserts.bms.com/pi/pi_pravachol.pdf. Accessed February 9, 2014.

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Elsevier/Gold Standard Inc. Clinical Pharmacology [database online]. Available at: http://www.goldstandard.com/product/gold-standard-drug-database. Accessed November, 2013.

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Statin/interactant	Simva	Lova	Atorva	Rosuva	Prava	Fluva	Pitava
Ketoconazole	Avoid	Avoid
Posaconazole	Avoid	Avoid
Boceprevir	Avoid	Avoid	No mention
Simeprevir	Caution	Caution	Caution	Caution	Caution		Caution
Nefazodone	Avoid	Avoid
Cyclosporine	Avoid	Avoid	Avoid	5 mg/d	20 mg/d	20 mg/d
Gemfibrozil	Avoid	Avoid	Avoid	10 mg/d	Avoid	Caution	Avoid
Danazol	Avoid	Avoid
Tipranavir			Avoid
Telaprevir			Avoid
HIV protease inhibitor	Avoid	Avoid	20 mg*	10 mg*
Verapamil diltiazem	10-mg limit
Clarithromycin			20-mg limit	40-mg limit
Itraconazole			20-mg limit
Fosamprenavir ± ritonavir			20-mg limit
Nelfinavir			40-mg limit
Fluconazole						20 mg/d
Amiodarone	20-mg limit
Amlodipine
Ranolazine
Grapefruit juice	Avoid large quantity	Avoid large quantity
Niacin	Limit to 1 g/d	Limit to 1 g/d	Limit to 1 g/d	Limit to 1 g/d	Limit to 1 g/d
Erythromycin							1 mg/d
Rifampin							2 mg/d

atorva, atorvastatin; fluva, fluvastatin; lova, lovastatin; pitava, pitavastatin; prava, pravastatin; rosuva, rosuvastatin; simva, simvastatin.

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Common interacting drugs and over-the-counter medications, supplements, and foods

When the potential for simvastatin/lovastatin interactions is examined, many common drugs can cause clinical issues. Atorvastatin, being less dependent on CYP3A4 for elimination, is not as susceptible to drug interactions by the CYP3A4 pathway. For example, the same CYP3A4 inhibitor will produce a much larger increase in simvastatin AUC compared with the increase in atorvastatin AUC.

³⁰

Neuvonen P.J.
Kantola T.
Kivisto K.T.

Simvastatin but not pravastatin is very susceptible to interaction with the CYP3A4 inhibitor itraconazole.

^,

³¹

Kantola T.
Kivisto K.T.
Neuvonen P.J.

Effect of itraconazole on the pharmacokinetics of atorvastatin.

Atorvastatin, although less likely to cause CYP3A4 interactions, has potentially similar drug interactions. If potentially interacting medications must be used, it is wise to choose a statin metabolized through a different enzyme system. Rosuvastatin, pravastatin, pitavastatin, and fluvastatin are associated with fewer potentially severe interactions than those noted previously. Although there are fewer interacting medications involving severe and major drug interactions for the non-CYP3A4 metabolized statins (Table 13), commonalities still exist.

•

Fibrate: Recently, the American College of Cardiology/American Heart Association guidance on cholesterol management made a strong statement against using gemfibrozil with ANY statin.

³²

Stone N.J.
Robinson J.
Lichtenstein A.H.
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 [e-pub ahead of print].

Gemfibrozil is known to reduce the glucuronidation and elimination of statins. If a fibrate is to be used in combination with a statin, then fenofibrate is generally the fibrate of choice. Each statin has its own limitations with respect to gemfibrozil, and some formularies still allow open gemfibrozil utilization. Understanding the potential for pharmacokinetic interactions between fibrates and statins may be a good guide for practitioners if gemfibrozil is still to be considered (Table 14).

Table 14Statin/fibrate combination therapy: pharmacokinetic interactions

²²

Merck & Co. Inc. ZOCOR (simvastatin) tablets prescribing information. Available at: http://www.merck.com/product/usa/pi_circulars/z/zocor/zocor_pi.pdf. Accessed February 8, 2014.

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Parke-Davis-Pfizer. Lipitor (atorvastatin calcium) tablets for oral administration prescribing information. Available at: http://labeling.pfizer.com/ShowLabeling.aspx?id=587. Accessed February 8, 2014.

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AstraZeneca. Crestor (rosuvastatin calcium) tablets prescribing information. Available at: http://www1.astrazeneca-us.com/pi/crestor.pdf. Accessed February 8, 2014.

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Kowa Pharmaceuticals America I. LIVALO (pitavastatin) tablet 1 mg, 2 mg, and 4 mg package insert - product labeling. Available at: http://www.kowapharma.com/documents/LIVALO_PI_CURRENT.pdf. Accessed February 8, 2014.

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Merck & Co. Inc. MEVACOR (lovastatin) tablets. Available at: http://www.merck.com/product/usa/pi_circulars/m/mevacor/mevacor_pi.pdf. Accessed February 9, 2014.

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Novartis Pharmaceuticals Corporation. Lescol (fluvastatin sodium) capsules/Lescol XL (fluvastatin sodium) extended-release tablets for oral use prescribing information. Available at: https://www.pharma.us.novartis.com/product/pi/pdf/Lescol.pdf. Accessed February 9, 2014.

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Company B-MS. PRAVACHOL (pravastatin sodium) tablets. Available at: http://packageinserts.bms.com/pi/pi_pravachol.pdf. Accessed February 9, 2014.

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Statin	Gemfibrozil	Fenofibrate
Atorvastatin	↑ in C_max (expected)	No change
Simvastatin	↑ in C_max by 2-fold	No change
Pravastatin	↑ in C_max by 2-fold	No change
Rosuvastatin	↑ in C_max by 2-fold	No change
Fluvastatin	No change	No change
Lovastatin	↑ in C_max by 2.8-fold	No change
Pitavastatin	↑ in C_max by 41%	Unknown

C_max, maximum concentration.

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•
Over-the-counter supplements, medications, and foods: The Natural Medicines Comprehensive Database is the most frequently used resource to investigate over-the-counter supplements/medicines and their effects on statin medications. For ease, the most common interactions can be divided into major (do not use) and moderate (clinical outcome not severe). Concomitant ingestion of alcohol and statins, and other medications metabolized through the liver, can result in DDIs. Although no specific quantity recommendations are available, moderate amounts of alcohol (2 standard drinks in a 24-hour period) offer less concern for pharmacokinetic and pharmacodynamic effects than larger amounts. Grapefruit juice contains bergamottin, a natural furanocoumarin, which can inhibit CYP3A4 and OAT. This inhibitory effect can last for up to 24 hours. Either grapefruit juice should be avoided with statins or the quantity consumed should be kept to less than 60 mL. Separating administration of grapefruit juice and statins by 4 hours may limit the interaction.

Like grapefruit, sweet orange (citrus sinensis) juice may inhibit OATP. Tangerines are related to the sweet orange and may also have an interaction. Separation of the fruit or juice from statin administration by 4 hours may be advisable. St John's wort induces CYP3A4. There are noted major interactions between statins and St. John's wort, and this combination should be avoided. St. John's wort mediates P-gp. It will decrease metabolism of simvastatin and possibly atorvastatin, but not likely pravastatin, fluvastatin, or rosuvastatin. Red yeast rice is a popular nonprescription treatment for hyperlipidemia. Red yeast rice has varying amounts of monacolin K (similar to lovastatin). Products are not standardized and no red yeast rice product should be given to a patient taking a prescription statin.

Special populations with potentially increased risk for DDIs

•
Elderly: More elderly patients are being treated with statins. As muscle mass decreases with aging, there may be an increased risk of myopathy in elderly patients. In addition, polypharmacy is pervasive in the elderly and increases the chance of a DDI. As age increases, metabolizing enzymes may be less functional as well, increasing the likelihood of increased AUC and more DDIs. It is critical that elderly patients on polypharmacy be regularly reevaluated for the risk of DDIs and drug lists be rigorously kept up to date.
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Atorvastatin and rosuvastatin may mildly increase serum concentrations of ethinyl estradiol and norgestrel, which may be used as part of postmenopausal therapies.
•
Chinese/Japanese: Pharmacokinetic data have shown that Asians taking statins have higher serum levels of these drugs than Caucasians. The FDA has issued caution when treating Chinese patients with simvastatin doses exceeding 20 mg/day administered with niacin.
³⁷
US Food and Drug Administration. FDA Drug Safety Communication: ongoing safety review of high-dose Zocor (simvastatin) and increased risk of muscle injury. Available at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm204882.htm. Accessed February 9, 2014.
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This followed the observation in the Heart Protection Study 2 of increased risk of myopathy in those taking simvastatin 40 mg administered with niacin-containing products (>1 g/day). Rosuvastatin labeling notes higher blood levels in patients of Asian heritage (Filipino, Chinese, Japanese, Korean, Vietnamese, or Asian-Indian). A 5-mg rosuvastatin initiation dose may be appropriate for this group. Pitavastatin was recently approved based on research in Japanese patients. Differences in Japanese and Caucasian pharmacokinetics with pitavastatin are still under investigation. No specific recommendations appear in the pitavastatin labeling. Atorvastatin and fluvastatin offer no current special population warning for Asian groups. Labeling in Asian countries differs from the higher doses used in the United States. Initiation of therapy with low doses of all statins in Asian and Asian-American patients remains the most prudent approach.
³⁷
US Food and Drug Administration. FDA Drug Safety Communication: ongoing safety review of high-dose Zocor (simvastatin) and increased risk of muscle injury. Available at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm204882.htm. Accessed February 9, 2014.
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•

HIV: Recently, the FDA issued warnings about protease inhibitors and non-nucleoside reverse transcriptase inhibitors used in highly active antiretroviral therapy and statins. These are usually specific to the drugs metabolized by CYP3A4. Current National Institutes of Health guidelines recommend fluvastatin, pitavastatin, and pravastatin (except for pravastatin with darunavir/ritonavir) over lovastatin and simvastatin. Atorvastatin and rosuvastatin may be used with caution. In combination with non-nucleoside reverse transcriptase inhibitors, some statins may have increased efficacy, whereas others may have decreased efficacy (Table 15).

³⁸

US Food and Drug Administration. FDA Drug Safety Communication: interaction between certain HIV or hepatitis C drugs and cholesterol-lowering statin drugs can increase the risk of muscle injury. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm293877.htm. Accessed February 9, 2014.

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Table 15Drug interactions between highly active antiretroviral therapy regimens and other drugs

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US Department of Health and Human Services. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents. Available at: http://aidsinfo.nih.gov/guidelines#. Accessed November 2013.

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Drug	PI	Effect on PI or concomitant drug concentrations	Recommendation
Atorvastatin	ATV/r	↑ atorvastatin possible	Titrate atorvastatin dose carefully and use lowest dose necessary
	ATV	↑ atorvastatin possible
	DRV/r	DRV/r + atorvastatin 10 mg similar to atorvastatin 40 mg administered alone;	Titrate atorvastatin dose carefully and use the lowest necessary dose. Do not exceed 20 mg atorvastatin daily
	FPV/r
	FPV	FPV ± RTV ↑ atorvastatin AUC 130% to 153%;
	SQV/r	SQV/r ↑ atorvastatin AUC 79%
	LPV/r	LPV/r ↑ atorvastatin AUC 488%	Use with caution and use the lowest atorvastatin dose necessary
	TPV/r	↑ atorvastatin AUC 836%	DO NOT COADMINISTER
Lovastatin	All PIs	Significant ↑ lovastatin expected	Contraindicated. Do not coadminister
Pitavastatin	All PIs	ATV ↑ pitavastatin AUC 31% and C_max ↑ 60%	No dose adjustment necessary
		ATV: no significant effect
		LPV/r ↓ pitavastatin AUC 20%
		LPV: no significant effect
Pravastatin	DRV/r	Pravastatin AUC ↑ 81%	Use lowest possible starting dose of pravastatin with careful monitoring
	LPV/r	Pravastatin AUC ↑ 33%	No dose adjustment necessary
	SQV/r	pravastatin AUC ↓ 47% to 50%	No dose adjustment necessary
Rosuvastatin	ATV/r LPV/r	ATV/r ↑ rosuvastatin AUC 3-fold and	Titrate rosuvastatin dose carefully and use the lowest necessary dose. Do not exceed 10 mg rosuvastatin daily
		C_max ↑ 7-fold
		LPV/r ↑ rosuvastatin AUC 108% and C_max ↑ 366%
	DRV/r	rosuvastatin AUC ↑ 48% and C_max ↑ 139%	Titrate rosuvastatin dose carefully and use the lowest necessary dose while monitoring for toxicities
	FPV ± RTV	No significant effect on rosuvastatin	No dosage adjustment necessary
	SQV/r	No data available	Titrate rosuvastatin dose carefully and use the lowest necessary dose while monitoring for toxicities
	TPV/r	rosuvastatin AUC ↑ 26% and C_max ↑ 123%	No dose adjustment necessary
Simvastatin	All PIs	Significant ↑ simvastatin level;	CONTRAINDICATED, do not coadminister
		SQV/r 400 mg/400 mg BID
		↑ simvastatin AUC 3059%
Concomitant drug class/name	NNRTI	Effect on NNRTI or concomitant drug concentrations	Recommendations
Fluvastatin	ETR	↑ fluvastatin possible	↑ fluvastatin possible
Lovastatin Simvastatin	EFV	Simvastatin AUC ↓ 68%	Adjust simvastatin dose according to lipid responses, not to exceed the maximum recommended dose. If EFV used with RTV-boosted PI, simvastatin and lovastatin should be avoided
	ETR NVP	↓ Lovastatin possible	Adjust lovastatin or simvastatin dose according to lipid responses, not to exceed the maximum recommended dose. If ETR or NVP used with RTV-boosted PI, simvastatin and lovastatin should be avoided
	ETR NVP	↓ Simvastatin possible
Pitavastatin	EFV, ETR NVP RPV	No data	No recommendation
Pravastatin, rosuvastatin	EFV	Pravastatin AUC ↓ 44% rosuvastatin: no data	Adjust statin dose according to lipid responses, not to exceed the maximum recommended dose.
	ETR	No significant effect expected	No dosage adjustment necessary

ABC, abacavir; APV, amprenavir; ATV/r, ritonavir-boosted atazanavir; AUC, area under the curve; DRV/r, ritonavir- boosted darunavir; ETR, etravirine; EFV, efavirenz; FPV/r, ritonavir-boosted fosamprenavir; LPV/r, ritonavir-boosted lopinavir; NFV, nelfinavir; NNRTI, non-nucleoside reverse transcriptase inhibitor; NVP, nevirapine; PI, protease inhibitor; RAL, raltegravir; RPV, rilpivirine; RTV, ritonavir; SQV/r, ritonavir-boosted saquinavir; T20, enfuvirtide; TDF, tenofovir disoproxil fumarate; TPV/r, ritonavir-boosted tipranavir.

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•
Hepatitis C and nonalcoholic fatty liver disease (NAFLD): Hepatitis C is a leading cause of liver failure and transplantation. Data have already demonstrated the increased cardiovascular risk of patients with hepatitis C. In this condition, statins may not only help prevent cardiovascular disease but may also block the protein synthesis necessary for hepatitis C replication. One study suggested that simvastatin administered as monotherapy has the strongest antiviral activity, lovastatin and fluvastatin have a moderate antiviral effect, and pravastatin has no antiviral activity. With respect to worrisome DDIs with antiviral drugs as part of new therapy for hepatitis C, boceprevir, classified as a nonstructural protein 3/4A protease inhibitor should not be given with simvastatin or lovastatin. Boceprevir is a potent inhibitor of CYP3A4. An atorvastatin/boceprevir interaction has not been noted. Conversely, telaprevir, also an NS3/4A protease inhibitor, is contraindicated with simvastatin, lovastatin, and atorvastatin. Non-CYP3A4 statins should be used when patients are subjected to treatment with these newer agents. Statins do not appear to affect the concentrations of sofosbuvir.

Simeprevir on the other hand inhibits OATP1B1. Rosuvastatin dose should be initiated at 5 mg once daily and not exceed 10 mg daily. Atorvastatin should be started at the lowest dose and not exceed 40 mg daily. Simvastatin doses should be kept lowest as needed and no data is noted with pitavastatin, lovastatin, or lovastatin and doses should also be kept as low as possible.

²⁸

Company B-MS. PRAVACHOL (pravastatin sodium) tablets. Available at: http://packageinserts.bms.com/pi/pi_pravachol.pdf. Accessed February 9, 2014.

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Using statins in patients with NAFLD has long been a subject of controversy. NAFLD includes disorders ranging from simple hepatic steatosis to nonalcoholic steatohepatitis and cirrhosis. Covered in another article in this publication, it should be noted that changes in alanine aminotransferase often occur independently of statin therapy. Most recently, the FDA has obviated the need for routine liver function testing because minor elevations have led to physicians inappropriately discontinuing statin therapy, putting patients at increased risk of cardiovascular disease. The currently labeled recommendations for statins should be used with caution in patients with liver disease who consume substantial amounts of alcohol.

⁴⁰

Weltman M.D.
Farrell G.C.
Hall P.
Ingelman-Sundberg M.
Liddle C.

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The liver and lovastatin.

•
Pediatrics: Young adults are rarely on interacting medications that would create a clinical dilemma. Some epileptics may be prone to DDIs. As noted previously, some statins may mildly increase serum concentrations of ethinyl estradiol and norgestrel (found in oral contraceptives). The clinical significance is unknown. There is little information with regard to safety issues in children who are on statins for familial hypercholesterolemia (FH). Little is known about safety issues in this population and more data and endpoints are needed. The 4 statins currently approved for use in children with FH by the FDA, all with labeling consistent with the recent American Heart Association pediatric statement in terms of age and when treatment should be started, are lovastatin, simvastatin, pravastatin, and atorvastatin.
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FH: FH patients present similar challenges with respect to DDIs as other patients on multiple drug regimens. The potential for statin and ezetimibe interactions is minor at best. Statins and bile acid resins have few interactions other than those attributed to the resin class. The potential for myopathic side effects with the higher doses of statins exists, but is similar to the general population.

•

Chronic kidney disease (CKD)/end-stage renal disease: Statins have been shown to reduce cardiovascular events in those with CKD (stages I-IV), but not for those with end-stage renal disease and receiving hemodialysis. Recommendations for statin dosing in CKD patients is shown in Table 16.

⁴⁶

National Kidney Foundation Inc. NFK KDOQI Guidelines. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease. Available at: http://www.kidney.org/professionals/kdoqi/guideline_diabetes/guide4.htm. Accessed February 9, 2014.

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Table 16Safety of statins in chronic kidney disease

•
Atorvastatin and fluvastatin are minimally excreted by the kidneys
•
Dosing modifications for other statins (NKF recommendations):
⁴⁶
National Kidney Foundation Inc. NFK KDOQI Guidelines. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease. Available at: http://www.kidney.org/professionals/kdoqi/guideline_diabetes/guide4.htm. Accessed February 9, 2014.
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- ➢
  Simvastatin and lovastatin: 50% dose reduction if GFR < 30 mg/mL
- ➢
  Pravastatin: no dose adjustment (package insert: start with 10 mg once daily in renal impairment)
- ➢
  Rosuvastatin: not discussed in NKF guidelines (prescribing information: start at 5 mg and do not exceed 10 mg in severe chronic renal insufficiency [creatinine clearance <30 mL/min] in patients not on dialysis
- ➢
  Pitavastatin: not discussed in NKF guidelines (package insert: patients with moderate and severe renal impairment [GFR 30-59 mL/min/1.73 m² and 15-29 mL/min/1.73 m² not receiving hemodialysis, respectively] as well as end-stage renal disease receiving hemodialysis: initial, 1 mg orally daily and maximum 2 mg daily)

GFR, glomerular filtration rate; NKF, National Kidney Foundation.

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Recommendations for classification of statin drug interactions and labeling

Thus, a recommendation of the National Lipid Association Statin Safety Taskforce would be to unify the FDA-mandated labeling to allow practitioners to readily compare statin drug interactions. Additionally, it is recommended that a system to express the likelihood for a statin DDI be created as an adjunctive tool for practitioners.

Conclusions

Statin absorption, distribution, metabolism, and excretion are complex and vary from statin to statin. The transporters and enzymes involved in these processes are now better understood and serve to explain the mechanisms of statin interactions with a variety of drugs that alter what is otherwise an excellent safety profile. As new drugs enter the US market, understanding these mechanisms allows the clinician to predict the impact new drugs may have on statin disposition, given the effect of a new drug on known transporters and metabolizing enzyme systems.

We propose that clinicians become familiar with the statins they prefer and refer to an individual statin table to identify drugs they often coprescribe that may interact with a particular statin. Once identified, the potential interacting agent can be classified as having mild, moderate, or severe interacting potential. One option would be to avoid the interaction by changing to a different statin or to a therapeutic equivalent to the interacting agent. This is the preferred option for severe interactions. If a combination cannot be avoided, the effected statin should be dosed according to its identified dosing limit. This is the preferred option for interactions with moderate intensity. Patients who receive drug combinations with mild potential for interaction may be carefully monitored for symptoms of statin toxicity because of a low potential for serious side effects.

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Article info

Publication history

Accepted: February 28, 2014

Received: February 27, 2014

Footnotes

Disclosures: Dr Bottorff and Dr Toth disclose that they have relationships with industry that might pose a potential conflict of interest. Dr Bottorff has received honoraria for serving as a speaker and/or consultant to AstraZeneca, Bristol-Myers Squibb, Sanofi, Boehringer Ingelheim, and Pfizer. Dr Toth is on the speaker bureaus for AbbVie, Amarin, AstraZeneca, Genzyme, Kowa, and Merck, and has served as a consultant to Amgen, Atherotech, Genzyme, Kowa, LipoScience, and Merck. Dr Kellick has no financial relationships with commercial entities producing health care goods or services.

Identification

DOI: https://doi.org/10.1016/j.jacl.2014.02.010

Copyright

Published by Elsevier Inc.

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A clinician's guide to statin drug-drug interactions

Highlights

Abstract

Keywords

Individual variation in enzyme induction, inhibition, and patient response

Focus on drugs that have the highest potential to interact with statins

Suggested nomenclature for classifying statin drug interaction

Understanding package labeling

Common interacting drugs and over-the-counter medications, supplements, and foods

Special populations with potentially increased risk for DDIs

Recommendations for classification of statin drug interactions and labeling

Conclusions

References

Article info

Publication history

Footnotes

Identification

Copyright

ScienceDirect

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