1.116.clinically Significant Statin Drug Interactions

PL Detail-Document #320303
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additional insight related to the Recommendations published in
PHARMACISTS LETTER / PRESCRIBERS LETTER
March 2016
Clinically Significant Statin Drug Interactions

Rhabdomyolysis is probably the most serious statin side effect. Risk is increased when statins are co-administered with medications that inhibit their
elimination. Due to differences among statins in elimination pathways, not all statins pose the same risk of drug interactions. Lovastatin, simvastatin, and to
a lesser extent atorvastatin, have the most drug interactions. Use the chart below to tailor medication choices to minimize risk. The chart suggests
interaction management, and rationale. If the statin must be held due to an interaction, some experts suggest restarting the statin three days or so after the
interacting drug has been discontinued. Information is from product labeling unless otherwise indicated. Canadian product monograph information is
included if it differs significantly (e.g., more conservative) from U.S. labeling. Information in chart may differ from product labeling, and is not
comprehensive.
*Caution may include monitoring for muscle symptoms, careful statin titration, conservative statin dosing (e.g., use of lowest necessary dose), or consideration
of statin dose reduction.
**Atorvastatin levels increase by 2.5-fold with 750 mL to 1.2 L/day of grapefruit juice.
Statin Suggested Management of Interactions, and Rationale
ATORVASTATIN (Lipitor, generics) Posaconazole (A): contraindicated; myopathy risk
Atorvastatin is metabolized by CYP3A4, Cyclosporine (A,2 C6), gemfibrozil (A, C6), grapefruit juice, excessive amounts** (Canada, A),
but less than lovastatin and simvastatin.1 telithromycin (A), tipranavir (A): avoid (Canada: may use atorvastatin 10 mg daily with tipranavir if use
OATP1B1 and P-glycoprotein unavoidable); myopathy risk
substrate.2,6,7 Inhibits P-glycoprotein.1,6 Clarithromycin (A), darunavir/ritonavir (A), fosamprenavir (A), itraconazole (A), saquinavir/ritonavir (A):
limit atorvastatin dose to 20 mg daily (Canada: start with 10 mg daily with darunavir); myopathy risk
Possible Mechanisms for Interactions: Boceprevir (A): limit atorvastatin dose to 40 mg daily (Canada: 20 mg); myopathy risk
A = impaired statin elimination (e.g., via Nelfinavir (A), simeprevir (A): limit atorvastatin dose to 40 mg daily; myopathy risk
CYP450 and/or drug transporter [e.g., P-
Lomitapide (D): limit lomitapide dose to 30 mg daily; hepatotoxicity
glycoprotein] inhibition)
B = impaired statin absorption Amiodarone (A), atazanavir (A), bezafibrate (C), cobicistat (A), colchicine (A,3 C), daclatasvir (A),
C = increased risk of myopathy due to danazol (A1), diltiazem6 (A), dronedarone (A), eltrombopag (A), erythromycin (A), fenofibrate (C),
pharmacodynamic factors fluconazole (A), ketoconazole6 (A), indinavir (A), isavuconazonium (A), lopinavir/ritonavir (A), niacin 1 g
D = statin interferes with elimination of or more/day (C), raltegravir (C), ritonavir (A), verapamil6 (A), voriconazole (A): use caution (see
interacting drug (e.g., via CYP450 and/or footnote*); myopathy risk
drug transporter [e.g., P-glycoprotein] Nefazodone (A): atorvastatin dose reduction recommended; myopathy risk
inhibition) Digoxin (D): monitor; digoxin level may increase by about 20%
E = enhanced statin elimination (e.g., via Rifampin (E): give at same time as atorvastatin to avoid reduced atorvastatin levels
CYP450 and/or drug transporter [e.g., P- Bile acid sequestrants (B): take statin at least one hour before or at least four hours after bile acid
glycoprotein] induction) sequestrant (Canada: separate by at least two hours); potential for reduced statin absorption
Note about macrolides: although there are case reports of rhabdomyolysis associated with
statin/azithromycin coadministration, azithromycin may be the safest choice when a macrolide is indicated.4,5
More. . .
Copyright 2016 by Therapeutic Research Center
3120 W. March Lane, Stockton, CA 95219 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249
www.PharmacistsLetter.com ~ www.PrescribersLetter.com ~ www.PharmacyTechniciansLetter.com
(PL Detail-Document #320303: Page 2 of 6)

FLUVASTATIN (Lescol, Lescol XL, Cyclosporine (A,C6), fluconazole (A): limit fluvastatin dose to 20 mg twice daily; myopathy risk
generics) Fluvastatin is metabolized by Gemfibrozil (A, C6): avoid; myopathy risk
CYP2C9.6 OATP1B1 substrate.7 Inhibits Glyburide (D6): monitor blood glucose; fluvastatin may increase risks of hypoglycemia
CYP2C9.6 Amiodarone (A1), bezafibrate (A,C), cobicistat (A), colchicine (C), daclatasvir (A), eltrombopag (A),
Possible Mechanisms for Interactions: fenofibrate (C), niacin 1 g or more/day (C), raltegravir (C): use caution (see footnote*); myopathy
A = impaired statin elimination (e.g., via risk
CYP450 and/or drug transporter [e.g., P- Phenytoin (D6): monitor phenytoin levels with changes to fluvastatin therapy; fluvastatin can
glycoprotein] inhibition) increase phenytoin levels
B = impaired statin absorption
Warfarin (D6): monitor INR with changes in fluvastatin therapy; fluvastatin can increase warfarin
C = increased risk of myopathy due to
pharmacodynamic factors levels
D = statin interferes with elimination of Bile acid sequestrants (B): take statin at least one hour before or four hours after bile acid
interacting drug (e.g., via CYP450 and/or sequestrant; potential for reduced statin absorption
drug transporter [e.g., P-glycoprotein]
inhibition)
LOVASTATIN (Mevacor, generics) Strong CYP3A4 inhibitors [e.g., boceprevir (A), clarithromycin (A), cobicistat (A), erythromycin (A),
Lovastatin is a sensitive CYP3A4 HIV protease inhibitors (A), Holkira Pak (A), itraconazole (A), ketoconazole (A), nefazodone (A),
substrate, meaning its levels may be posaconazole (A), Technivie (A), telithromycin (A), Viekira Pak (A), voriconazole (A)]:
increased five-fold or higher by CYP3A4 contraindicated; myopathy risk
inhibitors.7 OATP1B1 and P- Cyclosporine (A,2 C6), gemfibrozil (A, C6), grapefruit juice (A): avoid (Canada: cyclosporine
glycoprotein substrate.2,6 contraindicated); myopathy risk
Possible Mechanisms for Interactions:
Danazol (A1), diltiazem (A), dronedarone (A), verapamil (A): limit lovastatin dose to 20 mg daily
A = impaired statin elimination (e.g., via Bezafibrate (C), fenofibrate (C), fluconazole (A), niacin 1 g or more/day: use caution (see
CYP450 and/or drug transporter [e.g., P- footnote*)(Canada: limit lovastatin dose to 20 mg daily with fibrates or niacin); myopathy risk
glycoprotein] inhibition) Amiodarone (A), ticagrelor (A): limit lovastatin dose to 40 mg daily
B = impaired statin absorption Colchicine (A,3 C), daclatasvir (A), eltrombopag (A), lomitapide (A), raltegravir (C), ranolazine (A),
C = increased risk of myopathy due to simeprevir (A): use caution (see footnote*); myopathy risk
pharmacodynamic factors
Warfarin (U): monitor INR with changes in lovastatin therapy; lovastatin has been reported to
E = enhanced statin elimination (e.g., via
CYP450 and/or drug transporter [e.g., P- increase INR in patients taking warfarin
glycoprotein] induction) Bile acid sequestrants (B): take statin at least one hour before or four hours after bile acid sequestrant
U = unclear (Canada: separate by at least two hours); potential for reduced statin absorption
statin/azithromycin coadministration, azithromycin may be the safest choice when a macrolide is
indicated.4,5
More. . .

PITAVASTATIN (Livalo [U.S.]) Cyclosporine (A, C6): contraindicated; myopathy risk
Pitavastatin is not significantly Gemfibrozil (A, C6): avoid; myopathy risk
eliminated by CYP450 enzymes. Erythromycin (A7): limit pitavastatin dose to 1 mg daily; myopathy risk
Pitavastatin is mainly eliminated via Rifampin (A7): limit pitavastatin dose to 2 mg daily; myopathy risk
glucuronide conjugation, and to a minor Cobicistat (A), daclatasvir (A), eltrombopag (A), fenofibrate (C), niacin 1 g or more/day (C),
extent by CYP2C9, and to a lesser extent raltegravir (C), simeprevir (A): use caution (see footnote*); myopathy risk
by CYP2C8. OATP1B1 and P- Warfarin (U): monitor INR when pitavastatin is started; potential for increased INR
glycoprotein substrate.6 Bile acid sequestrants (B): take statin at least one hour before or four hours after bile acid sequestrant;
Possible Mechanisms for Interactions: potential for reduced statin absorption
A = impaired statin elimination (e.g., via
glycoprotein] inhibition)
C = increased risk of myopathy due to
U = unclear
PRAVASTATIN (Pravachol, generics) Gemfibrozil (A, C6): avoid; myopathy risk

Pravastatin is not significantly eliminated Cyclosporine (A, C6): limit pravastatin dose to 20 mg daily; myopathy risk
by CYP450 enzymes.6 CYP3A4 is only Clarithromycin (A6), Holkira Pak (A), Technivie (A), Viekira Pak (A): limit pravastatin dose to 40
a minor elimination pathway for mg daily; myopathy risk
pravastatin.6 OATP1B1 and P- Bezafibrate (C), cobicistat (A), colchicine (A,3 C), daclatasvir (A), darunavir/ritonavir (A),
glycoprotein substrate.6 dronedarone (Canada, A), eltrombopag (A), erythromycin (A). fenofibrate (C), niacin 1 g or more/day
(C), raltegravir (C), simeprevir (A), tipranavir (Canada, A): use caution (see footnote*); myopathy
A = impaired statin elimination (e.g., via risk
CYP450 and/or drug transporter [e.g., P- Bile acid sequestrants (B): take statin at least one hour before or four hours after bile acid sequestrant;
glycoprotein] inhibition) potential for reduced statin absorption
C = increased risk of myopathy due to Note about macrolides: although there are case reports of rhabdomyolysis associated with
pharmacodynamic factors statin/azithromycin coadministration, azithromycin may be the safest choice when a macrolide is
indicated.4,5
More. . .

ROSUVASTATIN (Crestor, generics ) Cyclosporine (A, C): limit rosuvastatin dose to 5 mg daily (Canada: contraindicated); myopathy
Rosuvastatin is not significantly risk
eliminated by CYP450 enzymes.6 Only Holkira Pak (A): avoid, or limit rosuvastatin dose to 5 mg daily if use unavoidable; myopathy risk
about 10% of rosuvastatin is Gemfibrozil (A, C6): avoid, but if used, start with rosuvastatin 5 mg daily, and do not exceed 10 mg
metabolized, mainly by CYP2C9, and to daily (Canada: 20 mg); myopathy risk
a lesser extent by CYP2C19.6 OATP1B1 Eltrombopag: consider 50% statin dose reduction
and BCRP substrate. Indinavir (A): use caution (see footnote*)(Canada: not recommended); myopathy risk
Ledipasvir/sofosbuvir (A): not recommended; myopathy risk
Atazanavir (A), simeprevir (A), Viekira Pak (A): limit rosuvastatin dose to 10 mg daily (initiate
CYP450 and/or drug transporter [e.g., P- with rosuvastatin 5 mg with simeprevir); myopathy risk
glycoprotein] inhibition) Lopinavir/ritonavir (A): limit rosuvastatin dose to 10 mg daily (Canada: 20 mg); myopathy risk
B = impaired statin absorption Clopidogrel (A), dronedarone (A), itraconazole (A): limit rosuvastatin dose to 20 mg daily
C = increased risk of myopathy due to (Canada); myopathy risk
pharmacodynamic factors Darunavir/ritonavir (A), tipranavir/ritonavir (A): use caution (see footnote*)(Canada: limit
U = unclear rosuvastatin dose to 20 mg daily); myopathy risk
Bezafibrate (C), cobicistat (A), colchicine (A, C), daclatasvir (A), fenofibrate (C),
fosamprenavir/ritonavir (A), niacin 1 g or more/day (C), raltegravir (C), ritonavir (A): use caution
(see footnote*)(Canada: rosuvastatin 40 mg contraindicated with fibrate or niacin); myopathy risk
Warfarin (U): monitor INR when rosuvastatin is started; potential for increased INR
Bile acid sequestrants (B): take statin at least one hour before or four hours after bile acid
sequestrant; potential for reduced statin absorption
SIMVASTATIN (Zocor, generics) Strong CYP3A4 inhibitors [e.g., boceprevir (A), clarithromycin (A), cobicistat (A), cyclosporine (A,2
Simvastatin is a sensitive CYP3A4 C6), danazol (A1), erythromycin (A), gemfibrozil (A, C6), HIV protease inhibitors (A), Holkira Pak
substrate, meaning its levels may be (A), itraconazole (A), ketoconazole (A), nefazodone (A), posaconazole (A), Technivie (A),
increased five-fold or higher by CYP3A4 telithromycin (A), Viekira Pak (A), voriconazole (A)]: contraindicated; myopathy risk
inhibitors.7 OATP1B1 and P- Grapefruit juice (A): avoid; myopathy risk
glycoprotein substrate.2,6 Bezafibrate (C), fenofibrate (C), fluconazole (A): use caution (see footnote*)(Canada: limit
simvastatin dose to 10 mg daily with bezafibrate); myopathy risk
Possible Mechanisms for Interactions: Diltiazem (A), dronedarone (A), verapamil (A): limit simvastatin dose to 10 mg daily
Amiodarone (A), amlodipine (A), ranolazine (A): limit simvastatin dose to 20 mg daily
glycoprotein] inhibition) Lomitapide (A): do not exceed simvastatin 20 mg daily, unless patient has been taking simvastatin
B = impaired statin absorption 80 mg daily for 12 months or more without evidence of myotoxicity, in which case limit simvastatin
Continued dose to 40 mg daily (Canada: cut simvastatin dose by 50% when starting lomitapide); myopathy risk
More. . .
Simvastatin, continued Ticagrelor (A): limit simvastatin dose to 40 mg daily; myopathy risk
Digoxin (D): monitor; digoxin level may increase slightly
C = increased risk of myopathy due to Colchicine (A,3 C), eltrombopag (A), raltegravir (C), simeprevir (A): use caution (see footnote*);
myopathy risk
D = statin interferes with elimination of
interacting drug (e.g., via CYP450 and/or Niacin 1 g or more/day (C); use caution (see footnote*). Chinese patients should not receive
drug transporter [e.g., P-glycoprotein] simvastatin 80 mg daily with niacin at these doses (>1 g/day). (Canada: do not combine in Chinese
inhibition) patients; monitor creatine kinase and potassium periodically.); myopathy risk
U = unclear Warfarin (U): monitor INR with changes in simvastatin therapy; simvastatin has been reported to
increase INR in patients taking warfarin
Bile acid sequestrants (B): take statin at least one hour before or four hours after bile acid sequestrant
(Canada: separate by at least two hours); potential for reduced statin absorption
statin/azithromycin coadministration, azithromycin may be the safest choice when a macrolide is
indicated.4,5
Product labeling used in preparation of this PL Detail-Document: Act Lovastatin (July 2015), Aptivus (March 2015, March 2014 [Canada]),
Brilinta (September 2015), cholestyramine (Par, July 2013), Colcrys (March 2012), Colestid (May 2014), Cordarone (March 2015), Cresemba (June
2015), Crestor (November 2015, April 2015 [Canada]), Crixivan (March 2015, October 2015 [Canada]), Daklinza (July 2015), Danazol (Teva,
January 2012), Diflucan (November 2014), Harvoni (November 2015), Holkira Pak (October 2015), Insentress (February 2015), Juxtapid (May
2015), Ketek (December 2015), Lescol/Lescol XL (October 2012), Lipitor (March 2015, May 2015 [Canada]), Livalo (November 2012), Mevacor
(February 2012), Multaq (March 2014, October 2014 [Canada]), nefazodone (Teva, September 2015), Niaspan (April 2015, October 2015 [Canada]),
Nizoral (October 2013), Norvir (November 2015), Noxafil (November 2015), Olysio (October 2015), Pravachol (August 2013, November 2015
[Canada]), Prezista (May 2015, September 2014 [Canada]), Promacta (June 2015), Ranexa (April 2010), Reyataz (September 2015), Technivie
(October 2015), Tybost (December 2015), Vfend (March 2015), Viekira Pak (October 2015), Zocor (March 2015, December 2014 [Canada])
Users of this PL Detail-Document are cautioned to use their own professional judgment and consult any other necessary or appropriate sources prior to making
clinical judgments based on the content of this document. Our editors have researched the information with input from experts, government agencies, and national
organizations. Information and internet links in this article were current as of the date of publication.
More. . .
Project Leader in preparation of this PL Detail- 5. Westphal JF. Macrolide-induced clinically significant
Document: Melanie Cupp, Pharm.D., BCPS drug interactions with cytochrome P-450 (CYP) 3A4:
an update focused on clarithromycin, azithromycin
and dirithromycin. Br J Clin Pharmacol 2000;50:285-
References 95.
1. Williams D, Feely J. Pharmacokinetic- 6. Neuvonen PJ, Niemi M, Backman JT. Drug
pharmacodynamic drug interactions with HMG-CoA interactions with lipid-lowering drugs: mechanisms
reductase inhibitors. Clin Pharmacokinet and clinical relevance. Clin Pharmacol Ther
2002;41:343-70. 2006;80:565-81.
2. Holtzman CW, Wiggins BS, Spinler SA. Role of P- 7. FDA. Drug development and drug interactions:
glycoprotein in statin drug interactions. table of substrates, inhibitors and inducers. October
Pharmacotherapy 2006;26:1601-7. 27, 2014.
3. Tufan A, Dede DS, Cavus S, et al. Rhabdomyolysis http://www.fda.gov/Drugs/DevelopmentApprovalProc
in a patient treated with colchicine and atorvastatin. ess/DevelopmentResources/DrugInteractionsLabelin
Ann Pharmacother 2006;40:1466-9. g/ucm093664.htm#classInhibit. (Accessed February
4. Strandell J, Bate A, Hagg S, Edwards IR. 4, 2016).
Rhabdomyolysis a result of azithromycin and statins:
an unrecognized interaction. Br J Clin Pharmacol
2009;68:427-34.
Cite this document as follows: PL Detail-Document, Clinically Significant Statin Drug Interactions. Pharmacists
Letter/Prescribers Letter. March 2016.
Evidence and Recommendations You Can Trust

3120 West March Lane, Stockton, CA 95219 ~ TEL (209) 472-2240 ~ FAX (209) 472-2249
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1.116.clinically Significant Statin Drug Interactions

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PL Detail-Document #320303

This PL Detail-Document gives subscribers

Clinically Significant Statin Drug Interactions

Statin Suggested Management of Interactions, and Rationale

Statin Suggested Management of Interactions, and Rationale

PRAVASTATIN (Pravachol, generics) Gemfibrozil (A, C6): avoid; myopathy risk

Statin Suggested Management of Interactions, and Rationale

Evidence and Recommendations You Can Trust

Subscribers to the Letter can get PL Detail-Documents, like this one,

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