Interaction Potential between Clarithromycin and Individual Statins - a Systematic Review

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Abstract

The high prevalence of statin and clarithromycin utilization creates potential for overlapping use. The objectives of this MiniReview were to investigate the evidence base for drug-drug interactions between clarithromycin and currently marketed statins and to present management strategies for these drug combinations. We conducted a systematic literature review following PRISMA guidelines with English language studies retrieved from PubMed and EMBASE (from inception through March 2019). We included 29 articles (16 case reports, 5 observational, 5 clinical pharmacokinetic and 3 in vitro studies). Based on mechanistic/clinical studies involving clarithromycin or the related macrolide erythromycin (both strong inhibitors of CYP3A4 and of hepatic statin uptake transporters OATP1B1 and OATP1B3), clarithromycin is expected to substantially increase systemic exposure to simvastatin and lovastatin (>5-fold increase in area under the plasma concentration time curve (AUC)), moderately increase AUCs of atorvastatin and pitavastatin (2-4-fold AUC increase) and slightly increase pravastatin exposure (≈ 2-fold AUC increase) while having little effect on fluvastatin or rosuvastatin. The 16 cases of statin-clarithromycin adverse drug reactions (rhabdomyolysis (n = 14) or less severe clinical myopathy) involved a CYP3A4-metabolized statin (simvastatin, lovastatin or atorvastatin). In line, a cohort study found concurrent use of clarithromycin and CYP3A4-metabolized statins to be associated with a doubled risk of hospitalisation with rhabdomyolysis or other statin-related adverse events as compared with azithromycin-statin co-administration. If clarithromycin is necessary, we recommend 1) avoiding co-administration with simvastatin, lovastatin or atorvastatin; 2) withholding or dose-reducing pitavastatin; 3) continuing pravastatin therapy with caution, limiting pravastatin dose to 40 mg daily and 4) continuing fluvastatin or rosuvastatin with caution.

Original languageEnglish
JournalBasic & Clinical Pharmacology & Toxicology Online
ISSN1742-7843
DOIs
Publication statusE-pub ahead of print - 19. Oct 2019

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Hydroxymethylglutaryl-CoA Reductase Inhibitors
Clarithromycin
Pravastatin
Lovastatin
Area Under Curve
Simvastatin
Cytochrome P-450 CYP3A
Rhabdomyolysis
Azithromycin
Muscular Diseases
Drug Combinations
Drug-Related Side Effects and Adverse Reactions
Drug Interactions
PubMed
Cohort Studies
Language
Pharmacokinetics
Guidelines
Liver

Keywords

  • MiniReview
  • case report
  • clarithromycin
  • drug-drug interaction
  • statins

Cite this

@article{6385be38a7574078bc5831db89ed2a5c,
title = "Interaction Potential between Clarithromycin and Individual Statins - a Systematic Review",
abstract = "The high prevalence of statin and clarithromycin utilization creates potential for overlapping use. The objectives of this MiniReview were to investigate the evidence base for drug-drug interactions between clarithromycin and currently marketed statins and to present management strategies for these drug combinations. We conducted a systematic literature review following PRISMA guidelines with English language studies retrieved from PubMed and EMBASE (from inception through March 2019). We included 29 articles (16 case reports, 5 observational, 5 clinical pharmacokinetic and 3 in vitro studies). Based on mechanistic/clinical studies involving clarithromycin or the related macrolide erythromycin (both strong inhibitors of CYP3A4 and of hepatic statin uptake transporters OATP1B1 and OATP1B3), clarithromycin is expected to substantially increase systemic exposure to simvastatin and lovastatin (>5-fold increase in area under the plasma concentration time curve (AUC)), moderately increase AUCs of atorvastatin and pitavastatin (2-4-fold AUC increase) and slightly increase pravastatin exposure (≈ 2-fold AUC increase) while having little effect on fluvastatin or rosuvastatin. The 16 cases of statin-clarithromycin adverse drug reactions (rhabdomyolysis (n = 14) or less severe clinical myopathy) involved a CYP3A4-metabolized statin (simvastatin, lovastatin or atorvastatin). In line, a cohort study found concurrent use of clarithromycin and CYP3A4-metabolized statins to be associated with a doubled risk of hospitalisation with rhabdomyolysis or other statin-related adverse events as compared with azithromycin-statin co-administration. If clarithromycin is necessary, we recommend 1) avoiding co-administration with simvastatin, lovastatin or atorvastatin; 2) withholding or dose-reducing pitavastatin; 3) continuing pravastatin therapy with caution, limiting pravastatin dose to 40 mg daily and 4) continuing fluvastatin or rosuvastatin with caution.",
keywords = "MiniReview, case report, clarithromycin, drug-drug interaction, statins",
author = "{Marie Hougaard Christensen}, Mette and {Bruun Haastrup}, Maija and Thomas {\O}hlenschlaeger and Peter Esbech and {Arnspang Pedersen}, Sidsel and {Bach Dunvald}, Ann-Cathrine and {Bjerregaard Stage}, Tore and {Pilsgaard Henriksen}, Daniel and {James Thestrup Pedersen}, Andreas",
note = "{\circledC} 2019 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).",
year = "2019",
month = "10",
day = "19",
doi = "10.1111/bcpt.13343",
language = "English",
journal = "Basic & Clinical Pharmacology & Toxicology",
issn = "1742-7835",
publisher = "Wiley-Blackwell",

}

TY - JOUR

T1 - Interaction Potential between Clarithromycin and Individual Statins - a Systematic Review

AU - Marie Hougaard Christensen, Mette

AU - Bruun Haastrup, Maija

AU - Øhlenschlaeger, Thomas

AU - Esbech, Peter

AU - Arnspang Pedersen, Sidsel

AU - Bach Dunvald, Ann-Cathrine

AU - Bjerregaard Stage, Tore

AU - Pilsgaard Henriksen, Daniel

AU - James Thestrup Pedersen, Andreas

N1 - © 2019 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

PY - 2019/10/19

Y1 - 2019/10/19

N2 - The high prevalence of statin and clarithromycin utilization creates potential for overlapping use. The objectives of this MiniReview were to investigate the evidence base for drug-drug interactions between clarithromycin and currently marketed statins and to present management strategies for these drug combinations. We conducted a systematic literature review following PRISMA guidelines with English language studies retrieved from PubMed and EMBASE (from inception through March 2019). We included 29 articles (16 case reports, 5 observational, 5 clinical pharmacokinetic and 3 in vitro studies). Based on mechanistic/clinical studies involving clarithromycin or the related macrolide erythromycin (both strong inhibitors of CYP3A4 and of hepatic statin uptake transporters OATP1B1 and OATP1B3), clarithromycin is expected to substantially increase systemic exposure to simvastatin and lovastatin (>5-fold increase in area under the plasma concentration time curve (AUC)), moderately increase AUCs of atorvastatin and pitavastatin (2-4-fold AUC increase) and slightly increase pravastatin exposure (≈ 2-fold AUC increase) while having little effect on fluvastatin or rosuvastatin. The 16 cases of statin-clarithromycin adverse drug reactions (rhabdomyolysis (n = 14) or less severe clinical myopathy) involved a CYP3A4-metabolized statin (simvastatin, lovastatin or atorvastatin). In line, a cohort study found concurrent use of clarithromycin and CYP3A4-metabolized statins to be associated with a doubled risk of hospitalisation with rhabdomyolysis or other statin-related adverse events as compared with azithromycin-statin co-administration. If clarithromycin is necessary, we recommend 1) avoiding co-administration with simvastatin, lovastatin or atorvastatin; 2) withholding or dose-reducing pitavastatin; 3) continuing pravastatin therapy with caution, limiting pravastatin dose to 40 mg daily and 4) continuing fluvastatin or rosuvastatin with caution.

AB - The high prevalence of statin and clarithromycin utilization creates potential for overlapping use. The objectives of this MiniReview were to investigate the evidence base for drug-drug interactions between clarithromycin and currently marketed statins and to present management strategies for these drug combinations. We conducted a systematic literature review following PRISMA guidelines with English language studies retrieved from PubMed and EMBASE (from inception through March 2019). We included 29 articles (16 case reports, 5 observational, 5 clinical pharmacokinetic and 3 in vitro studies). Based on mechanistic/clinical studies involving clarithromycin or the related macrolide erythromycin (both strong inhibitors of CYP3A4 and of hepatic statin uptake transporters OATP1B1 and OATP1B3), clarithromycin is expected to substantially increase systemic exposure to simvastatin and lovastatin (>5-fold increase in area under the plasma concentration time curve (AUC)), moderately increase AUCs of atorvastatin and pitavastatin (2-4-fold AUC increase) and slightly increase pravastatin exposure (≈ 2-fold AUC increase) while having little effect on fluvastatin or rosuvastatin. The 16 cases of statin-clarithromycin adverse drug reactions (rhabdomyolysis (n = 14) or less severe clinical myopathy) involved a CYP3A4-metabolized statin (simvastatin, lovastatin or atorvastatin). In line, a cohort study found concurrent use of clarithromycin and CYP3A4-metabolized statins to be associated with a doubled risk of hospitalisation with rhabdomyolysis or other statin-related adverse events as compared with azithromycin-statin co-administration. If clarithromycin is necessary, we recommend 1) avoiding co-administration with simvastatin, lovastatin or atorvastatin; 2) withholding or dose-reducing pitavastatin; 3) continuing pravastatin therapy with caution, limiting pravastatin dose to 40 mg daily and 4) continuing fluvastatin or rosuvastatin with caution.

KW - MiniReview

KW - case report

KW - clarithromycin

KW - drug-drug interaction

KW - statins

U2 - 10.1111/bcpt.13343

DO - 10.1111/bcpt.13343

M3 - Review

JO - Basic & Clinical Pharmacology & Toxicology

JF - Basic & Clinical Pharmacology & Toxicology

SN - 1742-7835

ER -