The clinical significance of statins-macrolides interaction: comprehensive review of in vivo studies, case reports, and population studies

Figures & data

Table 1 Summary of selected pharmacokinetic data of statins^{1,8,10,15,56,87}

	Simvastatin	Lovastatin	Atorvastatin	Pravastatin	Rosuvastatin	Fluvastatin	Pitavastatin
Pro-drug	Yes	Yes	No	No	No	No	No
Bioavailability (%)	<5	<5	12–14	17–18	20	24	51
Half-life (hours)	2–5	1.3–5	13–16	1–3	20	0.5–3	11
Protein binding (%)	>95	>95	80–99	43–55	88	>90	96
Hepatic extraction (%)	83	≥70	70	45	63	>68	>60
Renal excretion (%)	13	10	<5	20	10	5	15
CYP450 metabolism and isoenzyme	CYP3A4	CYP3A4	CYP3A4	Clinically not relevant	CYP2C9 minimally	CYP2C9	CYP2C9 minimally

Table 2 Summary of studies of the administration of different statins with different macrolides in healthy volunteers

Statin	Statin		Macrolide	Results	Reference
	Dose	Duration
Simvastatin	40 mg	Daily from day 1–7 and day 10–18	Clarithromycin 500 mg BID from day 10–18 (9 days)	Simvastatin: 10 fold ↑AUC Simvastatin acid: 12 fold ↑AUC	^Citation48
	40 mg	Single dose	Erythromycin 500 mg TID (4 doses)	Simvastatin: 6.2 fold ↑AUC Simvastatin acid: 3.9 fold ↑AUC	^Citation49
	NA	NA	Telithromycin (dose not mentioned)	Simvastatin acid: 8.9 fold ↑AUC	^Citation50
	20 mg	Daily for 7 days	Clarithromycin 250 mg BID for 7 days	Simvastatin: 3.9 fold ↑AUC	^Citation51
Atorvastatin	10 mg	Two single doses on day 7 and day 21	Erythromycin 500 mg QID for 25 days	1.32 fold ↑AUC	^Citation48
	10 mg	Single dose	Erythromycin 500 mg QID for 7 days	1.33 fold ↑AUC	^Citation49
	10 mg	Daily for 8 days	Clarithromycin 500 mg BID for 3 days (days 6–8)	1.82 fold ↑AUC	^Citation54
	10 mg	Daily for 8 days	Azithromycin 500 mg OD for 3 days (days 6–8)	No significant change to AUC	^Citation54
	80 mg	Daily from day 1–7 and day 10–18	Clarithromycin 500 mg BID from day 10–18 (9 days)	4.4 fold ↑AUC	^Citation48
	80 mg	Daily for 8 days	Clarithromycin 500 mg BID for 9 days	4.4 fold ↑AUC	^Citation49
Pravastatin	40 mg	Daily from day 1–7 and day 10–18	Clarithromycin 500 mg BID from day 10–18 (9 days)	2 fold ↑AUC	^Citation48
Rosuvastatin	80 mg	Single dose given on day 4	Erythromycin 500 mg QID for 7 days	Slight ↓AUC (20%)	^Citation55
Pitavastatin	4 mg	Single dose given on day 4	Erythromycin 500 mg QID for 6-days	2.8 fold ↑AUC	^Citation56

Abbreviations: OD, once daily; BID, twice daily; TID, three times daily; QID, four times daily; AUC, area under the concentration-time curve; NA, not available.

Table 3 Summary of case reports from literature implicating macrolides-statins interaction

Statin	Dose and duration	Macrolide dose and duration	Type of toxicity	Onset of toxicity	Other conditions	Other medications	Gender and age	Reference
Lovastatin	20 mg OD for 5 years	Erythromycin 200 mg TID started as a prokinetic agent	Myositis	After starting the AB, CK started to rise and patient started to complain of muscle ache	DM type 2, chronic renal failure, hypertension, IHD, CHF	Furosemide, aspirin, trimetazidine, amlodipine, prazocin, bisoprolol, ferrous fumarate, vitamin B complex, vitamin C, folic acid, mixtard insulin, calcium carbonate	73 year old woman	^Citation61
	20 mg BID for 7 months	Erythromycin for 10 days (dose not specified)	Rhabdomyolysis	5 days after completion of AB course	DM, CAD, CHF, chronic renal insufficiency	Amoxy-clavulinate, furosemide, sucrulfate, ranitidine, allopurinol, insulin, isosorbide dinitrate, enalapril, digoxin	68 year old woman	^Citation64
	40 mg OD for 5 years	Clarithromycin 500 mg BID for 10 days	Rhabdomyolysis	Muscle pain and weakness started 2 days after completing AB course	Polymyalgia rheumatica, DM type 2, asthma, gout, peptic ulcer disease, hypertension, and CAD	Famotidine, HCTZ/triamterene, probenecid, colchicine, prednisone, aspirin, diltiazem, clonidine, insulin, and albuterol inhaler	76 year old white woman	^Citation62
	40 mg OD for past 5 years	Azithromycin 250 mg OD for 5 days	Rhabdomyolysis	Muscle aches started 1 day after completing AB course	Hypertension, hypothyroidism, DM type 2, gout, and renal insufficiency, recurrent sinus infection	Cholestyramine powder, diltiazem, doxazocin, glyburide, thyroid grains, allopurinol, naproxen, prednisone, loratidine, and beclomethasone nasal spray	51 year old white man	^Citation62
Simvastatin	20 mg OD	Clarithromycin 500 mg BID for 14 days	Rhabdomyolysis	During the second week of the AB course	DM, gout, foot ulcer	Telmisartan, HCTZ, glibenclamide, allopurinol, bisoprolol, and aspirin	77 year old woman	^Citation66
	40 mg OD	Clarithromycin (dose not specified) Prescribed as a replacement for rifampicin 5 weeks prior to admission	Rhabdomyolysis	Started AB 5 weeks before admission (duration not specified)	Hypertension, hypercholesterolemia, chronic kidney disease stage 3a, gastro-oesophageal reflux, thrombocytopenia	Not specified	68 year old man	^Citation59
	80 mg OD	Erythromycin 400 mg TID for 10 days	Rhabdomyolysis	Muscle pain and weakness started several days after starting the AB	CHD, hypercholesterolemia, COPD, hypertension, osteoporosis, previous aortic aneurysm repair, Ramsay Hunt syndrome	Clopidogrel, lansoprazole, tiotropium bromide, budesonide/efemetrol, risedronate monthly	85 year old man	^Citation60
	↑to 80 mg OD 6 weeks before the interaction	Clarithromycin 500 mg BID for days before admission	Rhabdomyolysis	4 days after starting the AB	Familial combined hyperlipidemia, binge alcoholic	Not specified	49 year old man	^Citation63
	80 mg OD	Azithromycin 500 mg OD for the first days, followed by 250 mg OD for 4 days	Rhabdomyolysis	2–3 days after starting the AB	Chronic kidney disease, severe gout, polymyalgia rheumatica, DM type 2, hypertension, hyperlipidemia	Allopurinol 100 mg OD, prednisone 5 mg daily, labetalol, bumetanide, amlodipine, glargine insulin	73 year old man	^Citation65
	80 mg OD plus ezetimibe 10 mg OD	Clarithromycin 250 mg BD for 3 months (last month increased to 500 mg BID)	Rhabdomyolysis	1 week before admission	Severe COPD, acute coronary syndrome, iron-deficiency anemia, hyperparathyroidism	Aspirin, seretide 250 inhaler, Ventolin inhaler, tiotropium, propylthiouracil, metoprolol, ramipril, nitrolingual spray, recurrent chest infection	83 year old woman	^Citation67
	80 mg OD	Clarithromycin 500 mg BID for 21 days (sinusitis)	Rhabdomyolysis	Muscle symptoms started 4–5 days before admission, AB started 3 weeks before admission	DM, severe renal impairment, protein C deficiency, recurrent DVT, hypertension, dyslipidemia, prolactinoma, benign prostatic hypertrophy, and gout	Ranitidine, Heparin Sc, testosterone patch, pseudoephedrine, colchicine, allopurinol, bromocriptine, terazocin, tolbutamide, beclomethasone puffer, epoetin alfa, regular insulin, NPH insulin, etidronate, folic acid, acetaminophen/codeine	64 year old African-American man	^Citation68
	Stable on 80 mg dose OD	Erythromycin IV for 2 days followed by 10- day course of 500 mg QID	Rhabdomyolysis	15 days after completion of the AB	Rheumatoid arthritis, dermatitis, hypertension, CHD, AF, aortic stenosis, heart failure (after MI)	Metoprolol, amlodipine, valsartan/HCTZ, aspirin, methotrexate 2.5 mg once weekly, furosemide	83 year old man	^Citation69
	↑to 80 mg OD 8 months ago	Clarithromycin for 1 week (dose not specified)	Rhabdomyolysis	3–4 days after completion of the AB	CAD, AF, two cerebral infarctions with aphasia and dysarthria	Warfarin, aspirin, isosorbide mononitrate, atenolol, and NTG PRN	78 year old man	^Citation69

Abbreviations: OD, once daily; BID, twice daily; TID, three times daily; QID, four times daily; AB, antibiotic; DM, diabetes mellitus; CAD, coronary artery disease; IHD, ischemic heart disease; MI, myocardial infarction; CHF, congestive heart failure; AF, atrial fibrillation; COPD, chronic obstructive pulmonary disease; DVT, deep vein thrombosis; HCTZ, hydrochlorothiazide; NTG, nitroglycerine.

Table 4 Summary of population studies related to macrolides-statins interaction

Records	Search criteria	Results	Reference
Administrative managed care claims database (US). From July 2000 to December 2004	To evaluate the incidence of hospitalizations for myopathy, renal medical events, and hepatic medical events in patients on statins and other lipid-lowering agents. Also, when coadministered with CYP3A4 inhibitors	The concomitant use of statins with a CYP3A4 inhibitor caused a 6 fold increase in the rate of developing myopathy including rhabdomyolysis	^Citation72
World Health Organization Adverse Drug Reaction database, VigiBase, July 2008, (about 4 million case reports)	Rhabdomyolysis reported with azithromycin and statins. Also investigated reports of rhabdomyolysis with other macrolides	Number of rhabdomyolysis cases with macrolides: azithromycin (53), clarithromycin (118), erythromycin (36), roxithromycin (7), and telithromycin (8). Simvastatin followed by atorvastatin are the most common interacting drugs. Fluvastatin was never reported to cause rhabdomyolysis with azithromycin	^Citation77
FDA’s Adverse Event Reporting System. Drug utilization data were obtained from IMS HEALTH and the National Ambulatory Medical Care Survey (NAMCS). From the date of drug market launch until July 2001	Rhabdomyolysis reports associated with simvastatin and pravastatin with and without concomitant CYP3A4 inhibitors	Adverse event reporting rate (AER) for pravastatin with or without concomitant CYP3A4 inhibitor was 2.4 cases and 3.1 cases per 10 million prescriptions respectively. For simvastatin, the AER with or without CYP3A4 inhibitor was 38.4 cases and 6 cases respectively	^Citation78
The Health Improvement Network (UK) from 1990–2008	To compare the relative hazard of muscle toxicity associated with the drug interaction between statins and concomitant CYP3A4-inhibitor	No significantly increased hazard associated with statins (CYP3A4 substrate compared with non-CYP3A4 substrate) with a concomitant CYP3A4-inhibitor, adjusted for the hazard of each statin type without a concomitant CYP3A4 inhibitor. Interaction ratio =1.22, which means no significant difference in the relative hazards	^Citation79
Four linked health care databases in Ontario, Canada. From 2003–2010	To compare the absolute and RR of hospitalization due to rhabdomyolysis with concomitant use of statins (simvastatin, atorvastatin, and lovastatin) and clarithromycin/erythromycin. The reference group was patients using statin and azithromycin. Only older adults over 65 years were included	Co-prescription of clarithromycin or erythromycin with statin increased the absolute risk of rhabdomyolysis by 0.02% compared to co-prescription of azithromycin and statin. RR =2.17	^Citation80
Five large administrative databases housed at the Institute for Clinical Evaluative Sciences (ICES), Canada. From 2002–2013	To evaluate the risk of adverse events (rhabdomyolysis, kidney injury or hyperkalemia and all-cause mortality) associated with co-prescribing non-CYP3A4 substrate statins (pravastatin, rosuvastatin, and fluvastatin) and clarithromycin in older adults (66 years or older). The control group had co-prescription of same statins with azithromycin	In older adults, there was a modest increase in the risk of adverse events when non-CYP3A4 substrate statins were administered with clarithromycin compared to co-prescription with azithromycin. The absolute risk reduction for rhabdomyolysis was 0.02% in favor of azithromycin	^Citation81
Health claims data, Regional Sickness Fund Burgenland, Austria. From July 2009 until June 2012	To evaluate the risk of hospitalization or death within 30 days (composite end point) after concomitant use of clarithromycin and CYP3A4 substrate statins	The concomitant use of clarithromycin with CYP3A4 substrate statins did not increase the rate of hospitalization or death within 30 days from starting the combination	^Citation82

Abbreviation: FDA, US Food and Drug Administration.

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