Prevalence of potentially severe drug-drug interactions in ambulatory patients with dyslipidaemia receiving HMG-CoA reductase inhibitor therapy.
BACKGROUND
Drug-drug interactions (DDIs) are a well known risk factor for adverse drug reactions. HMG-CoA reductase inhibitors ('statins') are a cornerstone in the treatment of dyslipidaemia and patients with dyslipidaemia are concomitantly treated with a variety of additional drugs. Since DDIs are associated with adverse reactions, we performed a cross-sectional study to assess the prevalence of potentially critical drug-drug and drug-statin interactions in an outpatient adult population with dyslipidaemia.


METHODS
Data from patients with dyslipidaemia treated with a statin were collected from 242 practitioners from different parts of Switzerland. The medication list was screened for potentially harmful DDIs with statins or other drugs using an interactive electronic drug interaction program.


RESULTS
We included 2742 ambulatory statin-treated patients (mean age +/- SD 65.1 +/- 11.1 years; 61.6% males) with (mean +/- SD) 3.2 +/- 1.6 diagnoses and 4.9 +/- 2.4 drugs prescribed. Of those, 190 patients (6.9%) had a total of 198 potentially harmful drug-statin interactions. Interacting drugs were fibrates or nicotinic acid (9.5% of patients with drug-statin interactions), cytochrome P450 (CYP) 3A4 inhibitors (70.5%), digoxin (22.6%) or ciclosporin (cyclosporine) [1.6%]. The proportion of patients with a potential drug-statin interaction was 12.1% for simvastatin, 10.0% for atorvastatin, 3.8% for fluvastatin and 0.3% for pravastatin. Additionally, the program identified 393 potentially critical non-statin DDIs in 288 patients.


CONCLUSIONS
CYP3A4 inhibitors are the most frequent cause of potential drug interactions with statins. As the risk for developing rhabdomyolysis is increased in patients with drug-statin interactions, clinicians should be aware of the most frequently observed drug-statin interactions and how these interactions can be avoided.
Rätz Bravo
Alexandra E
AE
Division of Clinical Pharmacology & Toxicology, University Hospital, Basel, Switzerland.
Tchambaz
Lydia
L
Krähenbühl-Melcher
Anita
A
Hess
Lorenzo
L
Schlienger
Raymond G
RG
Krähenbühl
Stephan
S
D000368:Aged; D000553:Ambulatory Care; D001189:Aryl Hydrocarbon Hydroxylases / Q000008:administration & dosage / Q000009:adverse effects / Q000037:antagonists & inhibitors; D000069059:Atorvastatin; D015897:Comorbidity; D003430:Cross-Sectional Studies; D016572:Cyclosporine / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use; D051544:Cytochrome P-450 CYP3A; D004077:Digoxin / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use; D004347:Drug Interactions; D016903:Drug Monitoring / Q000379:methods; D004359:Drug Therapy, Combination; D005229:Fatty Acids, Monounsaturated / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use; D005260:Female; D000077340:Fluvastatin; D006538:Heptanoic Acids / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D006949:Hyperlipidemias / Q000175:diagnosis / Q000188:drug therapy* / Q000453:epidemiology; D007211:Indoles / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use; D008297:Male; D009525:Niacin / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use; D010089:Oxidoreductases, N-Demethylating / Q000008:administration & dosage / Q000009:adverse effects / Q000037:antagonists & inhibitors; D010820:Physicians / Q000145:classification / Q000706:statistics & numerical data; D017035:Pravastatin / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use; D015995:Prevalence; D011358:Product Surveillance, Postmarketing / Q000379:methods; D011758:Pyrroles / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use; D019821:Simvastatin / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use; D013997:Time Factors
D005229:Fatty Acids, Monounsaturated; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D011758:Pyrroles; D009525:Niacin; D000077340:Fluvastatin; D004077:Digoxin; D016572:Cyclosporine; D000069059:Atorvastatin; D019821:Simvastatin; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D017035:Pravastatin
Br J Clin Pharmacol. 1993 Sep;36(3):263-5
9114914
JAMA. 2003 Apr 2;289(13):1652-8
12672733
Circulation. 2003 Aug 26;108(8):921-4
12925453
J Biol Chem. 1999 Dec 24;274(52):37161-8
10601278
Arch Intern Med. 1984 Dec;144(12):2371-2
6391404
Clin Pharmacol Ther. 2003 Jun;73(6):538-44
12811363
J Am Acad Dermatol. 1979 Oct;1(4):365-74
159913
J Pharmacol Exp Ther. 2001 Jun;297(3):861-7
11356905
J Pharm Pharmacol. 2002 Mar;54(3):419-23
11902809
Drug Metab Dispos. 2003 Jan;31(1):53-9
12485953
Am J Med. 2002 Dec 15;113(9):746-50
12517365
Br J Clin Pharmacol. 2001 May;51(5):461-70
11422004
Clin Pharmacol Ther. 1998 Jul;64(1):123-8
9695727
Clin Pharmacokinet. 1997 Dec;33(6):454-71
9435993
South Med J. 2001 Oct;94(10):1023-6
11702815
Am J Med. 2001 Apr 15;110(6):438-41
11331054
Ann Pharmacother. 2003 Feb;37(2):178-81
12549942
BMJ. 2003 Jul 19;327(7407):147-9
12869459
Clin Pharmacokinet. 2002;41(5):343-70
12036392
Lancet. 1984 Mar 24;1(8378):679
6142365
Conn Med. 1992 Feb;56(2):107
1559329
Clin Ther. 2002 Dec;24(12):2126-36
12581550
Clin Pharmacokinet. 2003;42(13):1141-60
14531725
BMJ. 1996 Jan 20;312(7024):173-4
8563541
Ir J Med Sci. 2000 Jul-Sep;169(3):176-9
11272871
Transplant Proc. 1993 Aug;25(4):2732-4
8356729
J Pharmacol Exp Ther. 2003 Feb;304(2):610-6
12538813
Am J Hosp Pharm. 1971 Apr;28(4):247-53
5094043
Drug Saf. 2003;26(6):421-38
12688833
Lancet. 2000 Nov 11;356(9242):1667-71
11089838
N Engl J Med. 1999 Sep 2;341(10):709-17
10471456
Arthritis Rheum. 1986 Jan;29(1):82-7
3947418
Am J Med. 2001 Oct 1;111(5):390-400
11583643
Ann Pharmacother. 2002 Feb;36(2):288-95
11847951
CMAJ. 2001 Sep 4;165(5):632
11563216
Mayo Clin Proc. 1997 Sep;72(9):835-47
9294531
Eur J Clin Pharmacol. 2001 Aug;57(5):357-64
11599653
Drug Saf. 1992 Mar-Apr;7(2):159-61
1605901
Drugs Aging. 1997 Mar;10(3):209-18
9108894
Dan Med Bull. 1998 Apr;45(2):210-3
9587704
Best Pract Res Clin Gastroenterol. 2001 Dec;15(6):897-918
11866484
Ann Emerg Med. 2001 Dec;38(6):666-71
11719747
Acad Emerg Med. 2000 Nov;7(11):1321-9
11073486
Br J Clin Pharmacol. 2002 Mar;53(3):326-31
11874397
Congest Heart Fail. 2003 May-Jun;9(3):163-9
12826775
Ann Intern Med. 2003 Jun 3;138(11):917-24
12779302
JAMA. 1997 Jan 22-29;277(4):301-6
9002492
Lancet. 1984 Feb 25;1(8374):463
6142201
Am J Cardiol. 2003 Aug 1;92(3):285-8
12888133
Eur J Clin Pharmacol. 2003 Mar;58(11):773-8
12634985
Br J Pharmacol. 2001 Mar;132(6):1183-92
11250868
Chest. 1995 Aug;108(2):586
7634908
Drug Saf. 2000 Sep;23(3):197-213
11005703
Acad Emerg Med. 2002 Nov;9(11):1162-7
12414465
Heart Fail Monit. 2000;1(1):8-13
12634876
Am J Med. 2000 Mar;108(4):351-2
11014734
J Am Geriatr Soc. 1988 Dec;36(12):1092-8
3192887