Risk management of simvastatin or atorvastatin interactions with CYP3A4 inhibitors.
BACKGROUND
Co-administration of cytochrome P450 (CYP) 3A4 inhibitors with simvastatin or atorvastatin is associated with increased risk of developing myopathy or rhabdomyolysis.


OBJECTIVE
To detect co-prescriptions of CYP3A4 inhibitors with simvastatin or atorvastatin in community pharmacies and assess the risk-preventive actions taken by the prescribing physicians who were alerted about the co-prescription by the pharmacist.


METHODS
This naturalistic study was performed during four separate 6-week periods in 2004 and 2005, and involved 110 Norwegian community pharmacists (25-30 in each period). Co-prescription of the selected CYP3A4 inhibitors diltiazem, verapamil, clarithromycin, erythromycin, fluconazole, itraconazole and ketoconazole with either simvastatin or atorvastatin was detected with the aid of a simple computer programme. In instances where the pharmacist alerted the prescribing physician about the co-prescription, information on possible strategies to minimize the risk associated with the interaction was also provided. Odds ratios (ORs) were estimated to describe the associations between prescription variables and frequencies of physician information and prescription change, respectively.


RESULTS
In total, 245 co-prescriptions of CYP3A4 inhibitors with simvastatin (134 events) or atorvastatin (111) were detected. Diltiazem (86 events), verapamil (72), erythromycin (48) and clarithromycin (29) were the most commonly co-prescribed CYP3A4 inhibitors. Physicians were informed in 168 out of 245 cases (68.6%). The prescription was subsequently changed in 100 out of 168 cases (59.5%). Another 50 physicians (29.8%) responded that they would consult the patient and monitor potential adverse effects, while only 18 physicians (10.7%) replied that they had already managed the interactions or considered the issue as irrelevant. The adjusted OR for the informing of the physician was 1.89 (95% CI 0.98, 3.63) in patients receiving a daily HMG-CoA reductase inhibitor ('statin') dose of >or=40 mg compared with patients receiving a statin dose of <40 mg/day. The adjusted OR for prescription change was 4.98 (95% CI 2.36, 10.52) if co-prescription was detected prior to the initiation of concurrent use compared with if it was detected during concurrent use.


CONCLUSIONS
Nine out of ten physicians changed prescriptions or monitored potential adverse effects when informed by community pharmacists about the risk associated with co-prescription of CYP3A4 inhibitors with simvastatin or atorvastatin. This suggests that an important risk factor for myotoxicity due to these statins could be minimized through interdisciplinary co-operation.
School of Pharmacy, University of Oslo, Oslo, Norway. emolden@farmasi.uio.no
Espen
E
Molden
Eva
E
Skovlund
Pia
P
Braathen
D000328:Adult; D000368:Aged; D000069059:Atorvastatin; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000009:adverse effects*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects*; D008875:Middle Aged; D009135:Muscular Diseases / Q000139:chemically induced; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects*; D012308:Risk Management; D019821:Simvastatin / Q000008:administration & dosage / Q000009:adverse effects
D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D000069059:Atorvastatin; D019821:Simvastatin; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human