RiteMED Atorvastatin Drug Interactions

The risk of myopathy during treatment with other drugs in this class is increased with concurrent administration of cyclosporine, fibric acid derivatives, erythromycin, azole antifungals, or niacin. This increase in risk may also occur when combining these drugs with atorvastatin.
Phenazone (antipyrine) is a non-specific model for evaluation of drug metabolism by the hepatic microsomal enzyme system. Administration of multiple doses of atorvastatin with phenazone showed little or no detectable effect on the pharmacokinetics of phenazone in healthy subjects (no change in the clearance of phenazone but the formation clearance of 4-hydroxyphenazone increased by 20% and that of norphenazone by 8%).
More specific in vitro studies using human hepatic microsomes and cells expressing human cytochrome P450 isozymes show that atorvastatin, like other HMG-CoA reductase inhibitors, is metabolized by cytochrome P450 3A4 indicating the possibility of an interaction with drugs also metabolized by this isozyme. When combining atorvastatin with other drugs which are the substrate of this isozyme (e.g. immunomodulators, many antiarrhythmic agents, some calcium channel antagonists and some benzodiazepines) the possibility of a change in the plasma drug levels of either drug should be considered. In clinical studies in which atorvastatin was administered with antihypertensives (including ACE inhibitors, betablockers, calcium channel antagonists, and diuretics) or hypoglycemic agents, no clinically significant interactions were seen.
Based on experience with other HMG-CoA reductase inhibitors, caution should also be exercised when atorvastatin is administered with inhibitors of cytochrome P450 3A4 (e.g. certain macrolide antibiotics and azole antifungals). Increases and decreases in plasma phenytoin levels have been reported, but the relationship with atorvastatin is unknown.
Inhibitors of P-glycoprotein: Atorvastatin and atorvastatin metabolites are substrates of P-glycoprotein. Inhibitors of the P-glycoprotein (e.g. cyclosporine) can increase the bioavailability of atorvastatin and thereby increase the risk of dose-related side effects such as myopathy.
Gemfibrozil/fibric acid derivatives: The use of fibrates alone is occasionally associated with myopathy. An increased risk of muscle related adverse event has been described when fibrates are co-administered with HMG-CoA reductase inhibitors. The risk of atorvastatin induced myopathy may therefore be increased with concomitant use of fibric acid derivatives. Pre-clinical data suggest that gemfibrozil may also interact with atorvastatin by inhibiting its glucuronidation. Co-administration of atorvastatin with fibrates (especially gemfibrozil) should only be undertaken with caution.
Digoxin: When multiple doses of digoxin and 10 mg atorvastatin were coadministered, steady state plasma digoxin concentrations were unaffected. However, digoxin concentrations increased approximately 20% following administration of digoxin with 80 mg atorvastatin daily. Patients taking digoxin should be monitored appropriately.
Macrolide antibiotics: Erythromycin, clarithromycin: Coadministration of atorvastatin and erythromycin (500 mg QID), or clarithromycin (500 mg BID), known inhibitors of cytochrome P450 3A4, were associated with higher plasma concentrations of atorvastatin.
Azithromycin: Coadministration of atorvastatin (10 mg OD) and azithromycin (500 mg OD) did not alter the plasma concentrations of atorvastatin.
Oral contraceptives: Administration of atorvastatin with an oral contraceptive containing norethisterone and ethinyl estradiol produced increases in plasma concentrations of norethisterone and ethinyl estradiol. These increased concentrations should be considered when selecting oral contraceptive doses.
Amlodipine: Atorvastatin pharmacokinetics were not altered by the coadministration of atorvastatin 80 mg and amlodipine 10 mg at steady state.
Colestipol: Plasma concentrations of atorvastatin were lower (approximately 25%) when colestipol was administered with atorvastatin. However, lipid effects were greater when Atorvastatin and colestipol were administered together than when either drug was given alone.
Antacid: Administration of atorvastatin with an oral antacid suspension containing magnesium and aluminum hydroxides decreased atorvastatin plasma concentrations approximately 35%; however, LDL-C reduction was not altered.
Warfarin: Administration of atorvastatin with warfarin caused a minimal decrease in prothrombin time (mean ± SE of 1.7 ± 0.4 seconds) during the first 4 days of dosing with 80 mg atorvastatin. Dosing continued for 15 days and prothrombin time returned to normal by the end of atorvastatin treatment. Nevertheless, patients receiving warfarin should be closely monitored when atorvastatin is added to their therapy.
Cimetidine: An interaction study with cimetidine and atorvastatin was conducted, and no interaction was seen.
Grapefruit juice: Contains one or more components that inhibit CYP3A4 and can increase plasma concentrations of drugs metabolized by CYP3A4. Intake of one 240 mL glass of grapefruit juice resulted in an increase in atorvastatin AUC of 37% and a decreased AUC of 20.4% for the active orthohydroxy metabolite. However, large quantities of grapefruit juice (over 1.2 L daily for 5 days) increased AUC of atorvastatin 2.5 fold and AUC of active (atorvastatin and metabolites) HMG-CoA reductase inhibitors 1.3 fold. Concomitant intake of large quantities of grapefruit juice and atorvastatin is therefore not recommended.
Protease inhibitors: Co-administration of atorvastatin and protease inhibitors, known inhibitors of cytochrome P450 3A4, was associated with an approximately two-fold increase in plasma concentrations of atorvastatin. Consideration should be given to starting atorvastatin at a lower dose when co-administered with a protease inhibitor.