The risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of cyclosporine, fibric acid derivatives, lipid-modifying doses of niacin or cytochrome P450 3A4 inhibitors (e.g erythromycin and azole antifungals) (see the following and also Use in Combination with Other Medicinal Compounds under Dosage & Administration and Skeletal Muscle Effects under Precautions).
Inhibitors of cytochrome P450 3A4: Atorvastatin is metabolized by cytochrome P450 3A4. Concomitant administration of Atorvastatin with inhibitors of cytochrome P450 3A4 can lead to increases in plasma concentrations of Atorvastatin. The extent of interaction and potentiation of effects depends on the variability of effect on cytochrome P450 3A4.
Transporter Inhibitors: Atorvastatin and Atorvastatin-metabolites are substrates of the OATP1B1 transporter. Inhibitors of the OATP1B1 (e.g. cyclosporine) can increase the bioavailability of Atorvastatin. Concomitant administration of Atorvastatin 10 mg and cyclosporine 5.2 mg/kg/day resulted in an 8.7-fold increase in Atorvastatin AUC. In cases where co-administration of Atorvastatin with cyclosporine is necessary, the dose of Atorvastatin should not exceed 10 mg.
Clarithromycin: Concomitant administration of Atorvastatin 80 mg with clarithromycin (500 mg twice daily) resulted in a 4.4-fold increase in Atorvastatin AUC (see Skeletal Muscle Effects under Precautions, and Use in Combination with Other Medicinal Compounds under Dosage & Administration).
Erythromycin: In healthy individuals, plasma concentrations of Atorvastatin increased approximately 40% with co-administration of Atorvastatin and erythromycin, a known inhibitor of cytochrome P450 3A4 (see Skeletal Muscle Effects under Precautions).
Protease inhibitors: Concomitant administration of Atorvastatin 40 mg with ritonavir plus saquinavir (400 mg twice daily) resulted in a 3-fold increase in Atorvastatin AUC. Concomitant administration of Atorvastatin 20 mg with lopinavir plus ritonavir (400 mg + 100 mg twice daily) resulted in a 5.9-fold increase in Atorvastatin AUC (see Pharmacology: Pharmacokinetics under Actions and Use in Combination with Other Medicinal Compounds under Dosage & Administration).
Diltiazem hydrochloride: Co-administration of Atorvastatin (40 mg) with diltiazem (240 mg) was associated with higher plasma concentrations of Atorvastatin.
Cimetidine: An Atorvastatin interaction study with cimetidine was conducted, and no clinically significant interactions were seen.
Itraconazole: Concomitant administration of Atorvastatin (20 to 40 mg) and itraconazole (200 mg) was associated with a 2.5-3.3-fold increase in Atorvastatin AUC.
Grapefruit juice: Contains one or more components that inhibit CYP 3A4 and can increase plasma concentrations of Atorvastatin, especially with excessive grapefruit juice consumption (>1.2 liters per day).
Inducers of cytochrome P450 3A: Concomitant administration of Atorvastatin with inducers of cytochrome P450 3A4 (eg efavirenz, rifampin) can lead to variable reductions in plasma concentrations of Atorvastatin. Due to the dual interaction mechanism of rifampin, (cytochrome P450 3A4 induction and inhibition of hepatocyte uptake transporter OATP1B1), simultaneous co-administration of Atorvastatin with rifampin is recommended, as delayed administration of Atorvastatin after administration of rifampin has been associated with a significant reduction in Atorvastatin plasma concentrations.
Antacids: Co-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.
Antipyrine: Because Atorvastatin does not affect the pharmacokinetics of antipyrine, interactions with other drugs metabolized via the same cytochrome isozymes are not expected.
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 co-administered than when either drug was given alone.
Digoxin: When multiple doses of digoxin and 10 mg Atorvastatin were co-administered, 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.
Azithromycin: Co-administration of Atorvastatin (10 mg once daily) and azithromycin (500 mg once daily) did not alter the plasma concentrations of Atorvastatin.
Oral Contraceptives: Co-administration with an oral contraceptive containing norethindrone and ethinyl estradiol increased AUC values for norethindrone and ethinyl estradiol by approximately 30% and 20%. These increases should be considered when selecting an oral contraceptive for a woman taking Atorvastatin.
Warfarin: An Atorvastatin interaction study with warfarin was conducted, and no clinically significant interactions were seen.
Amlodipine: In a drug-drug interaction study in healthy subjects, co-adminstration of Atorvastatin 80 mg and amlodipine 10 mg resulted in an 18% increase in exposure to Atorvastatin which was not clinically meaningful.
Fusidic acid: Although interaction studies with Atorvastatin and fusidic acid have not been conducted, severe muscle problems such as rhabdomyolysis have been reported in post-marketing experience with this combination. Patients should be closely monitored and temporary suspension of Atorvastatin treatment may be appropriate.
Colchicine: Although interaction studies with Atorvastatin and Colchicine have not been conducted, cases of myopathy have been reported with Atorvastatin co-administered with Colchicine, and caution should be exercised when prescribing Atorvastatin with Colchicines.
Other Concomitant Therapy: In clinical studies, Atorvastatin was used concomitantly with antihypertensive agents and estrogen replacement therapy without evidence of clinically significant adverse interactions. Interaction studies with specific agents have not been conducted.
Paediatric population: Drug-drug interaction studies have only been performed in adults. The extent of interactions in the paediatric population is not known. The previously-mentioned interactions for adults and the warning in Precautions should be taken into account for the paediatric population.