Effects of drugs on the effects of atorvastatin
The risk of myopathy when treated with HMG-CoA reductase inhibitors increases with simultaneous use with cyclosporine, fibrates, macrolides (including erythromycin), azole antifungal agents or nicotinic acid.
In some rare cases, these combinations can cause rhabdomyolysis, accompanied by renal failure. In this regard, a careful evaluation of the relationship between the possible risk and the expected benefit of combined treatment is needed (see section "Special instructions").
Inhibitors of the isoenzyme CYP3A4
Atorvastatin is metabolized with the participation of the CYP3A4 isoenzyme. With simultaneous use of atorvastatin with inhibitors isoenzyme CYP3A4 (e.g., cyclosporine, macrolide antibiotics, such as erythromycin and clarithromycin, nefazodone, azole antifungals, e.g., itraconazole,and HIV protease inhibitors), drug interactions may occur.
With combined use medicationElevated levels of atorvastatin in the blood plasma may be noted. Simultaneous use with drugs that reduce the concentration of endogenous steroid hormones (including cimetidine, ketoconazole, spironolactone) increases the risk of reducing endogenous steroid hormones.
Inhibitors of transport protein OATP1B1
Atorvastatin and its metabolites are substrates for the transport protein OATP1B1. Inhibitors of the transport protein OATP1B1 (for example, ciclosporin) may increase the bioavailability of atorvastatin.
Itraconazole
With the simultaneous use of atorvastatin and itraconazole, an increase AUC up to an indicator that exceeded the norm by three times
Inhibitors of proteases
The simultaneous use of atorvastatin with protease inhibitors, known as isoenzyme inhibitors CYP3A4, was accompanied by an increase in the concentration of atorvastatin in blood plasma.
Grapefruit juice
Grapefruit juice contains at least one ingredient that is an inhibitor of the isoenzyme CYP3A4, and can cause an increase in plasma concentration other than those drugs that are metabolized by the isoenzyme CYP3A4. Daily intake of 240 ml of grapefruit juice increased AUC atorvastatin by 37% and decreased AUC active orthohydroxy metabolite by 20.4%. Consumption of a large amount of grapefruit juice (more than 1.2 liters per day for 5 days) increased AUC atorvastatin 2.5 times, and AUC active inhibitors of HMG-CoA reductase (atorvastatin + its metabolites) - in 1,3 times. In this regard, the consumption of large quantities of grapefruit juice during treatment with atorvastatin is not recommended.
Inductors of isoenzyme CYP3A4
Simultaneous use of atorvastatin with isozyme-inducing drugs CYP3A4 (rifampicin, phenazone, efavirenz, drugs of St. John's wort) can significantly reduce the concentration of atorvastatin in the blood plasma. The mechanism of interaction with atorvastatin and other isoenzyme substrates CYP3A4 unknown; however, the possibility of these interactions should be taken into account when using drugs with a low therapeutic index - in particular, antiarrhythmics III class, for example, amiodarone.
Ezetimibe, fusidic acid
With simultaneous use, the risk of undesirable effects from the musculoskeletal system increases, including rhabdomyolysis.
Gemfibrosil / Fibrates
The risk of myopathy caused by atorvastatin may increase with simultaneous use with fibrates. Research in vitro suggest that gemfibrozil can also interact with atorvastatin by inhibiting its glucuronation, which can cause an increase in the concentrations of atorvastatin in the blood plasma (see section "Special instructions").
Kolestypol
With simultaneous application with colestipol, there was a decrease in the concentration of atorvastatin in the blood plasma by approximately 25%. However, with the combined use of atorvastatin and colestipol, the effect on lipids was more pronounced than with each of these drugs alone.
Antacids
With simultaneous ingestion of atorvastatin and a suspension containing magnesium and aluminum hydroxide, the concentration of atorvastatin in blood plasma decreased by approximately 35%; however, the concentration of LDL at This has not changed.
Fenazone
With simultaneous use of atorvastatin does not affect the pharmacokinetics of phenazone, so it can be assumed that the interactionaction with other drugs that are metabolized by the same isoenzymes of cytochrome P450, is not expected.
Cimetidine
The study of simultaneous use of cimetidine and atorvastatin did not reveal a significant interaction between these drugs.
Amlodipine
With the simultaneous use of 80 mg of atorvastatin and 10 mg of amlodipine, there was no change in atorvastatin in the equilibrium state.
Other
There was no clinically significant undesirable interaction of atorvastatin and antihypertensive agents.
Atorvastatin did not have a clinically significant effect on the concentration of terfenadine in the blood plasma, which is metasolized by the CYP3A4 isoenzyme. In this regard, it seems unlikely that atorvastatin can significantly affect the pharmacokinetic parameters of other drugs that are metabolized by the isoenzyme CYP3A4.
Table 1. Effect of drugs on the pharmacokinetics of atorvastatin with simultaneous application
| A medicinal preparation used simultaneously, and a dosing regimen | Atorvastatin |
| Dose, mg | Change in AUC | Clinical recommendations |
| Tipranavir 500 mg 2 times a day / Ritonavir 200 mg 2 times a day for 8 days (day 14-21) | 40 mg per day 1 10 mg per day 20 | The increase of 9.4 times | In cases where the use of atorvastatin is necessary, do not exceed the dose of 10 mg of atorvastatin per day. Patients need medical supervision. |
| Cyclosporine 5.2 mg / kg / day - a constant dose | 10 mg once a day | Increase in 8,7 times |
| Lopinavir 400 mg 2 times a day / Ritonavir 2 times a day for 14 days | 20 mg once daily for 4 days | Increase 5.9 times | In cases where the use of atorvastatin is necessary, a reduction in the dose of atorvastatin is required. In the event that the dose of atorvastatin exceeds 20 mg per day, medical supervision is required. |
| Clarithromycin 500 mg 2 times a day for 9 days | 80 mg once a day for 8 days | An increase of 4.4 times |
| Saquinavir 400 mg 2 times a day / Ritonavir 300 mg 2 times a day 5-7, 400 mg from day 8, from 5 to 18 days in 30 minutes after admission atorvastatin | 40 mg once a day for 4 days | 3.9-fold increase | In cases where the use of atorvastatin is necessary, a reduction in the dose of atorvastatin is required. If the dose of atorvastatin exceeds 40 mg per day, medical supervision is required. |
| Darunavir 300 mg 2 times a day / Ritonavir 100 mg 2 times a day for 9 days 10 mg once a day for 4 days | 10 mg once a day for 4 days | Increase 3.3 times |
| Itraconazole 200 mg once a day for 4 days | 40 mg, single administration | Increase 3.3 times |
| Fozamprenavir 700 mg 2 times a day / Ritonavir 100 mg 2 times a day for 14 days | 10 mg once a day for 4 days | 2.5 times increase |
| Fozamprenavir 1400 mg 2 times a day for 14 days | 10 mg once a day for 28 days | Increase by 2.3 times |
| Nelfinavir 1250 mg 2 times a day for 14 days | 10 mg once a day for 28 days | Increase 1.7 times | Dose correction is not required |
| Grapefruit juice, 240 ml once a day | 40 mg, single administration | Increase by 37% | The use of a significant amount of grapefruit juice with the simultaneous use of atorvastatin is not recommended. |
| Diltiazem 240 mg once a day for 28 days | 40 mg, single-entry admission | Increase by 51% | When prescribing or correcting diltiazem dose, medical supervision is required. |
| Erythromycin 500 mg 4 times a day for 7 days | 10 mg, single administration | Increase by 33% | Correction of the maximum dose of atorvastatin is necessary and medical supervision is required |
| Amlodipine 10 mg, single dose | 80 mg, single administration | Increase by 18% | Dose correction is not required |
| Cimetidine 300 mg 4 times a day for 2 weeks | 10 mg once a day for 4 weeks | Decrease less than 1% | Dose correction is not required |
| Suspension, which includes magnesium and aluminum 30 mg 4 times a day for 2 weeks | 10 mg once a day for 4 weeks | Decrease by 35% | Dose correction is not required |
| Evafirenz 600 mg once a day for 14 days | 10 mg for 3 days | Decrease by 41% | Dose correction is not required |
| Rifampicin 600 mg once a day for 7 days (simultaneous administration) | 40 mg, single administration | Increase by 30% | In the event that simultaneous reception with rifampicin can not be avoided, medical supervision is required. |
| Rifampicin 600 mg once daily for 5 days (divided doses) | 40 mg, single administration | Reduction by 80% |
| Gemfibrozil 600 mg 2 times a day for 7 days | 40 mg, single administration | Increase by 35% | It is necessary to reduce the initial dose and require medical supervision. |
| Fenofibrate 160 mg once a day for 7 days | 40 mg, single administration | Increase by 3% | It is necessary to reduce the initial dose and require medical supervision. |
The effect of atorvastatin on other drugs
Digoxin
With repeated administration of digoxin and atorvastatin at a dose of 10 mg, the equilibrium concentrations of digoxin in the blood plasma did not change. However, with the use of digoxin in combination with atorvastatin at a dose of 80 mg / day, the digoxin concentration increased by about 20%.
Oral contraceptives
With the simultaneous use of atorvastatin with an oral contraceptive containing norethisterone and ethinyl estradiol, there was an increase in the concentrations of norethisterone and ethinylestradiol in blood plasma. These concentrations increase should be account for when choosing doses of oral contraceptives. With simultaneous use of atorvastatin and oral contraceptive containing norethisterone and ethinyl estradiol, there was a significant increase AUC of ethethylethylone and ethinylestradiol by 30% and 20%, respectively. This effect should be considered when choosing an oral contraceptive for a woman receiving atorvastatin.
Warfarin
With simultaneous use of atorvastatin with warfarin, there was a slight decrease in prothrombin time in the first days of atorvastatin administration; However, in the next 15 days the prothrombin time returned to normal.
Table 2. Effects of atorvastatin on the pharmacokinetics of other drugs while simultaneously applying | Atorvastatin, dosing regimen | Drug used simultaneously |
| Medicinal preparation / dose (ml) | Change in AUC | Clinical recommendations |
| 80 mg once a day for 10 days | Digoxin 0.25 mg once daily for 20 days | Increase by 15% | Requires medical supervision |
| 40 mg once a day for 22 days | Oral contraceptive once a day for 2 months Norethindrone 1 mg Ethinylestradiol 35 μg | An increase of 28% Increase by 19% | Dose correction is not required |
| 80 mg once a day for 15 days | Phenazone 600 mg, single dose | Increase by 3% | Dose correction is not required |