Interactions of atorvastatin with other drugs
Most serious complications of statin therapy — myopathy and rhabdomyolysis — are related not so much to the drug itself as to its interaction with other medications that sharply increase the concentration of the statin in the blood. Atorvastatin has clearly described metabolic pathways, so risky combinations can be predicted. The editors explain which combinations require special attention and why.
Mechanisms of interactions: CYP3A4 and transporters
Atorvastatin enters liver cells with the help of the transport protein OATP1B1, and is then metabolized by the cytochrome P450 3A4 enzyme (CYP3A4). Part of the drug in the intestine and liver is also "pumped" out by the transporter P-glycoprotein. Each of these links is a potential point of interaction.
If another drug inhibits CYP3A4, atorvastatin is broken down more slowly and accumulates in the blood. If OATP1B1 is blocked, the drug is captured by the liver less well and circulates longer in the systemic bloodstream, where it comes into contact with muscle tissue. In both cases the risk of muscle toxicity rises.
The opposite effect is produced by enzyme inducers — for example rifampicin or St. John's wort: they accelerate the metabolism of atorvastatin, and its effectiveness decreases. That is, interactions can be either dangerous or ones that simply "quench" the therapeutic effect.
A systematization of clinically significant interactions of statins with cardiovascular and other drugs is provided by the scientific statement of the American Heart Association (Wiggins et al., 2016). Detailed mechanisms are described in the review by Neuvonen et al. (2006). It is precisely on these sources and the official prescribing information that the editors rely.
Drugs that raise the level of atorvastatin
The most potent inhibitors of CYP3A4 are the antifungal drugs of the azole group (itraconazole, ketoconazole, posaconazole), the macrolide antibiotics clarithromycin and erythromycin, and also the protease inhibitors for HIV and hepatitis C. In their presence the concentration of atorvastatin can rise several-fold.
Cyclosporine, used after transplantation and in autoimmune diseases, inhibits CYP3A4, OATP1B1 and P-glycoprotein at the same time. The atorvastatin prescribing information recommends avoiding this combination. Similar restrictions apply to some combined antiviral regimens.
Moderate inhibitors of CYP3A4 — diltiazem, verapamil, fluconazole — also raise the level of atorvastatin, though less. For them, caution and symptom monitoring are usually sufficient, but a doctor may limit the statin dose. Amiodarone, used in arrhythmias, also has an interaction, especially significant for simvastatin.
| Drug group | Examples | Effect | Typical approach (at the doctor's discretion) |
|---|---|---|---|
| Strong CYP3A4 inhibitors | Clarithromycin, itraconazole, protease inhibitors | Significant increase in the statin level | Avoid, limit the dose or temporarily discontinue the statin |
| Inhibitors of several pathways | Cyclosporine | Sharp increase in the level | Avoid the combination |
| Moderate inhibitors | Diltiazem, verapamil, fluconazole | Moderate increase | Caution, symptom monitoring |
| Inducers | Rifampicin, St. John's wort | Reduced effectiveness | Lipid monitoring, adjustment of therapy |
The practical conclusion is simple: when any antibiotic or antifungal drug is prescribed, a patient on atorvastatin must inform the doctor about the statin. Often the simplest solution is to temporarily stop the statin for the few days of a short antibiotic course.
Pharmacodynamic interactions: fibrates, colchicine, fusidic acid
Some drugs do not change the concentration of atorvastatin significantly but themselves have myotoxic potential. The best-known example is fibrates. Gemfibrozil additionally inhibits the glucuronidation and transport of statins, so its combination with statins is considered undesirable. Fenofibrate has a considerably more favorable profile and, when indicated, can be combined with a statin.
Colchicine, used in gout and pericarditis, in isolated cases in combination with statins was associated with myopathy, especially in patients with reduced kidney function. Niacin in high doses is also mentioned in the prescribing information as a factor of increased risk of muscle reactions.
Regulators pay separate attention to systemic fusidic acid — an antibiotic used in staphylococcal infections. Cases of rhabdomyolysis, including fatal ones, have been described when it is combined with statins. Therefore, during systemic treatment with fusidic acid the statin is, as a rule, temporarily discontinued.
- Gemfibrozil — combination with statins is undesirable.
- Fenofibrate — possible when indicated, under supervision.
- Colchicine — caution, especially in kidney failure.
- Systemic fusidic acid — the statin is temporarily discontinued.
How atorvastatin affects other drugs
Interactions work in the reverse direction too. According to the prescribing information, atorvastatin moderately raises the concentration of digoxin, so patients taking both drugs are advised to monitor the digoxin level.
Atorvastatin raises the levels of ethinylestradiol and norethindrone in some combined oral contraceptives. The clinical significance of this effect is small, but it is taken into account when choosing a contraceptive.
In patients taking warfarin, at the start of atorvastatin therapy or when its dose is changed, the international normalized ratio (INR) is usually monitored. As a rule, no significant effect on the INR is observed, but checking is considered a reasonable precaution.
As for the combination with ezetimibe: these drugs have different metabolic pathways, and the combination is widely used in clinical practice to enhance the reduction of LDL. No significant pharmacokinetic interaction between them has been found.
Food, supplements and the sporting environment
Grapefruit juice contains substances that inhibit CYP3A4 in the intestinal wall. Studies have shown that large amounts of juice raise the concentration of atorvastatin (Lilja et al., 1999). The prescribing information warns specifically against consuming large volumes — more than 1.2 L a day; an ordinary glass of juice rarely matters, but people with risky combinations had better avoid grapefruit.
Among supplements, the greatest attention is drawn by red yeast rice: it contains monacolin K, chemically identical to lovastatin. Combining such a supplement with atorvastatin effectively means taking two statins at once and increases the risk of side effects. St. John's wort, on the contrary, reduces the effectiveness of the statin.
In the sporting environment the editors draw attention to several risks. Oral anabolic steroids are themselves hepatotoxic, and their combination with a statin complicates the interpretation of liver tests. Some drugs that athletes use without a prescription interact with the CYP3A4 system, and their composition on the illegal market is unpredictable.
Intense training, dehydration and drastic diets, which often occur before competitions, also increase the load on the muscles and kidneys. In combination with drugs that raise the statin level, this creates conditions for rhabdomyolysis. Therefore the full list of drugs and supplements must always be known to the doctor.
Editorial conclusions
Most dangerous interactions of atorvastatin are explained by inhibition of CYP3A4 or the transporter OATP1B1: macrolides, azoles, protease inhibitors and cyclosporine can sharply raise the statin level.
Separate attention is required for gemfibrozil, colchicine and systemic fusidic acid, as well as the red yeast rice supplement, which contains a natural statin.
Atorvastatin itself moderately affects digoxin and some contraceptives, and combines with ezetimibe without significant pharmacokinetic problems.
To complete the picture, the editors recommend the articles "Side effects and contraindications of atorvastatin", "Tests during the use of atorvastatin" and "Ezetimibe: mechanism of action".
References
- Wiggins BS, Saseen JJ, Page RL 2nd, et al. Recommendations for management of clinically significant drug-drug interactions with statins and select agents used in patients with cardiovascular disease: a scientific statement from the American Heart Association. Circulation. 2016;134(21):e468–e495.
- Neuvonen PJ, Niemi M, Backman JT. Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance. Clin Pharmacol Ther. 2006;80(6):565–581.
- Lennernäs H. Clinical pharmacokinetics of atorvastatin. Clin Pharmacokinet. 2003;42(13):1141–1160.
- Lilja JJ, Kivistö KT, Neuvonen PJ. Grapefruit juice increases serum concentrations of atorvastatin and has no effect on pravastatin. Clin Pharmacol Ther. 1999;66(2):118–127.
- Newman CB, Preiss D, Tobert JA, et al. Statin safety and associated adverse events: a scientific statement from the American Heart Association. Arterioscler Thromb Vasc Biol. 2019;39(2):e38–e81.
- Lipitor (atorvastatin calcium) tablets. Prescribing information. U.S. Food and Drug Administration.
Andriy Melnyk
A strength-sports coach and author of programs for beginner and intermediate levels. Writes about training planning.
