HMG-CoA reductase inhibitors (statins)
Brand names: Lipitor, Atorvaliq
Updated · Methodology
First line
In adults without established CVD, statin therapy is guided by risk stratification. 2022 recommends statins in adults 40–75 with at least one CV risk factor and a 10-year ASCVD risk of 10 % or more. 2019 uses and titrates aggressiveness by risk category.
Sources
ICD-10: E78.5 · ICD-11: 5C80
First line
High-intensity statins (atorvastatin 40–80 mg daily) are the foundation of secondary prevention after ACS, MI, ischemic stroke, TIA, revascularization, or in established atherosclerotic vascular disease. Target per 2019 is a ≥ 50 % reduction from baseline and LDL below 1.4 mmol/L. Cholesterol Treatment Trialists meta-analyses show a 20 % reduction in major vascular events per 1 mmol/L LDL lowering.
Sources
ICD-10: I25 · ICD-11: BA5Z
First line
Heterozygous FH requires high-intensity statins started early (from age 8–10 per pediatric consensus). target is below 2.5 mmol/L in adults without additional risk factors and below 1.8 mmol/L with them. Ezetimibe and, if needed, PCSK9 inhibitors are added when targets are not met.
Sources
ICD-10: E78.0 · ICD-11: 5C80.00
The drug is promoted for these uses outside international guidelines. Each entry below is analyzed against AEMPS, FDA, EMA, Cochrane and major RCTs.
Not recommended
– Vessel cleansing: 'Vessel cleansing' is not a concept used in international clinical guidelines. Statins are prescribed based on cardiovascular risk stratification, not for 'cleansing'. The idea of mechanically 'removing plaques' with a drug contradicts pharmacokinetics. The evidence-based benefit of statins is reduced cardiovascular mortality via plaque stabilization and reduction, not 'dissolution'.
Reversible competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme of hepatic cholesterol synthesis. Depletes intracellular cholesterol, upregulates receptors on hepatocytes, and increases LDL clearance from plasma. Lowers LDL by 35–55 % depending on dose, triglycerides by 15–30 %, with a small rise in .
AEMPS summary of product characteristics (section 4.6): atorvastatin is contraindicated during pregnancy. Its safety in pregnant women has not been established and no controlled clinical trials have been done; congenital anomalies after intrauterine exposure to HMG-CoA reductase inhibitors have been reported rarely, and animal studies have shown reproductive toxicity. Maternal atorvastatin may lower fetal levels of mevalonate, a precursor in cholesterol synthesis, while pausing lipid-lowering therapy during pregnancy should normally have little impact on the long-term risk of primary hypercholesterolaemia. Atorvastatin is therefore not used in women who are pregnant, trying to conceive or suspect pregnancy; it is stopped for the duration of pregnancy or until pregnancy is ruled out, and women of childbearing potential should use adequate contraception during treatment.
Systemic safety data during lactation are limited. The manufacturer and most international sources recommend avoidance. In patients with a statin indication, options include a temporary switch to formula feeding or deferring therapy until breastfeeding is complete.
Reference information, not a clinical decision. Discuss feeding pauses or changes with your physician or an IBCLC.
Atorvastatin is also broken down by CYP3A4, but grapefruit affects it less than simvastatin or lovastatin. In the Cardyl SmPC, one 240 ml glass a day raised exposure by 37%, and more than 1.2 litres a day for 5 days raised it 2.5-fold. The SmPC advises only against large amounts of grapefruit juice. Unexplained muscle pain or weakness, or dark urine, calls for a creatine kinase test.
Source: AEMPS: Ficha técnica de Cardyl 10 mg comprimidos recubiertos con película (atorvastatina) (2024)
36 pairs found. Sorted from critical to minor.
Mechanism
Erythromycin inhibits CYP3A4. Atorvastatin rises 2-3 fold. recommends dose cap.
Symptoms
Myalgia, weakness, dark urine, rising CK within 5-10 days.
Management
The AEMPS label for erythromycin lists the combination with atorvastatin as contraindicated. The label caps atorvastatin at 20 mg/day instead. Alternative antibiotic: azithromycin, which does not inhibit CYP3A4; otherwise pause the statin for the course.
Sources
Mechanism
Posaconazole is a strong CYP3A4 inhibitor. Atorvastatin rises 3-4 fold.
Symptoms
Myalgia, weakness, dark urine, rising CK within 5-10 days.
Management
The AEMPS label for posaconazole lists the combination with atorvastatin as contraindicated. The label caps atorvastatin at 10 mg/day instead. For the posaconazole course, pause the statin or switch to pravastatin or rosuvastatin, which do not depend on CYP3A4.
Sources
Mechanism
Amiodarone inhibits CYP3A4, which takes part in atorvastatin metabolism, so atorvastatin levels can rise (amiodarone and atorvastatin labels). No interaction studies have been done for this pair, and the size of the effect is unknown (atorvastatin label). The risk of muscle damage, up to rhabdomyolysis, rises with statin exposure (amiodarone label). Because of amiodarone's long half-life, the interaction can persist for several months after it is stopped (amiodarone label).
Symptoms
Muscle pain, cramps or weakness, especially with fever and malaise, and raised creatine kinase. In severe cases rhabdomyolysis develops: creatine kinase above 10 times the upper limit of normal, myoglobin in blood and urine (dark urine) and possible kidney failure (atorvastatin label).
Management
The Spanish amiodarone label recommends using a statin that is not metabolized by CYP3A4 (amiodarone label). If atorvastatin is kept, consider a lower starting dose ( amiodarone label) and a lower maximum dose (atorvastatin label). Monitor the patient closely after amiodarone is started and after each dose change (atorvastatin label). Ask the patient to report muscle pain, cramps or weakness at once. If they appear, measure creatine kinase and stop atorvastatin if it is above 5 times the upper limit of normal (atorvastatin label). Amiodarone interactions persist for weeks to months after it is stopped (amiodarone labels).
Sources
Mechanism
Atazanavir inhibits CYP3A4. Atorvastatin rises 8-fold – rhabdomyolysis risk.
Symptoms
Myalgia, weakness, dark urine, rising CK within 5-10 days.
Management
Cap atorvastatin at 10 mg/day. Better – pravastatin 40 mg.
Sources
Mechanism
Carbamazepine induces CYP3A4 – the main atorvastatin metabolic route. Atorvastatin plasma levels fall by 30–60%; lipid-lowering effect drops proportionally.
Symptoms
The patient feels nothing. Laboratory: cholesterol and total cholesterol rise. In high cardiovascular risk patients, myocardial infarction and stroke risk increase.
Management
During carbamazepine therapy, increase atorvastatin 1.5- to 2-fold with lipid profile and creatine kinase monitoring, or switch to pravastatin (CYP3A4-independent). Alternative anticonvulsants without induction: levetiracetam, lamotrigine.
Sources
Mechanism
Cyclosporine blocks the OATP1B1 transporter and CYP3A4 – two atorvastatin clearance routes. Atorvastatin plasma levels rise 8- to 15-fold, with high myopathy and rhabdomyolysis risk, particularly in transplant patients.
Symptoms
Pain and weakness in large muscle groups (thighs, shoulders, calves), dark urine, elevated creatine kinase. Severe cases progress to rhabdomyolysis with acute kidney injury. Symptoms appear within 1–4 weeks of co-administration.
Management
For transplant patients needing a statin, use pravastatin up to 20 mg/day or fluvastatin (minimal cyclosporine interaction). Use atorvastatin only when no alternative exists, capped at 10 mg/day, with creatine kinase every 4 weeks.
Sources
Mechanism
Clarithromycin is a strong inhibitor of CYP3A4 and P-glycoprotein. Atorvastatin plasma levels rise 4–5-fold, and so does the risk of rhabdomyolysis with acute kidney injury. The labels do not ban the pair. The caps atorvastatin at 20 mg/day while clarithromycin is taken. The AEMPS label advises avoiding the combination where possible and, if it cannot be avoided, using lower starting and maximum statin doses.
Symptoms
Within 5–10 days: muscle pain, especially thighs and shoulder girdle, dark urine, creatine kinase above 10× ULN, rising creatinine.
Management
Hold atorvastatin or reduce it to 10–20 mg/day for the duration of clarithromycin (typically 7–14 days). Alternative: switch clarithromycin to azithromycin, which does not inhibit CYP3A4.
Sources
Mechanism
Additive myopathy and rhabdomyolysis risk. Atorvastatin injures muscle fibre by suppressing ubiquinone synthesis; colchicine disrupts microtubule function in myocytes. Particularly dangerous in older patients and chronic kidney disease.
Symptoms
Pain and weakness in large muscle groups (thighs, shoulders, calves), dark urine, elevated creatine kinase. Severe cases progress to rhabdomyolysis with acute kidney injury. Symptoms appear within 1–4 weeks of co-administration.
Management
Avoid prolonged combination. For acute gout, a short colchicine course (3–5 days) at 0.3 mg every other day is acceptable with muscle symptom and creatine kinase monitoring. Alternative for gout: intra-articular or short systemic glucocorticoid.
Sources
Mechanism
Atorvastatin slightly raises digoxin levels: by about 22%, with a 15% rise in AUC, according to the digoxin label. Digoxin has a narrow therapeutic range, so even this increase can lead to toxicity.
Symptoms
Nausea, anorexia, visual disturbances (yellow-green halos around lights), arrhythmias. Older patients: confusion.
Management
Before starting atorvastatin, measure the serum digoxin concentration, then reduce the digoxin dose by about 15–30% or give it less often and keep monitoring the concentration ( digoxin label). Draw the sample just before the next digoxin dose or at least 6 hours after the last one (FDA digoxin label). The atorvastatin labels ask for appropriate monitoring of patients taking digoxin (atorvastatin labels).
Sources
Mechanism
CYP3A4 takes part in atorvastatin metabolism (atorvastatin labels), and diltiazem is a moderate CYP3A4 inhibitor (diltiazem and atorvastatin labels). With diltiazem 240 mg daily, atorvastatin AUC rose 1.51-fold (atorvastatin labels in Spain and the US). The risk of muscle damage, up to rhabdomyolysis, rises with statin exposure (diltiazem labels). The effect is stronger with simvastatin, whose AUC diltiazem raised 5-fold (diltiazem labels).
Symptoms
Muscle pain, cramps or weakness, especially with fever and malaise, and raised creatine kinase. In severe cases rhabdomyolysis develops: creatine kinase above 10 times the upper limit of normal, myoglobin in blood and urine (dark urine) and possible kidney failure (atorvastatin label).
Management
When possible, combine diltiazem with a statin that is not metabolized by CYP3A4 (diltiazem labels in Spain and the US). Pravastatin is an example: diltiazem did not change its pharmacokinetics (diltiazem labels). If atorvastatin is kept, start it at the lowest effective dose (diltiazem label) and consider a lower maximum dose (atorvastatin label); the diltiazem label also allows dose adjustment of both drugs. Monitor the patient closely after diltiazem is started and after each dose change (atorvastatin and diltiazem labels). Ask the patient to report muscle pain, cramps or weakness at once. If they appear, measure creatine kinase and stop atorvastatin if it is above 5 times the upper limit of normal (atorvastatin label).
Sources
Mechanism
The label lists atorvastatin among OATP1B1 substrates whose exposure rises with gemfibrozil. The class-wide warning adds to that: combining a fibrate with any HMG-CoA reductase inhibitor raises the risk of skeletal muscle injury.
Symptoms
Muscle pain, weakness and tenderness, dark urine, rising creatine kinase up to rhabdomyolysis with renal failure.
Management
The combination is avoided. When both a statin and triglyceride lowering are needed, fenofibrate replaces gemfibrozil. If joint use still goes ahead, the atorvastatin dose is kept minimal and muscle complaints and creatine kinase are monitored.
Sources
Mechanism
Itraconazole inhibits CYP3A4 and P-glycoprotein. Atorvastatin concentration rises 3–4 fold. does not contraindicate the combination outright but caps atorvastatin at 20 mg/day and requires CK monitoring.
Symptoms
Myalgia and weakness within 1–3 weeks; CK above 5× ULN.
Management
Cap atorvastatin at 20 mg/day. For short itraconazole courses (up to 14 days) the safer option is to hold atorvastatin altogether.
Sources
Mechanism
Ketoconazole strongly inhibits CYP3A4 – the main atorvastatin metabolic route. Atorvastatin plasma levels rise 3- to 4-fold. Lipitor 2017 advises avoiding concomitant use.
Symptoms
Pain and weakness in large muscle groups (thighs, shoulders, calves), dark urine, elevated creatine kinase. Severe cases progress to rhabdomyolysis with acute kidney injury. Symptoms appear within 1–4 weeks of co-administration.
Management
During ketoconazole therapy, hold atorvastatin or switch to pravastatin/rosuvastatin (no CYP3A4 dependence). Alternative antifungals: terbinafine for dermatophytosis or echinocandins for systemic mycoses.
Sources
Mechanism
Rifampicin strongly induces CYP3A4 and the OATP1B1 transporter – two atorvastatin clearance routes. Atorvastatin plasma levels fall by 80%; lipid-lowering effect weakens.
Symptoms
The patient feels nothing. Laboratory: cholesterol and total cholesterol rise. In high cardiovascular risk patients, myocardial infarction and stroke risk increase.
Management
During anti-TB therapy, switch to pravastatin (less induction-sensitive metabolism) or temporarily stop the statin for a short course. Induction persists for 2 weeks after rifampicin stops.
Sources
Mechanism
Atorvastatin is broken down in the liver by CYP3A4, and ritonavir inhibits this enzyme. In studies of ritonavir-containing regimens, atorvastatin area under the curve (AUC) rose 2.5- to 9.4-fold depending on the partner protease inhibitor: 5.9-fold with lopinavir/ritonavir and 9.4-fold with tipranavir/ritonavir. Higher atorvastatin levels raise the risk of muscle damage.
Symptoms
Muscle pain, cramps or weakness, sometimes with fever and malaise, dark urine, raised creatine kinase in the blood. Severe cases progress to rhabdomyolysis with kidney injury.
Management
Avoid the combination where possible and consider non-interacting alternatives (atorvastatin label). If atorvastatin is still needed, start with a lower dose, use a lower maximum dose and monitor the patient (atorvastatin label). The European Medicines Agency () advises the lowest possible atorvastatin dose and, if a statin is needed, pravastatin or fluvastatin (ritonavir label, EMA). The dose cap depends on the other drug in the regimen. The US Food and Drug Administration () does not recommend atorvastatin with tipranavir plus ritonavir and limits it to 20 mg a day with ritonavir-boosted darunavir, saquinavir or fosamprenavir (atorvastatin FDA label). Ask the patient to report muscle pain, cramps or weakness right away. If these occur, check creatine kinase and stop atorvastatin if it is more than 5 times the upper limit of normal (atorvastatin label).
Sources
Mechanism
Verapamil inhibits CYP3A4, the enzyme that breaks down atorvastatin, and may raise atorvastatin levels (both SmPCs). No interaction study of this pair has been done, so the atorvastatin SmPC gives no figure. The interaction also works the other way: atorvastatin increases systemic exposure to verapamil by 43% (verapamil SmPC). The higher the atorvastatin level, the higher the risk of muscle damage (atorvastatin SmPC).
Symptoms
Muscle pain, cramps or weakness, sometimes with fever and malaise, and raised creatine kinase on blood tests. In rhabdomyolysis the urine turns dark and kidney function can suffer.
Management
If the patient already takes verapamil, atorvastatin is started at the lowest possible dose and titrated up: the verapamil SmPC requires this and names atorvastatin. If verapamil is added to existing atorvastatin, a statin dose reduction is considered and cholesterol is rechecked (verapamil SmPC). For verapamil and other moderate CYP3A4 inhibitors, the atorvastatin SmPC advises considering a lower maximum atorvastatin dose and monitoring the patient; the documents set no specific dose limit for this pair. Ask the patient to report muscle pain, cramps or weakness promptly. Check creatine kinase if they occur, and stop atorvastatin if it is more than 5 times the upper limit of normal (atorvastatin SmPC). Fluvastatin, pravastatin and rosuvastatin are not metabolised by CYP3A4 and are less likely to interact with verapamil (verapamil SmPC).
Sources
Mechanism
Voriconazole inhibits CYP3A4. Atorvastatin rises 3-4 fold.
Symptoms
Myalgia, weakness, dark urine, rising CK within 5-10 days.
Management
Cap atorvastatin at 20 mg/day.
Sources
Mechanism
Amlodipine weakly inhibits CYP3A4 – a partial atorvastatin metabolic route. Atorvastatin plasma levels rise by about 18%. Clinically significant myopathy is rare.
Symptoms
Usually no additional symptoms. In patients with risk factors (older age, chronic kidney disease, hypothyroidism): muscle pain and weakness are possible.
Management
The combination is acceptable without dose change. Cap atorvastatin at 40 mg/day if needed. Check creatine kinase on muscle symptoms.
Sources
Mechanism
Atorvastatin is broken down by the CYP3A4 enzyme and carried by the transporter P-glycoprotein (atorvastatin SmPC). Azithromycin is a weak inhibitor of cytochrome P450 enzymes, but inhibition of CYP3A4 cannot be fully ruled out (azithromycin SmPC). In a study, azithromycin 500 mg daily for 3 days did not change blood levels of atorvastatin 10 mg (azithromycin labels). Even so, post-marketing cases of rhabdomyolysis have been reported in patients taking azithromycin with statins (azithromycin SmPC).
Symptoms
Muscle pain, weakness, cramps or tenderness, sometimes with malaise and fever. In rhabdomyolysis, urine turns dark from myoglobin and there is a risk of acute kidney injury (statin SmPCs).
Management
Use the combination with caution: post-marketing cases of rhabdomyolysis have been reported in patients taking azithromycin with statins (azithromycin SmPC). The atorvastatin label of the US Food and Drug Administration () advises weighing the risks and benefits of combining atorvastatin with macrolides and watching for signs of muscle damage, especially when starting treatment and when raising the dose of either drug. Ask the patient to report muscle pain, cramps or weakness at once, especially with fever or malaise. If these occur, measure creatine kinase (CK): stop atorvastatin if CK is above 5 times the upper limit of normal (atorvastatin SmPC).
Sources
Mechanism
Ciprofloxacin is a weak CYP3A4 inhibitor. Atorvastatin plasma levels may rise slightly during short ciprofloxacin courses.
Symptoms
Usually no changes. In patients with myopathy risk factors: rare muscle pain.
Management
For short ciprofloxacin courses (5–7 days), no special adjustment. In patients with myopathy risk factors, check creatine kinase on muscle symptoms.
Sources
Mechanism
Dexamethasone induces CYP3A4. With prolonged therapy, atorvastatin plasma levels may fall modestly and lipid-lowering effect weakens.
Symptoms
The patient feels nothing. Laboratory: cholesterol and total cholesterol rise during prolonged systemic glucocorticoid therapy.
Management
For short dexamethasone courses, no adjustment. For prolonged systemic therapy, monitor lipid profile every 2–3 months; increase atorvastatin by 25–50% if needed.
Sources
Mechanism
Dronedarone blocks CYP3A4 – a partial atorvastatin metabolic route. Atorvastatin plasma levels rise 2-fold, raising myalgia risk.
Symptoms
Pain and weakness in large muscle groups (thighs, shoulders, calves), dark urine, elevated creatine kinase. Symptoms usually appear 2–6 weeks after starting the combination.
Management
Cap atorvastatin at 20 mg/day when combined. If targets are missed, switch to pravastatin or rosuvastatin (no CYP3A4 dependence).
Sources
Mechanism
Esomeprazole weakly affects CYP3A4 (mainly via CYP2C19). Atorvastatin levels are essentially unchanged. DDInter notes rare myalgia.
Symptoms
Usually no changes. Rare muscle pain cases, especially in patients with myopathy risk factors.
Management
The combination is acceptable without dose change. In patients with myopathy risk factors (older age, chronic kidney disease, hypothyroidism), check creatine kinase on muscle symptoms.
Mechanism
Fluconazole moderately inhibits CYP3A4, the enzyme that metabolises atorvastatin (fluconazole and atorvastatin SmPCs). Atorvastatin blood levels can rise, and with them the risk of muscle damage up to rhabdomyolysis (fluconazole SmPC).
Symptoms
Pain and weakness in large muscle groups (thighs, shoulders, calves), dark urine, elevated creatine kinase. Severe cases progress to rhabdomyolysis with acute kidney injury.
Management
The combination is not contraindicated. The atorvastatin SmPC classes fluconazole as a moderate CYP3A4 inhibitor: consider a lower maximum atorvastatin dose while the drugs are combined, and monitor the patient, especially after fluconazole is started or its dose changed (atorvastatin SmPC). While both drugs are taken, watch for muscle pain and weakness and check creatine kinase. If creatine kinase rises markedly or myopathy or rhabdomyolysis is suspected, stop atorvastatin (fluconazole SmPC).
Sources
Mechanism
Fluvoxamine blocks CYP3A4 – a partial atorvastatin metabolic route. Atorvastatin plasma levels may rise modestly, raising myalgia risk.
Symptoms
Pain and weakness in large muscle groups (thighs, shoulders, calves), dark urine, elevated creatine kinase. Symptoms usually appear 2–6 weeks after starting the combination.
Management
When combined, cap atorvastatin at 40 mg/day if needed. Check creatine kinase on muscle symptoms. Alternative antidepressants without CYP3A4 effect: sertraline or escitalopram.
Sources
Mechanism
Linezolid does not inhibit the CYP3A4 enzyme and is not expected to change the levels of drugs cleared through it (linezolid SmPC), so atorvastatin levels are not expected to rise. The risk lies elsewhere: rhabdomyolysis has been reported with linezolid (linezolid SmPC), and atorvastatin itself can damage muscle, up to rhabdomyolysis (atorvastatin SmPC). The labels give no data on the combination itself.
Symptoms
Muscle pain, tenderness, cramps or weakness, sometimes with fever and malaise, dark urine and raised creatine kinase in blood tests (linezolid and atorvastatin labels).
Management
The linezolid SmPC asks for caution in patients with risk factors for rhabdomyolysis (linezolid SmPC), and atorvastatin can itself cause rhabdomyolysis (atorvastatin SmPC). Linezolid does not inhibit CYP3A4, so the atorvastatin label's lower maximum dose for drugs that raise atorvastatin levels does not apply to it (linezolid and atorvastatin labels). Ask the patient to report muscle pain, cramps or weakness at once, especially with fever or malaise. If they occur, measure creatine kinase; stop atorvastatin if it is more than 5 times the upper limit of normal or if rhabdomyolysis is suspected (atorvastatin SmPC). At signs of rhabdomyolysis, stop linezolid as well and start appropriate treatment (linezolid SmPC).
Sources
Mechanism
Atorvastatin blocks OATP1B1 – the hepatic methotrexate uptake route. Methotrexate plasma levels may rise. The effect is clinically significant at high oncologic methotrexate doses.
Symptoms
Stomatitis, diarrhoea, falling leukocyte and platelet counts. In patients with borderline renal function: severe toxicity risk.
Management
At low rheumatological methotrexate doses (5–25 mg/week), the combination is acceptable without adjustment. At high oncologic doses, temporarily withhold atorvastatin for 24–48 hours after methotrexate administration.
Mechanism
Metronidazole does not block CYP3A4 but increases myopathy risk with statins (mechanism not fully established; reported in post-marketing data). The effect is rare.
Symptoms
Pain and weakness in large muscle groups (thighs, shoulders, calves), dark urine, elevated creatine kinase. Symptoms usually appear 2–6 weeks after starting the combination.
Management
For short metronidazole courses (5–7 days), no special adjustment. In patients with myopathy risk factors, check creatine kinase on muscle symptoms. For prolonged metronidazole therapy, temporarily reduce atorvastatin.
Mechanism
Omeprazole weakly blocks CYP3A4 – atorvastatin exposure rises modestly (by 10–20%). Clinically significant myopathy beyond baseline is rare.
Symptoms
Usually no changes. In patients with risk factors (older age, chronic kidney disease, hypothyroidism): muscle pain and weakness possible.
Management
The combination is acceptable without dose change. In patients with myopathy risk factors, check creatine kinase on muscle symptoms. Alternative PPI without CYP3A4 effect: pantoprazole or rabeprazole.
Sources
Mechanism
Pantoprazole is the most CYP-neutral PPI. No clinically significant interaction with statins.
Symptoms
No changes.
Management
The combination is acceptable without dose change. Pantoprazole is the preferred PPI in patients on statins and other CYP3A4-dependent drugs.
Mechanism
Dual statin therapy – doubling the same pharmacological class with additive myopathy risk and no therapeutic benefit.
Symptoms
Pain and weakness in large muscle groups (thighs, shoulders, calves), dark urine, elevated creatine kinase. Symptoms usually appear 2–6 weeks after starting the combination.
Management
The combination is not prescribed. Use one statin titrated to target. If LDL is not at goal on the maximum statin dose, add ezetimibe or a PCSK9 inhibitor, not a second statin.
Mechanism
Dual statin therapy – additive myopathy and rhabdomyolysis risk. Simvastatin additionally depends on CYP3A4 (by 98%), amplifying risk.
Symptoms
Pain and weakness in large muscle groups (thighs, shoulders, calves), dark urine, elevated creatine kinase. Symptoms usually appear 2–6 weeks after starting the combination.
Management
The combination is not prescribed. Use one statin titrated to target. If insufficient, add ezetimibe.
Mechanism
Tacrolimus is a weak CYP3A4 inhibitor; atorvastatin is a substrate. Atorvastatin plasma levels rise by 30–50%, raising myalgia risk. Tacrolimus itself can cause myopathy.
Symptoms
Pain and weakness in large muscle groups (thighs, shoulders, calves), dark urine, elevated creatine kinase. Symptoms usually appear 2–6 weeks after starting the combination.
Management
For transplant patients needing a statin, use pravastatin up to 20 mg/day or fluvastatin (minimal tacrolimus interaction). Atorvastatin is acceptable when no alternative exists, capped at 10 mg/day with creatine kinase every 4 weeks.
Mechanism
The US warfarin label () lists atorvastatin among inhibitors of CYP3A4, the enzyme that clears the R-enantiomer of warfarin, so in theory it could increase the warfarin effect. In practice, in a clinical study in patients on long-term warfarin, atorvastatin 80 mg a day slightly shortened prothrombin time, by about 1.7 seconds over the first 4 days, and it returned to normal by day 15. Clinically significant interactions have been reported only very rarely (atorvastatin SmPC). The US atorvastatin label also describes no clinically significant effect on prothrombin time.
Symptoms
Gum bleeding, epistaxis, bruising without trauma, blood in urine or stool, menorrhagia. Severe cases include gastrointestinal or intracranial haemorrhage. Risk rises in patients over 65 and with prior peptic ulcer disease.
Management
Measure prothrombin time (INR) before starting atorvastatin and often enough early in treatment to make sure there is no significant change; after that, monitoring follows the usual warfarin schedule. Repeat this if the atorvastatin dose is changed or the drug is stopped (atorvastatin SmPC). The also advises close INR monitoring when a CYP3A4 inhibitor is started, stopped or changed in dose (US warfarin label).
Sources
Mechanism
An early study (Lau et al., Circulation 2003) in 44 patients showed in vitro competition between atorvastatin and clopidogrel for CYP3A4. Subsequent large clinical trials (PROVE-IT, MIRACL, CHARISMA) did not confirm clinically significant attenuation of clopidogrel's antiplatelet activity.
Symptoms
The combination usually causes no specific symptoms. Each drug's individual side effects remain.
Management
Standard combination after acute coronary syndrome and in coronary artery disease. No dose adjustment needed. In patients at high risk of recurrent thrombosis with unclear antiplatelet activity, consider switching to ticagrelor or prasugrel (CYP3A4-independent).
Sources
Mechanism
Hypothyroidism itself raises . Restoring euthyroid status on levothyroxine reduces statin need. No direct pharmacokinetic interaction.
Symptoms
The combination usually causes no specific symptoms. Each drug's individual side effects remain.
Management
On starting levothyroxine in patients on stable atorvastatin, check lipids 6–8 weeks after TSH normalises. If drops below target, atorvastatin can be reduced. In newly diagnosed hypothyroidism with hypercholesterolaemia, delay statin start until euthyroid status is achieved.
Sources
Verbatim lines from the interaction sections, in the language of the label
«Inhibidores de la CYP3A4: Los inhibidores potentes de la CYP3A4 han demostrado que producen concentraciones notablemente elevadas de atorvastatina (ver Tabla 1 y la información específica a…»AEMPS, section 4.5 · Open on CIMA
«Inhibidores de la CYP3A4: Los inhibidores potentes de la CYP3A4 han demostrado que producen concentraciones notablemente elevadas de atorvastatina (ver Tabla 1 y la información específica a…»AEMPS, section 4.5 · Open on CIMA
«Inhibidores de la CYP3A4: Los inhibidores potentes de la CYP3A4 han demostrado que producen concentraciones notablemente elevadas de atorvastatina (ver Tabla 1 y la información específica a…»AEMPS, section 4.5 · Open on CIMA
«DRUG INTERACTIONS: Intervention: In patients taking clarithromycin or itraconazole, do not exceed atorvastatin calcium 20 mg [see Dosage and Administration ( 2.5 )]. Consider the risk/FDA, section 7 · Open on DailyMed
«Daptomicina: Se han notificado casos de miopatía y/AEMPS, section 4.5 · Open on CIMA
«Inhibidores de la CYP3A4: Los inhibidores potentes de la CYP3A4 han demostrado que producen concentraciones notablemente elevadas de atorvastatina (ver Tabla 1 y la información específica a…»AEMPS, section 4.5 · Open on CIMA
«DRUG INTERACTIONS: Intervention: Concomitant use of tipranavir plus ritonavir or glecaprevir plus pibrentasvir with atorvastatin calcium is not recommended. In patients taking lopinavir plus…»FDA, section 7 · Open on DailyMed
«Gemfibrozilo/AEMPS, section 4.5 · Open on CIMA
«Gemfibrozilo/AEMPS, section 4.5 · Open on CIMA
«DRUG INTERACTIONS: Intervention: Concomitant use of cyclosporine or gemfibrozil with atorvastatin calcium is not recommended.»FDA, section 7 · Open on DailyMed
«Inhibidores de la CYP3A4: Los inhibidores potentes de la CYP3A4 han demostrado que producen concentraciones notablemente elevadas de atorvastatina (ver Tabla 1 y la información específica a…»AEMPS, section 4.5 · Open on CIMA
«DRUG INTERACTIONS: Intervention: In patients taking clarithromycin or itraconazole, do not exceed atorvastatin calcium 20 mg [see Dosage and Administration ( 2.5 )]. Consider the risk/FDA, section 7 · Open on DailyMed
«Inhibidores de la CYP3A4: Los inhibidores potentes de la CYP3A4 han demostrado que producen concentraciones notablemente elevadas de atorvastatina (ver Tabla 1 y la información específica a…»AEMPS, section 4.5 · Open on CIMA
«Inhibidores de la CYP3A4: Los inhibidores potentes de la CYP3A4 han demostrado que producen concentraciones notablemente elevadas de atorvastatina (ver Tabla 1 y la información específica a…»AEMPS, section 4.5 · Open on CIMA
«Inductores de la CYP3A4: La administración conjunta de atorvastatina con inductores del citocromo P450 3A4 (por ejemplo, efavirenz, rifampicina, hierba de San Juan) puede reducir de forma variable…»AEMPS, section 4.5 · Open on CIMA
«Inhibidores de la CYP3A4: Los inhibidores potentes de la CYP3A4 han demostrado que producen concentraciones notablemente elevadas de atorvastatina (ver Tabla 1 y la información específica a…»AEMPS, section 4.5 · Open on CIMA
«DRUG INTERACTIONS: Intervention: Concomitant use of tipranavir plus ritonavir or glecaprevir plus pibrentasvir with atorvastatin calcium is not recommended. In patients taking lopinavir plus…»FDA, section 7 · Open on DailyMed
«Inhibidores de la CYP3A4: Los inhibidores potentes de la CYP3A4 han demostrado que producen concentraciones notablemente elevadas de atorvastatina (ver Tabla 1 y la información específica a…»AEMPS, section 4.5 · Open on CIMA
«Inhibidores de la CYP3A4: Los inhibidores moderados de la CYP3A4 (por ejemplo, eritromicina, diltiazem, verapamilo y fluconazol) pueden aumentar las concentraciones plasmáticas de atorvastatina (ver…»AEMPS, section 4.5 · Open on CIMA
«Warfarina: En un ensayo clínico en pacientes que recibían tratamiento crónico con Warfarina, la administración concomitante de 80 mg al día de atorvastatina con Warfarina produjo una pequeña…»AEMPS, section 4.5 · Open on CIMA
«DRUG INTERACTIONS: Intervention: In patients taking clarithromycin or itraconazole, do not exceed atorvastatin calcium 20 mg [see Dosage and Administration ( 2.5 )]. Consider the risk/FDA, section 7 · Open on DailyMed
«Colchicina: Aunque no se han realizado estudios de interacciones con atorvastatina y colchicina, se han notificado casos de miopatía con atorvastatina cuando se administró de forma conjunta con…»AEMPS, section 4.5 · Open on CIMA
«DRUG INTERACTIONS: Intervention: Consider the risk/FDA, section 7 · Open on DailyMed
«Digoxina: Cuando se administraron conjuntamente dosis múltiples de digoxina y 10 mg de atorvastatina, las concentraciones plasmáticas en el estado estacionario de digoxina aumentaron ligeramente. Los…»AEMPS, section 4.5 · Open on CIMA
«DRUG INTERACTIONS: Digoxin: May increase digoxin plasma levels; monitor patients appropriately ( 7.3 ).»FDA, section 7 · Open on DailyMed
«Inhibidores de la CYP3A4: Los inhibidores moderados de la CYP3A4 (por ejemplo, eritromicina, diltiazem, verapamilo y fluconazol) pueden aumentar las concentraciones plasmáticas de atorvastatina (ver…»AEMPS, section 4.5 · Open on CIMA
«Tratamiento simultáneo con astemizol, terfenadina, disopiramida, cisaprida, pimocida, alcaloides del cornezuelo (como la ergotamina y la dihidroergotamina), simvastatina, atorvastatina o lovastatina.»AEMPS, section 4.3 · Open on CIMA
«Administración concomitante con los inhibidores de la HMG-CoA reductasa simvastatina, lovastatina y atorvastatina (ver sección 4.5).»AEMPS, section 4.3 · Open on CIMA
«HMG-CoA Reductase Inhibitors Primarily Metabolized Through CYP3A4: Coadministration with the HMG-CoA reductase inhibitors that are primarily metabolized through CYP3A4 (e.g., atorvastatin…»FDA, section 4 · Open on DailyMed
«DRUG INTERACTIONS: HMG-CoA Reductase Inhibitors simvastatin, lovastatin, atorvastatin Increased plasma concentration of HMGCoA reductase inhibitor. Limit the dose of lovastatin to 40 mg. Limit the…»FDA, section 7 · Open on DailyMed
«Established and Other Potentially Significant Drug Interactions: atorvastatin, rosuvastatin ↑ atorvastatin ↑ rosuvastatin Titrate atorvastatin dose carefully and use the lowest necessary dose…»FDA, section 7 · Open on DailyMed
«DRUG INTERACTIONS: Lomitapide Lovastatin Simvastatin Contraindicated Lomitapide, Lovastatin, Simvastatin: Clarithromycin may increase the exposure of these drugs by inhibition of CYP3A metabolism…»FDA, section 7 · Open on DailyMed
«Established and Other Potentially Significant Drug Interactions: Lipid Modifying Agents: HMG-CoA reductase inhibitors: lovastatin, simvastatin atorvastatin, pravastatin, rosuvastatin Other lipid…»FDA, section 7 · Open on DailyMed
«Pharmacokinetic Drug Interactions: Atorvastatin 22% 15% Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately…»FDA, section 7 · Open on DailyMed
«Inhibidores de la HMG Co-reductasa: Los inhibidores de la HMG-Co-reductasa, como lovastatina y simvastatina, son altamente dependientes del metabolismo por CYP3A, se espera que presenten un marcado…»AEMPS, section 4.5 · Open on CIMA
«Established and Other Potentially Significant Drug Interactions: Lipid-modifying agents HMG-CoA Reductase Inhibitor: lovastatin simvastatin atorvastatin rosuvastatin ↑ lovastatin ↑ simvastatin ↑…»FDA, section 7 · Open on DailyMed
«El tratamiento con inhibidores de HMG CoA reductasa (por ejemplo simvastatina, atorvastatina o lovastatina) en un paciente que tome verapamilo debe iniciarse con la dosis más baja posible y valorarse…»AEMPS, section 4.5 · Open on CIMA
«Fármacos que pueden disminuir los niveles plasmáticos de carbamazepina: Medicamentos cardiovasculares: bloqueantes de los canales de calcio (grupo dihidropiridina), p. ej. felodipino, digoxina…»AEMPS, section 4.5 · Open on CIMA
«Table 4. Other Potentially Significant Drug Interactions Concomitant Drug Class or Food Noted or Anticipated Outcome Clinical Comment HMG-Co A Reductase Inhibitors: atorvastatin, fluvastatin…»FDA, section 7 · Open on DailyMed
«INHIBIDORES DE LA HMG CO-A REDUCTASA: atorvastatina AUC ↑ 3-4 veces atorvastatina C min ↑ ≈5,5-10 veces atorvastatina C max ↑ ≈2 veces # darunavir/AEMPS, section 4.5 · Open on CIMA
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Atorvastatin is evaluated for the following indications with varying evidence strength: Familial hypercholesterolemia (evidence tier A), Dyslipidemia, primary CV prevention (evidence tier A), Established ASCVD, secondary prevention (evidence tier A). See the full indication matrix with dosing and citations above on this page.
Common side effects of Atorvastatin (≥ 1 in 100): Myalgia without CK elevation, Headache, Dyspepsia, nausea, Arthralgia, Transient transaminase elevation (usually below 3× ULN). See the Safety section for uncommon and serious reactions.
AEMPS summary of product characteristics (section 4.6): atorvastatin is contraindicated during pregnancy. Its safety in pregnant women has not been established and no controlled clinical trials have been done; congenital anomalies after intrauterine exposure to HMG-CoA reductase inhibitors have been reported rarely, and animal studies have shown reproductive toxicity. Maternal atorvastatin may lower fetal levels of mevalonate, a precursor in cholesterol synthesis, while pausing lipid-lowering therapy during pregnancy should normally have little impact on the long-term risk of primary hypercholesterolaemia. Atorvastatin is therefore not used in women who are pregnant, trying to conceive or suspect pregnancy; it is stopped for the duration of pregnancy or until pregnancy is ruled out, and women of childbearing potential should use adequate contraception during treatment.
Systemic safety data during lactation are limited. The manufacturer and most international sources recommend avoidance. In patients with a statin indication, options include a temporary switch to formula feeding or deferring therapy until breastfeeding is complete.
Atorvastatin is contraindicated in: Active liver disease or unexplained persistent transaminase elevation; Pregnancy and planned pregnancy; Breastfeeding; Hypersensitivity to any component. Full list in the Safety section.
clinically significant transaminase elevation occurs in less than 1 % of patients and is usually transient. Routine liver enzyme monitoring in asymptomatic patients is not required.
statins are long-term (usually lifelong) therapy. Discontinuation rapidly returns LDL to baseline and raises cardiovascular risk.
a small excess risk exists (roughly 1 case of T2D per 250 patients over 4 years), but the benefit from reduced cardiovascular events clearly outweighs it in patients with an indication.
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Atorvastatin + Ezetimibe, Cod liver oil, Ezetimibe, Fluvastatin, Krill oil, Pitavastatin, Rosuvastatin + Ezetimibe, Gemfibrozil