HMG-CoA reductase inhibitors (statins)
ATC code: C10AA01 (Simvastatin)
A prodrug – converted in the liver to an active β-hydroxy acid metabolite that competitively inhibits HMG-CoA reductase. Reduces hepatic cholesterol synthesis, upregulates receptors, and increases LDL clearance from plasma. Metabolized by CYP3A4 – considerably more sensitive to CYP3A4 inhibitors than atorvastatin. The restricted the 80 mg dose in 2011 due to elevated myopathy risk. Maximum dose is 20 mg with amlodipine and ranolazine, and 20 mg with amiodarone/verapamil/diltiazem; combination with azoles/macrolides/cyclosporine/gemfibrozil is contraindicated.
First line
Prescribed for primary prevention in patients with elevated cardiovascular risk. Dose 20-40 mg in the evening. The 80 mg dose is no longer recommended – restricted it in 2011 due to increased myopathy and rhabdomyolysis risk. New patients do not start at 80 mg; it is retained only for those who have taken it for over 12 months without adverse effects.
First line
Simvastatin demonstrated efficacy in landmark RCTs – 4S (30% reduction in all-cause mortality) and HPS (24% reduction in vascular events). These trials laid the evidence foundation for the entire statin class. In current practice, atorvastatin and rosuvastatin are preferred due to more potent reduction and fewer interactions. Simvastatin remains a reasonable choice at doses up to 40 mg.
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
Simvastatin is a moderate-potency statin, one of the most prescribed statins worldwide. It is prescribed for hyperlipidemia and for primary/secondary CV prevention ( 2019). In healthy adults, simvastatin is occasionally prescribed for general vascular protection or anti-aging, citing older meta-analyses. In people without confirmed CV risk factors, clinical studies do not justify prophylactic use. Simvastatin interacts with CYP3A4 more strongly than other statins (combinations with clarithromycin, erythromycin, itraconazole, and large amounts of grapefruit juice are prohibited due to rhabdomyolysis risk). In 2011 the limited the maximum simvastatin dose to 40 mg/day due to dose-dependent muscle toxicity risk. If simvastatin was prescribed at normal lipid levels, consider seeking a second opinion.
Grapefruit furanocoumarins irreversibly inhibit intestinal CYP3A4. Simvastatin exposure rises 3–7 fold; myopathy and rhabdomyolysis risk. Effect persists up to 72 hours after juice intake. Avoid, or switch to pravastatin/rosuvastatin (not CYP3A4-metabolized).
Source: FDA: Zocor (simvastatin) prescribing information (2020)
24 pairs found. Sorted from critical to minor.
Mechanism
Amiodarone inhibits CYP3A4 and P-glycoprotein. Simvastatin concentration rises 2–4 fold with risk of rhabdomyolysis and acute kidney injury. Zocor Section 4.3 caps simvastatin at 20 mg/day with amiodarone; above 20 mg – strict contraindication.
Symptoms
Myalgia, weakness, dark urine within 1–4 weeks. CK above 10× ULN.
Management
Cap simvastatin at 20 mg/day. Better option: switch to pravastatin or rosuvastatin (not metabolised via CYP3A4).
Sources
Mechanism
Atazanavir inhibits CYP3A4. Simvastatin rises 10+ fold – fatal rhabdomyolysis.
Symptoms
Myalgia, dark urine within 5-10 days.
Management
Combination contraindicated. Switch to pravastatin or rosuvastatin.
Mechanism
Cyclosporine blocks two simvastatin clearance routes: the OATP1B1 transporter (uptake into hepatocytes) and CYP3A4. Active simvastatin levels rise 5- to 8-fold. The Zocor label specifically lists cyclosporine as an absolute contraindication.
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 1–2 weeks of co-prescription.
Management
The combination is not prescribed. For transplant patients needing a statin, use pravastatin up to 20 mg/day or fluvastatin (minimal interaction with cyclosporine). Check creatine kinase every 4–6 weeks.
Mechanism
Simvastatin clearance is 98% dependent on hepatic CYP3A4. Clarithromycin is a potent inhibitor of this enzyme; simvastatin plasma concentrations rise 10-fold or more. The lists this combination as an absolute contraindication.
Symptoms
Pain and weakness in large muscle groups, dark urine, elevated creatine kinase on lab work. Severe cases progress to rhabdomyolysis with acute kidney injury. First signs appear within 3–7 days of concurrent dosing.
Management
The combination is not prescribed. Hold simvastatin for the duration of clarithromycin therapy or switch the patient to pravastatin or rosuvastatin – these statins use a different metabolic pathway and do not interact. If simvastatin cannot be paused, replace the antibiotic: azithromycin or a non-macrolide class based on susceptibility.
Mechanism
Cobicistat is a strong CYP3A4 inhibitor. Simvastatin rises 30-fold with fatal rhabdomyolysis risk. Tybost Section 4.3.
Symptoms
Myalgia, weakness, dark urine within 5 days.
Management
Combination contraindicated. Alternative statin: pravastatin 20–40 mg or rosuvastatin 5–10 mg.
Mechanism
Darunavir inhibits CYP3A4. Simvastatin rises 10+ fold – fatal rhabdomyolysis.
Symptoms
Myalgia, CK above 50× ULN.
Management
Combination contraindicated. Pravastatin or rosuvastatin.
Mechanism
Erythromycin inhibits CYP3A4. Simvastatin is a sensitive substrate; its concentration rises 6-fold. High rate of rhabdomyolysis with fatal cases reported. Zocor Section 4.3 – strict contraindication.
Symptoms
Muscle pain, weakness, dark urine within 7 days. Labs show sharp rise in creatine kinase and creatinine.
Management
Combination contraindicated. Hold simvastatin during erythromycin therapy. Alternative: pravastatin or rosuvastatin – neither is metabolised via CYP3A4.
Mechanism
Itraconazole is the strongest CYP3A4 inhibitor in clinical use. Simvastatin is a sensitive substrate; its concentration rises 10–20 fold. Risk of rhabdomyolysis with acute kidney injury is the highest among statin–azole combinations.
Symptoms
Rhabdomyolysis within 3–7 days: myalgia, weakness, dark urine. CK above 50× ULN, oliguria.
Management
Combination contraindicated. Stop simvastatin one week before starting itraconazole and resume 2 weeks after the last dose. Alternative: pravastatin or rosuvastatin.
Mechanism
Simvastatin clearance is 98% via hepatic CYP3A4. Ketoconazole is one of the strongest CYP3A4 inhibitors. Simvastatin plasma levels rise 10-fold or more. The lists the combination as an absolute contraindication.
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 1–2 weeks of co-prescription.
Management
The combination is not prescribed. Hold simvastatin during ketoconazole therapy or switch to pravastatin or rosuvastatin (no CYP3A4 use). Alternative antifungals: terbinafine or echinocandins.
Mechanism
Posaconazole is a strong CYP3A4 inhibitor. Simvastatin rises 10+ fold, rhabdomyolysis risk. Noxafil Section 4.3.
Symptoms
Rhabdomyolysis within 5–10 days.
Management
Combination contraindicated. Pravastatin or rosuvastatin.
Mechanism
Simvastatin is cleared via hepatic CYP3A4. Ritonavir is the strongest available CYP3A4 inhibitor. Simvastatin plasma levels rise 30-fold or more. The lists the combination as an absolute contraindication.
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 1–2 weeks of co-prescription.
Management
The combination is not prescribed. For HIV patients on ritonavir-boosted therapy who need a statin, use low-dose pravastatin or rosuvastatin. Cap rosuvastatin at 10 mg/day with ritonavir.
Mechanism
Amlodipine moderately inhibits CYP3A4 – the main simvastatin metabolic route. Simvastatin plasma levels rise by about 77%. Rhabdomyolysis has been reported at simvastatin doses of 40 mg or above.
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
Cap simvastatin at 20 mg/day when combined with amlodipine. If targets are missed, switch to pravastatin or rosuvastatin (no CYP3A4 dependence) or replace amlodipine with lisinopril or telmisartan.
Mechanism
Carbamazepine induces CYP3A4 – the main simvastatin metabolic route. Simvastatin plasma levels fall 5- to 10-fold; 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 simvastatin 2- to 3-fold with lipid profile and creatine kinase monitoring, or switch to pravastatin/rosuvastatin (metabolism less CYP3A4-dependent). Alternative anticonvulsants without induction: levetiracetam, lamotrigine.
Mechanism
Simvastatin is metabolised by CYP3A4; colchicine uses the same route and inhibits it. Simvastatin plasma levels rise, amplifying additive myotoxicity.
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. For long-term gout prophylaxis, switch to pravastatin (no CYP3A4 dependence) or replace colchicine with allopurinol.
Mechanism
Diltiazem inhibits CYP3A4. Simvastatin concentration rises 2.7-fold. Zocor Section 7 caps simvastatin at 10 mg/day with diltiazem due to myopathy and rhabdomyolysis risk.
Symptoms
Pain in thighs and shoulder girdle, CK above 5× ULN, dark urine.
Management
Cap simvastatin at 10 mg/day. Alternative: pravastatin 40 mg or rosuvastatin 10–20 mg with comparable effect.
Sources
Mechanism
Dronedarone inhibits CYP3A4 – the main simvastatin metabolic route. Simvastatin plasma levels rise 4-fold. Zocor 2012 caps simvastatin at 10 mg/day with dronedarone.
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
Cap simvastatin at 10 mg/day when combined. If targets are missed, switch to pravastatin or rosuvastatin (no CYP3A4 dependence).
Sources
Mechanism
Efavirenz induces CYP3A4. Simvastatin falls 60% – lipid-lowering effect lost.
Symptoms
returns to baseline.
Management
Alternative statin – pravastatin or rosuvastatin.
Mechanism
Fluconazole at 200 mg/day or above moderately inhibits CYP3A4 – the main simvastatin metabolic route. Simvastatin plasma levels rise 2- to 3-fold, with increased myopathy risk.
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 short fluconazole courses (up to 7 days), hold simvastatin or halve the dose. For prolonged systemic therapy, switch to pravastatin/rosuvastatin or use an alternative antifungal (echinocandins).
Mechanism
Phenytoin induces CYP3A4. Simvastatin level falls 60%, lipid-lowering effect is lost. cholesterol returns to baseline, cardiovascular risk rises.
Symptoms
returns to baseline over 4–6 weeks.
Management
Alternative statin: pravastatin or rosuvastatin (not CYP3A4-metabolised). Alternative anticonvulsant: levetiracetam.
Mechanism
Rifampicin strongly induces CYP3A4 and the OATP1B1 transporter – the routes of simvastatin activation and hepatocyte uptake. Simvastatin plasma levels fall by 87%; lipid-lowering effect practically disappears.
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 simvastatin to pravastatin (less induction-sensitive metabolism). Induction persists for 2 weeks after rifampicin stops – reintroduce simvastatin gradually.
Mechanism
Verapamil inhibits CYP3A4 and P-glycoprotein. Simvastatin rises 2–3 fold with myopathy and rhabdomyolysis risk. Zocor Section 7 caps simvastatin at 10 mg/day with verapamil.
Symptoms
Myalgia, weakness, rising CK within 1–3 weeks.
Management
Cap simvastatin at 10 mg/day. Alternative: pravastatin or rosuvastatin.
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
Simvastatin weakly inhibits CYP3A4 and partly displaces warfarin from protein binding. INR may rise by 0.5–1 in the first 2 weeks.
Symptoms
Gum bleeding, epistaxis, bruising without trauma, black or tarry stools, haematuria. Higher risk in older patients, prior peptic ulcer disease, and chronic kidney disease.
Management
On simvastatin initiation, check INR at 1 and 2 weeks, then per usual schedule. If INR rises, reduce warfarin by 10%. Alternatives: pravastatin or rosuvastatin (minimal warfarin effect).
Sources
Mechanism
Azithromycin does not significantly inhibit CYP3A4, unlike clarithromycin and erythromycin (the labels these as absolute contraindications with simvastatin due to rhabdomyolysis risk). Simvastatin does not accumulate.
Symptoms
The combination usually causes no specific symptoms. Each drug's individual side effects remain.
Management
No dose adjustment needed. When a macrolide is needed on simvastatin, azithromycin is the preferred choice. Clarithromycin and erythromycin are not combined with simvastatin — switch to azithromycin or to pravastatin/rosuvastatin (minimal CYP3A4 metabolism).
Sources
Opens the checker prefilled with this drug. Pick the second one from your regimen.
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In July 2021 the FDA removed the automatic contraindication during pregnancy from labels of all statins (Drug Safety Communication, 2021-07-20). The FDA pregnancy categories (A/B/C/D/X) were retired in 2015 under the PLLR — historically simvastatin was classified as X. The decision is now individualized: in patients without atherosclerotic CVD, statins are usually discontinued before conception and throughout pregnancy; in those with documented atherosclerosis and high event risk, continuation is possible after shared decision-making with a cardiologist. An unplanned pregnancy is a trigger for discussion, not for default discontinuation.
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.
Simvastatin is evaluated for the following indications with varying evidence strength: Established ASCVD, secondary prevention (evidence tier A), Dyslipidemia, primary CV prevention (evidence tier A), Anti-aging and longevity (evidence tier F). See the full indication matrix with dosing and citations above on this page.
Common side effects of Simvastatin (≥ 1 in 100): Myalgia, Headache, Dyspepsia, nausea, constipation, Transaminase elevation (usually transient). See the Safety section for uncommon and serious reactions.
FDA category X. In July 2021 the FDA removed the automatic contraindication during pregnancy from labels of all statins (Drug Safety Communication, 2021-07-20). The FDA pregnancy categories (A/B/C/D/X) were retired in 2015 under the PLLR — historically simvastatin was classified as X. The decision is now individualized: in patients without atherosclerotic CVD, statins are usually discontinued before conception and throughout pregnancy; in those with documented atherosclerosis and high event risk, continuation is possible after shared decision-making with a cardiologist. An unplanned pregnancy is a trigger for discussion, not for default discontinuation.
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.
Simvastatin is contraindicated in: Active liver disease or unexplained persistent transaminase elevation; Concurrent potent CYP3A4 inhibitors – itraconazole, ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors; Concurrent gemfibrozil, cyclosporine, or danazol. Full list in the Safety section.