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.
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)
4 pairs found. Sorted from critical to minor.
Mechanism
Сильная ингибиция CYP3A4 кларитромицином увеличивает концентрацию симвастатина до 10 раз. Высокий риск рабдомиолиза и острой почечной недостаточности.
Management
Сочетание противопоказано. Прерывать прием симвастатина на курс кларитромицина либо заменить антибиотик на азитромицин (без CYP3A4-ингибиции).
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 evaluated for the following indications with varying evidence strength: Established ASCVD, secondary prevention (evidence tier A), Dyslipidemia, primary CV prevention (evidence tier A). 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.
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.
Mechanism
Amiodarone inhibits CYP3A4, the enzyme responsible for simvastatin metabolism. Active simvastatin acid concentrations rise 2–3-fold, and the risk of myopathy and rhabdomyolysis increases proportionally. The caps simvastatin at 20 mg/day when used with amiodarone.
Management
Do not exceed 20 mg simvastatin per day. If intolerance occurs or more intensive lipid lowering is needed, switch to pravastatin, fluvastatin, or rosuvastatin (not metabolized by CYP3A4), or use moderate-dose atorvastatin with caution.
Mechanism
Amlodipine moderately inhibits CYP3A4 – simvastatin exposure rises 30–80 %, and the risk of myopathy and rhabdomyolysis increases.
Management
The caps simvastatin at 20 mg/day when used with amlodipine. For patients needing more intensive therapy, switch to atorvastatin or rosuvastatin.
Sources
Mechanism
Simvastatin inhibits CYP3A4 and to a lesser extent CYP2C9, raising warfarin concentration. Average INR rise is 0.5–1.5 units, with significantly larger increases in some patients.
Management
Check INR 1–2 weeks after starting simvastatin and after dose changes. In warfarin patients, statins with minimal interaction – pravastatin or rosuvastatin – are preferred.
Sources
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.