SIMVASTATIN
Clinical safety rating: avoid
Contraindicated (not allowed)
Competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis. Reduces hepatic cholesterol synthesis, increases LDL receptor expression, and lowers plasma LDL cholesterol.
| Metabolism | Primarily via CYP3A4; also CYP3A5. Metabolites include active beta-hydroxy acid form. Undergoes extensive first-pass metabolism. |
| Excretion | Primarily hepatic metabolism, with approximately 13% excreted in urine as metabolites and 60% in feces via biliary elimination; less than 0.5% of the active form is excreted unchanged in urine. |
| Half-life | The terminal elimination half-life of simvastatin is approximately 2-3 hours, but for the active metabolite (simvastatin acid) it is about 1.9 hours; clinical lipid-lowering effects persist longer due to sustained HMG-CoA reductase inhibition. |
| Protein binding | Approximately 95% bound to plasma proteins, primarily albumin. |
| Volume of Distribution | Volume of distribution is about 1.2 L/kg; this large Vd indicates extensive tissue distribution, notably to the liver (target organ). |
| Bioavailability | Oral bioavailability is about 5% due to extensive first-pass hepatic metabolism; the active metabolite (simvastatin acid) has a bioavailability of <5%. |
| Onset of Action | Oral: Onset of reduction in LDL cholesterol is observed within 2 weeks of therapy initiation. |
| Duration of Action | Duration of action after oral administration is approximately 24 to 36 hours for the lipid-lowering effect, as the inhibition of HMG-CoA reductase persists beyond the plasma half-life; once-daily dosing is effective. |
| Molecular Weight | 418.56 |
10-40 mg orally once daily in the evening; maximum 80 mg/day.
| Dosage form | TABLET |
| Renal impairment | If GFR <30 mL/min, start with 5 mg/day and increase cautiously; maximum 10 mg/day. |
| Liver impairment | Contraindicated in active liver disease or unexplained transaminase elevations; use with caution in Child-Pugh class A; avoid in Child-Pugh class B or C. |
| Pediatric use | Children 10-17 years: 10-40 mg orally once daily in the evening; maximum 40 mg/day; safety not established for <10 years. |
| Geriatric use | Start at lower end of dosing range (5-10 mg/day) due to increased risk of myopathy; titrate slowly. |
| 1st trimester | Simvastatin is contraindicated in pregnancy due to risk of fetal harm; HMG-CoA reductase inhibitors decrease synthesis of cholesterol and possibly other bioactive substances derived from cholesterol, which are essential for fetal development. Cases of congenital anomalies have been reported. |
| 2nd trimester | Contraindicated; use should be avoided. There is no indication for use during pregnancy. If pregnancy occurs, therapy should be discontinued immediately. |
| 3rd trimester | Contraindicated; use should be avoided. Potential adverse effects include decreased fetal cholesterol synthesis, risk of developmental toxicity, and possible neonatal adverse effects. |
Clinical note
Strong CYP3A4 inhibitors (eg itraconazole) can significantly increase levels and risk of myopathy Can cause myopathy and rhabdomyolysis.
| Placental transfer | Simvastatin and its active metabolite, simvastatin acid, cross the placenta. Animal studies demonstrate fetal transfer, and human data indicate measurable levels in fetal tissues. The degree of transfer is moderate, with fetal:maternal ratio estimated around 0.3-0.5 based on limited human data. |
■ FDA Black Box Warning
No FDA black box warning.
| Common Effects | Headache |
| Serious Effects |
Active liver disease or unexplained persistent elevations of serum transaminasesPregnancyBreastfeedingConcomitant use with strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, and cobicistat-containing products)Hypersensitivity to simvastatin or any component of the formulation
| Precautions | Myopathy/rhabdomyolysis risk increased with high doses, interacting drugs (e.g., strong CYP3A4 inhibitors), renal impairment, hypothyroidism, Hepatic enzyme elevations; monitor LFTs, Increased risk of diabetes mellitus, Avoid grapefruit juice intake |
| Food/Dietary |
Loading safety data…
| Breastfeeding | Simvastatin is excreted into human breast milk in small amounts. Due to potential for serious adverse reactions in nursing infants, including interference with lipid metabolism and potential for tumorigenicity, breastfeeding is not recommended during simvastatin therapy. Use an alternative agent if lipid-lowering is required. |
| Lactation Rating | L4 - Hazardous |
| Teratogenic Risk | Simvastatin is contraindicated in pregnancy. HMG-CoA reductase inhibitors decrease cholesterol synthesis and may reduce levels of other mevalonate derivatives, which are essential for fetal development. First trimester: Exposure associated with congenital anomalies including CNS defects, limb reduction defects, and cardiac abnormalities based on case reports and limited animal studies. Second and third trimesters: Continued risk of fetal harm; drug should be discontinued immediately if pregnancy occurs. |
| Fetal Monitoring | For inadvertent use in pregnancy, perform fetal ultrasound to assess for structural anomalies. Monitor maternal liver function tests and creatine kinase if exposure continues. No routine fetal monitoring recommended beyond standard prenatal care. |
| Fertility Effects | Limited data in humans. Animal studies show no significant effect on fertility at clinically relevant doses. However, lipid-lowering therapy may be discontinued in women planning pregnancy. |
| Grapefruit juice (increases simvastatin exposure); avoid consumption. Alcohol (hepatotoxicity risk); limit intake. High-fat meals may delay absorption but not significantly affect efficacy. No specific restrictions with other foods. |
| Clinical Pearls | Simvastatin is a prodrug metabolized by CYP3A4; avoid coadministration with potent CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone) and grapefruit juice due to increased risk of myopathy/rhabdomyolysis. Maximum dose is 40 mg/day when used with amiodarone, verapamil, diltiazem, or amlodipine; do not exceed 20 mg/day with amlodipine. Contraindicated in active liver disease or unexplained persistent transaminase elevations. Monitor for myalgias, muscle weakness, and CK levels; discontinue if CK markedly elevated or myopathy suspected. |
| Patient Advice | Take simvastatin once daily in the evening with or without food. · Do not take with grapefruit or grapefruit juice; can increase risk of severe muscle injury. · Report unexplained muscle pain, tenderness, weakness, or dark urine immediately. · Avoid alcohol consumption; may increase risk of liver problems. · Inform your doctor about all other medications, especially antifungals, antibiotics, and heart medications. · Do not exceed prescribed dose; higher doses increase muscle damage risk. · Continue statin even if feeling well; it helps prevent heart attack and stroke. · Keep regular appointments for blood tests to monitor liver function and cholesterol. |