ZOCOR
Clinical safety rating: caution
Comprehensive clinical and safety monograph for ZOCOR (ZOCOR).
Competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis. Increases hepatic LDL receptor expression, enhancing clearance of LDL from plasma.
| Metabolism | Extensively metabolized via CYP3A4; active metabolite (beta-hydroxyacid). Also undergoes glucuronidation and oxidation. |
| Excretion | Approximately 13% renal, 60% biliary/fecal as metabolites; parent drug and active metabolites. |
| Half-life | Terminal elimination half-life of simvastatin is approximately 2 hours for the parent drug, but for the active metabolite (simvastatin acid), it is about 1.9 hours. Clinical context: Due to extensive first-pass metabolism, the effective half-life for HMG-CoA reductase inhibition is longer (approximately 4-6 hours), supporting once-daily dosing in the evening. |
| Protein binding | Approximately 95% bound to plasma proteins, primarily albumin. |
| Volume of Distribution | Mean volume of distribution is about 0.9 L/kg, indicating extensive distribution into tissues. |
| Bioavailability | Oral bioavailability of simvastatin is less than 5% due to extensive first-pass metabolism; however, the active metabolite (simvastatin acid) has an oral bioavailability of approximately 5%. |
| Onset of Action | Oral: Reductions in LDL cholesterol are detectable within 2 weeks, with maximal effect observed after 4-6 weeks of continuous therapy. |
| Duration of Action | LDL cholesterol reduction persists for the duration of daily dosing. After discontinuation, lipid levels return to baseline within several weeks. Clinical notes: Once-daily dosing is sufficient due to prolonged suppression of hepatic cholesterol synthesis. |
| Molecular Weight | 418.57 |
| Action Class | HMG CoA inhibitors (statins) |
| Brand Substitutes | StayHappi Simvastatin 20mg Tablet, Simastin 20mg Tablet, Simvastol 20mg Tablet, Simlip 20mg Tablet, Simlup 20mg Tablet, Starstat 40mg Tablet, Zosta 40mg Tablet, Simvotin 40 Tablet, Simvatic 40 Tablet, Sim 10mg Tablet, Biosim 10mg Tablet, Stn 10mg Tablet, Simvas 10mg Tablet, Satin 10mg Tablet, Colors Syrup, Eclor 125mg Premix Syrup, Mytex 125mg Syrup, Sporicef 125mg Syrup, Acticlor 125mg Syrup |
5-40 mg orally once daily in the evening; initial dose 10-20 mg, maximum 40 mg.
| Dosage form | TABLET |
| Renal impairment | CrCl <30 mL/min: contraindicated; CrCl 30-80 mL/min: no adjustment required but use cautiously. |
| Liver impairment | Contraindicated in active liver disease or unexplained persistent transaminase elevations. Child-Pugh class A: no adjustment; Child-Pugh class B or C: contraindicated. |
| Pediatric use | Heterozygous familial hypercholesterolemia (age 10-17): 10-40 mg orally once daily in the evening; start at 10 mg, adjust at 4-week intervals. |
| Geriatric use | Initiate at lower end of dosing range (5-10 mg) due to increased risk of myopathy; monitor renal function (CrCl) and adjust accordingly. |
| 1st trimester | Contraindicated due to risk of fetal skeletal malformations and congenital anomalies based on animal studies and limited human data. |
| 2nd trimester | Contraindicated; simvastatin crosses the placenta and may interfere with fetal cholesterol synthesis essential for development. |
| 3rd trimester | Contraindicated; continued exposure may further impair fetal development and increase risk of neonatal complications. |
Clinical note
Comprehensive clinical and safety monograph for ZOCOR (ZOCOR).
| Placental transfer | Simvastatin and its active metabolite cross the placenta in measurable amounts based on ex vivo human placental perfusion studies and in vivo cord blood measurements. |
| Breastfeeding | Excreted into human milk at low levels, but due to potential for serious adverse effects in nursing infants (e.g., disruption of lipid metabolism), use is not recommended; alternative agents with more safety data are preferred. |
■ FDA Black Box Warning
None
| Serious Effects |
Hypersensitivity to simvastatin or any componentActive liver disease or unexplained persistent elevations of serum transaminasesConcurrent use of strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, and cobicistat-containing products)Concurrent use of gemfibrozil, cyclosporine, or danazolPregnancyLactationConcurrent use of large quantities of grapefruit juice (>1 quart/day)
| Precautions | Risk of myopathy/rhabdomyolysis, especially with concurrent use of CYP3A4 inhibitors (e.g., cyclosporine, gemfibrozil, azole antifungals, macrolide antibiotics, protease inhibitors, grapefruit juice), Hepatic enzyme elevations; monitor liver function before and during therapy, Avoid use in patients with active liver disease or unexplained persistent transaminase elevations, Use caution in patients with predisposing factors for myopathy (e.g., renal impairment, hypothyroidism, age >65, female sex) |
| Food/Dietary |
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| Lactation Rating | L4 - Possibly Hazardous |
| Teratogenic Risk | FDA Pregnancy Category X. Contraindicated in pregnancy. HMG-CoA reductase inhibitors may cause fetal harm when administered to pregnant women. There are reports of congenital anomalies following intrauterine exposure to statins. Risk of skeletal and neurological defects. First trimester exposure may increase risk of spontaneous abortion; second and third trimester exposure may increase risk of fetal abnormalities. Discontinue therapy immediately if pregnancy occurs. |
| Fetal Monitoring | Not indicated due to contraindication. If inadvertent exposure, monitor fetal development via ultrasound. Perform liver function tests (ALT, AST) and creatine kinase (CK) as clinically indicated. Monitor maternal lipid levels if therapy is resumed postpartum. |
| Fertility Effects | No human data on fertility effects. In animal studies, simvastatin did not impair fertility at clinically relevant doses. However, statins may theoretically affect steroidogenesis and gametogenesis; no clinical evidence of significant impairment. |
| Avoid large amounts of grapefruit juice ( >1 quart/day) as it inhibits CYP3A4 and increases simvastatin levels. No other specific food interactions; maintain a heart-healthy diet low in saturated fats and cholesterol. |
| Clinical Pearls | ZOCOR (simvastatin) is a prodrug requiring hepatic metabolism via CYP3A4; avoid coadministration with strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, nefazodone). Contraindicated with gemfibrozil due to increased risk of myopathy/rhabdomyolysis. Use caution in patients with renal impairment (CrCl <30 mL/min) and consider lower starting doses. Hepatotoxicity risk: monitor LFTs at baseline and as clinically indicated. Myopathy risk increases with high doses (80 mg); avoid 80 mg dose in most patients except those who have been stable on 80 mg for >12 months without muscle toxicity. |
| Patient Advice | Take ZOCOR once daily in the evening, with or without food. · Avoid grapefruit juice while taking ZOCOR; it can increase drug levels and side effects. · Report unexplained muscle pain, tenderness, or weakness, especially with fever or malaise. · Avoid alcohol to reduce risk of liver damage. · Do not take ZOCOR if pregnant or breastfeeding; use effective contraception. · Inform your doctor of all medications you take, especially antifungals, antibiotics, or other cholesterol medicines. · Do not change dose or stop without consulting your doctor. |