VYTORIN
Clinical safety rating: caution
Comprehensive clinical and safety monograph for VYTORIN (VYTORIN).
VYTORIN is a combination of ezetimibe and simvastatin. Ezetimibe inhibits the absorption of cholesterol at the brush border of the small intestine via the Niemann-Pick C1-Like 1 (NPC1L1) transporter, reducing delivery of intestinal cholesterol to the liver. Simvastatin competitively inhibits HMG-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis, leading to increased LDL receptor expression and enhanced clearance of LDL cholesterol from the plasma.
| Metabolism | Simvastatin is a substrate of CYP3A4 and is extensively metabolized in the liver via oxidation, hydrolysis, and glucuronidation. Ezetimibe is primarily metabolized via glucuronidation in the small intestine and liver (UGT enzymes), with minimal CYP-mediated metabolism. Ezetimibe undergoes enterohepatic recycling. |
| Excretion | Ezetimibe: primarily fecal (78%) and renal (11%) as glucuronide conjugate. Simvastatin: fecal (60%) and renal (13%); active metabolite via CYP3A4. Biliary excretion of both. |
| Half-life | Ezetimibe: ~22 hours (terminal) for total ezetimibe (parent plus glucuronide); simvastatin: ~2-3 hours for active metabolite; clinical effect sustained due to enterohepatic recirculation of ezetimibe. |
| Protein binding | Ezetimibe and its glucuronide: >90% bound to plasma proteins; simvastatin: ~95% bound primarily to albumin. |
| Volume of Distribution | Ezetimibe: ~10 L/kg (extensive tissue distribution); simvastatin: ~1.9 L/kg (moderate distribution). Clinical meaning: large Vd indicates extensive extravascular distribution. |
| Bioavailability | Ezetimibe: 35-65% (oral); simvastatin: <5% (oral, extensive first-pass); food does not affect ezetimibe absorption but may reduce simvastatin absorption. |
| Onset of Action | LDL-C reduction begins within 2 weeks, maximal effect by 4-6 weeks; no acute clinical effect (oral). |
| Duration of Action | LDL-C reduction persists for duration of daily dosing; effect wanes over 2-3 weeks after discontinuation; no acute hemodynamic duration. |
VYTORIN (ezetimibe/simvastatin) is dosed once daily in the evening. The usual starting dose is 10/20 mg, titrated up to a maximum of 10/40 mg. Dose selection should be based on the patient's LDL-C level, cardiovascular risk, and response. The 10/80 mg dose is restricted to patients who have been taking this dose for ≥12 months without evidence of myopathy.
| Dosage form | TABLET |
| Renal impairment | For patients with moderate to severe renal impairment (eGFR <30 mL/min/1.73 m²), the dose of simvastatin should be limited to 10/20 mg once daily. No adjustment is recommended for eGFR ≥30 mL/min/1.73 m². |
| Liver impairment | VYTORIN is contraindicated in patients with active liver disease or unexplained persistent elevations of hepatic transaminases. For patients with Child-Pugh A (mild hepatic impairment), no dose adjustment is recommended. Child-Pugh B (moderate impairment): use with caution; the effect of ezetimibe/simvastatin in Child-Pugh B has not been studied. Child-Pugh C (severe impairment): contraindicated (do not use). |
| Pediatric use | For pediatric patients aged 10–17 years with heterozygous familial hypercholesterolemia: Starting dose is 10/10 mg once daily in the evening. Dose may be increased at intervals of ≥4 weeks based on LDL-C response and tolerability, up to a maximum of 10/40 mg once daily. Use is not recommended in children <10 years of age. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for VYTORIN (VYTORIN).
| Breastfeeding | Excretion into human milk is unknown for ezetimibe; simvastatin is excreted in trace amounts. Due to potential for adverse effects in nursing infants (e.g., interference with lipid metabolism), breastfeeding is not recommended. M/P ratio not established. |
| Teratogenic Risk | Pregnancy Category X. Vytorin (ezetimibe/simvastatin) is contraindicated in pregnancy. Simvastatin inhibits HMG-CoA reductase, essential for cholesterol synthesis, which is critical for fetal development. First trimester exposure may cause neural tube defects, skeletal abnormalities, and spontaneous abortions. Second and third trimester exposure may impair fetal growth and organogenesis. Use is not recommended at any stage. |
■ FDA Black Box Warning
Simvastatin is contraindicated in patients with active liver disease or unexplained persistent elevations of serum transaminases. Simvastatin may cause myopathy/rhabdomyolysis. Risk is increased by high dose (80 mg simvastatin), concomitant use of certain drugs (e.g., potent CYP3A4 inhibitors, gemfibrozil, cyclosporine, danazol), and in certain patient populations. The 80 mg dose of simvastatin should be used only in patients who have been taking this dose for 12 months without evidence of myopathy.
| Serious Effects |
["Active liver disease or unexplained persistent elevations of serum transaminases","Known hypersensitivity to ezetimibe, simvastatin, or any component of the formulation","Pregnancy or breastfeeding","Concomitant use of potent CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, cobicistat-containing products)","Concomitant use of gemfibrozil, cyclosporine, or danazol"]
| Precautions | ["Myopathy/Rhabdomyolysis: Risk factors include age ≥65 years, female gender, renal impairment, hypothyroidism, and concomitant use of interacting drugs. Discontinue if creatine kinase is markedly elevated or if myopathy is diagnosed.","Hepatic effects: Persistent elevations in serum transaminases may occur. Perform liver function tests before initiation and as clinically indicated.","Increased risk of myopathy with high-dose simvastatin (80 mg) and with certain concomitant medications (e.g., amiodarone, verapamil, diltiazem, dronedarone, amlodipine, ranolazine, ticagrelor, or in patients of Chinese descent taking niacin doses ≥1 g/day).","Severe dermatologic reactions (e.g., Stevens-Johnson syndrome) have been reported with ezetimibe.","Pancreatitis has been reported with ezetimibe.","Interstitial lung disease has been reported with statins."] |
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| Geriatric use |
| In elderly patients (≥65 years), dosing should be based on renal function. Start at the lower end of the dosing range (10/10 mg or 10/20 mg) due to increased risk of myopathy. Titrate cautiously; maximum recommended dose is 10/40 mg once daily. The 10/80 mg dose is contraindicated in this population. |
| Fetal Monitoring | Monitor maternal liver function (ALT, AST) at baseline and periodically; monitor for myopathy/rhabdomyolysis (CPK levels if symptoms). Fetal monitoring via ultrasound if inadvertent exposure occurs; assess for congenital anomalies. Postnatal monitoring of infant for growth and development if exposure in late pregnancy. |
| Fertility Effects | Ezetimibe: No significant impact on fertility in animal studies. Simvastatin: May reduce sperm motility and testosterone levels in males; effects on female fertility not well-established. Use may impair fertility in some patients. |