Vytorin Drug Interactions

VYTORIN: No clinically significant pharmacokinetic interaction was seen when ezetimibe was coadministered with simvastatin.
VYTORIN is bioequivalent to coadministered ezetimibe and simvastatin.
Multiple mechanisms may contribute to potential interactions with HMG-CoA reductase inhibitors. Drugs or herbal products that inhibit certain enzymes (e.g. CYP3A4) and/or transporter (e.g. OATP1B) pathways may increase simvastatin and simvastatin acid plasma concentrations and may lead to an increased risk of myopathy/rhabdomyolysis.
Consult the prescribing information of all concomitantly used drugs to obtain further information about their potential interactions with simvastatin and/or the potential for enzyme or transporter alterations and possible adjustments to dose and regimens.
Contraindicated drugs: Concomitant use of the following drugs is contraindicated: Potent Inhibitors of CYP3A4: In preclinical studies, it has been shown that ezetimibe does not induce cytochrome P450 drug metabolizing enzymes. No clinically significant pharmacokinetic interactions have been observed between ezetimibe and drugs known to be metabolized by cytochromes P450 1A2, 2D6, 2C8, 2C9, and 3A4, or N-acetyltransferase. Simvastatin is metabolized by CYP3A4 but has no CYP3A4 inhibitory activity; therefore it is not expected to affect the plasma concentrations of other drugs metabolized by CYP3A4. Potent inhibitors of CYP3A4 increase the risk of myopathy by reducing the elimination of the simvastatin component of VYTORIN: Concomitant use of drugs labeled as having a potent inhibitory effect on CYP3A4 (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, drugs containing cobicistat) is contraindicated. (See Contraindications, Myopathy/Rhabdomyolysis under Precautions and Pharmacology: Pharmacokinetics under Actions.)
Gemfibrozil, Cyclosporine, or Danazol (see Contraindications and Myopathy/Rhabdomyolysis under Precautions): Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. This increase is not considered clinically significant. No clinical data are available. (See Contraindications and Myopathy/Rhabdomyolysis under Precautions.)
Cyclosporine: In a study of eight post-renal transplant patients with creatinine clearance of >50 mL/min on a stable dose of cyclosporine, a single 10-mg dose of ezetimibe resulted in a 3.4-fold (range 2.3- to 7.9-fold) increase in the mean AUC for total ezetimibe compared to a healthy control population from another study (n=17). In a different study, a renal transplant patient with severe renal insufficiency (creatinine clearance of 13.2 mL/min/1.73 m²) who was receiving multiple medications, including cyclosporine, demonstrated a 12-fold greater exposure to total ezetimibe compared to concurrent controls. In a two-period crossover study in twelve healthy subjects, daily administration of 20 mg ezetimibe for 8 days with a single 100-mg dose of cyclosporine on Day 7 resulted in a mean 15% increase in cyclosporine AUC (range 10% decrease to 51% increase) compared to a single 100-mg dose of cyclosporine alone (see Contraindications and Myopathy/Rhabdomyolysis under Precautions).
Other drug interactions: Other Fibrates: The safety and effectiveness of VYTORIN administered with fibrates have not been studied.
Simvastatin - Fibrates can cause myopathy when given alone. Severe myositis with myoglobinuria has been reported with concomitant use of statins and fibrates. Therefore, the concomitant use of VYTORIN and fibrates, should be avoided. Concomitant use of gemfibrozil is contraindicated (see Contraindications).
Ezetimibe - Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. Coadministration of ezetimibe with other fibrates has not been studied. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Although the relevance of this preclinical finding to humans is unknown, coadministration of VYTORIN with fibrates, is not recommended until use in patients is studied.
Fusidic Acid: The risk of myopathy/rhabdomyolysis may be increased by concomitant administration of fusidic acid (see Myopathy/Rhabdomyolysis under Precautions).
Amiodarone: The risk of myopathy/rhabdomyolysis is increased by concomitant administration of amiodarone with VYTORIN (see Dosage & Administration and Myopathy/Rhabdomyolysis under Precautions).
Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe (ezetimibe + ezetimibe glucuronide) approximately 55%. The incremental LDL-C reduction due to adding VYTORIN to cholestyramine may be lessened by this interaction.
Calcium Channel Blockers: The risk of myopathy/rhabdomyolysis is increased by concomitant administration of verapamil, diltiazem, or amlodipine (see Dosage & Administration and Myopathy/Rhabdomyolysis under Precautions).
Lomitapide: The risk of myopathy/rhabdomyolysis may be increased by concomitant administration of lomitapide (see Dosage & Administration and Myopathy/Rhabdomyolysis under Precautions).
Moderate Inhibitors of CYP3A4: Patients taking other medicines labeled as having a moderate inhibitory effect on CYP3A4 concomitantly with VYTORIN, particularly higher VYTORIN doses may have an increased risk of myopathy (see Myopathy/Rhabdomyolysis under Precautions).
Inhibitors of the Transport Protein OATP1B1: Simvastatin acid is a substrate of the transport protein OATP1B1. Concomitant administration of medicinal products that are inhibitors of the transport protein OATP1B1 may lead to increased plasma concentrations of simvastatin acid and an increased risk of myopathy (see Contraindications; Myopathy/Rhabdomyolysis under Precautions).
Inhibitors of Breast Cancer Resistant Protein (BCRP): Simvastatin is a substrate of the efflux transporter BCRP. Concomitant administration of products that are inhibitors of BCRP (e.g., elbasvir and grazoprevir) may lead to increased plasma concentrations of simvastatin and an increased risk of myopathy. When coadministering simvastatin with an inhibitor of BCRP, a dose adjustment of VYTORIN may be necessary (see Dosage & Administration and Myopathy/Rhabdomyolysis under Precautions).
Niacin: In a study of 15 healthy adults, concomitant VYTORIN (10/20 mg daily for 7 days) caused a small increase in the mean AUCs of niacin (22%) and nicotinuric acid (19%) administered as NIASPAN extended-release tablets (1000 mg for 2 days and 2000 mg for 5 days following a low-fat breakfast). In the same study, concomitant NIASPAN slightly increased the mean AUCs of ezetimibe (9%), total ezetimibe (26%), simvastatin (20%) and simvastatin acid (35%).
Cases of myopathy/rhabdomyolysis have been observed with simvastatin coadministered with lipid-modifying doses (≥1 g/day) of niacin (see Myopathy/Rhabdomyolysis under Precautions).
Colchicine: There have been reports of myopathy and rhabdomyolysis with the concomitant administration of colchicine and VYTORIN in patients with renal insufficiency. Close clinical monitoring of such patients taking this combination is advised.
Daptomycin: The risk of myopathy and/or rhabdomyolysis may be increased by concomitant administration of HMG-CoA reductase inhibitors and daptomycin (see Myopathy/Rhabdomyolysis under Precautions).
Other Interactions: Grapefruit juice contains one or more components that inhibit CYP3A4 and can increase the plasma levels of drugs metabolized by CYP3A4. The effect of typical consumption (one 250-mL glass daily) is minimal (13% increase in active plasma HMG-CoA reductase inhibitory activity as measured by the area under the concentration-time curve) and of no clinical relevance. However, because larger quantities significantly increase the plasma levels of HMG-CoA reductase inhibitory activity, grapefruit juice should be avoided during VYTORIN therapy (see Myopathy/Rhabdomyolysis under Precautions).
Anticoagulants: In two clinical studies, one in normal volunteers and the other in hypercholesterolemic patients, simvastatin 20-40 mg/day modestly potentiated the effect of coumarin anticoagulants: the prothrombin time, reported as International Normalized Ratio (INR), increased from a baseline of 1.7 to 1.8 and from 2.6 to 3.4 in the volunteer and patient studies, respectively. In patients taking coumarin anticoagulants, prothrombin time should be determined before starting VYTORIN and frequently enough during early therapy to ensure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of VYTORIN is changed or discontinued, the same procedure should be repeated. Simvastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants.
Concomitant administration of ezetimibe (10 mg once daily) had no significant effect on bioavailability of warfarin and prothrombin time in a study of twelve healthy adult males. There have been post-marketing reports of increased International Normalized Ratio in patients who had ezetimibe added to warfarin or fluindione. Most of these patients were also on other medications (see Precautions).
The effect of VYTORIN on the prothrombin time has not been studied.
Antacids: Concomitant antacid administration decreased the rate of absorption of ezetimibe but had no effect on the bioavailability of ezetimibe. This decreased rate of absorption is not considered clinically significant.