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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.
Pharmacodynamic interactions: Interactions with lipid-lowering medicinal products that can cause myopathy when given alone: The risk of myopathy, including rhabdomyolysis, is increased during concomitant administration of simvastatin with fibrates. Additionally, there is a pharmacokinetic interaction of simvastatin with gemfibrozil resulting in increased simvastatin plasma levels (see Pharmacokinetic interactions as follows and Contraindications and Precautions). Rare cases of myopathy/rhabdomyolysis have been associated with simvastatin co-administered with lipid-modifying doses (≥ 1 g/day) of niacin (see Precautions).
Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile (see Pharmacology: Toxicology: Preclinical safety data under Actions). Although the relevance of this preclinical finding to humans is unknown, co-administration of VYTORIN with fibrates is not recommended (see Precautions).
Pharmacokinetic interactions: Prescribing recommendations for interacting agents are summarised in the following table (further details are provided in the text; see also Dosage & Administration, Contraindications and Precautions). (See Table 6.)
Click on icon to see table/diagram/imageEffects of other medicinal products on VYTORIN: VYTORIN: 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%). (See Dosage & Administration and Precautions.)
Drug interaction studies with higher doses of simvastatin have not been investigated.
Ezetimibe: 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.
Cholestyramine: Concomitant cholestyramine administration decreased the mean area under the curve (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 (see Dosage & Administration).
Ciclosporin: In a study of eight post-renal transplant patients with creatinine clearance of >50 ml/min on a stable dose of ciclosporin, 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, receiving ezetimibe alone, from another study (n=17). In a different study, a renal transplant patient with severe renal impairment who was receiving ciclosporin and multiple other medications demonstrated a 12-fold greater exposure to total ezetimibe compared to concurrent controls receiving ezetimibe alone. 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 ciclosporin on Day 7 resulted in a mean 15% increase in ciclosporin AUC (range 10% decrease to 51% increase) compared to a single 100-mg dose of ciclosporin alone. A controlled study on the effect of co-administered ezetimibe on ciclosporin exposure in renal transplant patients has not been conducted. Concomitant administration of VYTORIN with ciclosporin is contraindicated (see Contraindications).
Fibrates: Concomitant fenofibrate or gemfibrozil administration increased total ezetimibe concentrations approximately 1.5- and 1.7-fold, respectively. Although these increases are not considered clinically significant, co-administration of VYTORIN with gemfibrozil is contraindicated and with other fibrates is not recommended (see Contraindications and Precautions).
Simvastatin: Simvastatin is a substrate of cytochrome P450 3A4. Potent inhibitors of cytochrome P450 3A4 increase the risk of myopathy and rhabdomyolysis by increasing the concentration of HMG-CoA reductase inhibitory activity in plasma during simvastatin therapy. Such inhibitors include itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors (e.g. nelfinavir), boceprevir, telaprevir, nefazodone, and medicinal products containing cobicistat. Concomitant administration of itraconazole resulted in a more than 10-fold increase in exposure to simvastatin acid (the active beta-hydroxyacid metabolite). Telithromycin caused an 11-fold increase in exposure to simvastatin acid.
Combination with itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors (e.g. nelfinavir), boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, and medicinal products containing cobicistat is contraindicated, as well as gemfibrozil, ciclosporin, and danazol (see Contraindications). If treatment with potent CYP3A4 inhibitors (agents that increase AUC approximately 5-fold or greater) is unavoidable, therapy with VYTORIN must be suspended (and use of an alternative statin considered) during the course of treatment. Caution should be exercised when combining VYTORIN with certain other less potent CYP3A4 inhibitors: fluconazole, verapamil, or diltiazem (see Dosage & Administration and Precautions).
Fluconazole: Rare cases of rhabdomyolysis associated with concomitant administration of simvastatin and fluconazole have been reported. (See Precautions.)
Ciclosporin: The risk of myopathy/rhabdomyolysis is increased by concomitant administration of ciclosporin with VYTORIN; therefore, use with ciclosporin is contraindicated (see Contraindications and Precautions). Although the mechanism is not fully understood, ciclosporin has been shown to increase the AUC of HMG-CoA reductase inhibitors. The increase in AUC for simvastatin acid is presumably due, in part, to inhibition of CYP3A4 and/or OATP1B1.
Danazol: The risk of myopathy and rhabdomyolysis is increased by concomitant administration of danazol with VYTORIN; therefore, use with danazol is contraindicated (see Contraindications and Precautions).
Gemfibrozil: Gemfibrozil increases the AUC of simvastatin acid by 1.9-fold, possibly due to inhibition of the glucuronidation pathway and/or OATP1B1 (see Contraindications and Precautions). Concomitant administration with gemfibrozil is contraindicated.
Fusidic acid: The risk of myopathy including rhabdomyolysis may be increased by the concomitant administration of systemic fusidic acid with statins. The mechanism of this interaction (whether it is pharmacodynamics or pharmacokinetic, or both) is yet unknown. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving this combination. Co-administration of this combination may cause increased plasma concentrations of both agents. If treatment with fusidic acid is necessary, VYTORIN treatment should be discontinued throughout the duration of the fusidic acid treatment. Also see Precautions.
Amiodarone: The risk of myopathy and rhabdomyolysis is increased by concomitant administration of amiodarone with simvastatin (see Precautions). In a clinical trial, myopathy was reported in 6% of patients receiving simvastatin 80 mg and amiodarone. Therefore, the dose of VYTORIN should not exceed 10/20 mg daily in patients receiving concomitant medication with amiodarone.
Ranolazine: The risk of myopathy and rhabdomyolysis is increased by concomitant administration of ranolazine with simvastatin (see Precautions). Therefore, the dose of VYTORIN should not exceed 10/20 mg daily in patients receiving concomitant medication with ranolazine.
Calcium Channel Blockers: Verapamil: The risk of myopathy and rhabdomyolysis is increased by concomitant administration of verapamil with simvastatin 40 mg or 80 mg (see Precautions). In a pharmacokinetic study, concomitant administration of simvastatin with verapamil resulted in 2.3-fold increase in exposure of simvastatin acid, presumably due, in part, to inhibition of CYP3A4. Therefore, the dose of VYTORIN should not exceed 10/10 mg daily in patients receiving concomitant medication with verapamil.
Diltiazem: The risk of myopathy and rhabdomyolysis is increased by concomitant administration of diltiazem with simvastatin 80 mg (see Precautions). In a pharmacokinetic study, concomitant administration of diltiazem with simvastatin caused a 2.7-fold increase in exposure of simvastatin acid, presumably due to inhibition of CYP3A4. Therefore, the dose of VYTORIN should not exceed 10/10 mg daily in patients receiving concomitant medication with diltiazem.
Amlodipine: Patients on amlodipine treated concomitantly with simvastatin have an increased risk of myopathy. In a pharmacokinetic study, concomitant administration of amlodipine caused a 1.6-fold increase in exposure of simvastatin acid. Therefore, the dose of VYTORIN should not exceed 10/20 mg daily in patients receiving concomitant medication with amlodipine.
Lomitapide: The risk of myopathy and rhabdomyolysis may be increased by concomitant administration of lomitapide with simvastatin (see Contraindications and Precautions). Therefore, in patients with HoFH, the dose of VYTORIN must not exceed 10/40 mg daily in patients receiving concomitant medication with lomitapide.
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 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 and Precautions).
Inhibitors of Breast Cancer Resistant Protein (BCRP): Concomitant administration of medicinal products that are inhibitors of BCRP, including products containing elbasvir or grazoprevir, may lead to increased plasma concentrations of simvastatin and an increased risk of myopathy (see Dosage & Administration and Precautions).
Grapefruit juice: Grapefruit juice inhibits cytochrome P450 3A4. Concomitant intake of large quantities (over 1 litre daily) of grapefruit juice and simvastatin resulted in a 7-fold increase in exposure to simvastatin acid. Intake of 240 ml of grapefruit juice in the morning and administration of simvastatin in the evening also resulted in a 1.9-fold increase. Intake of grapefruit juice during treatment with VYTORIN should therefore be avoided.
Colchicine: Cases of myopathy, including rhabdomyolysis, have been reported with simvastatin co-administered with colchicine, in patients with renal impairment. Caution should be exercised when prescribing simvastatin with colchicine.
Rifampicin: Because rifampicin is a potent CYP3A4 inducer, patients undertaking long-term rifampicin therapy (e.g. treatment of tuberculosis) may experience loss of efficacy of simvastatin. In a pharmacokinetic study in normal volunteers, the area under the plasma concentration curve (AUC) for simvastatin acid was decreased by 93% with concomitant administration of rifampicin.
Niacin: Cases of myopathy/rhabdomyolysis have been observed with simvastatin co-administered with lipid-modifying doses (≥1 g/day) of niacin (see Precautions).
Daptomycin: The risk of myopathy and/or rhabdomyolysis may be increased by concomitant administration of HMG-CoA reductase inhibitors (e.g. simvastatin and ezetimibe/simvastatin) and daptomycin (see Precautions).
Effects of VYTORIN on the pharmacokinetics of other medicinal products: Ezetimibe: In preclinical studies, it has been shown that ezetimibe does not induce cytochrome P450 drug metabolising enzymes. No clinically significant pharmacokinetic interactions have been observed between ezetimibe and drugs known to be metabolised by cytochromes P450 1A2, 2D6, 2C8, 2C9, and 3A4, or N-acetyltransferase.
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. However, there have been post-marketing reports of increased International Normalised Ratio (INR) in patients who had ezetimibe added to warfarin or fluindione. If VYTORIN is added to warfarin, another coumarin anticoagulant, or fluindione, INR should be appropriately monitored (see Precautions).
Simvastatin: Simvastatin does not have an inhibitory effect on cytochrome P450 3A4. Therefore, simvastatin is not expected to affect plasma concentrations of substances metabolised via cytochrome P450 3A4.
Oral anticoagulants: In two clinical studies, one in normal volunteers and the other in hypercholesterolaemic 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. Very rare cases of elevated INR have been reported. 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.
Paediatric population: Interaction studies have only been performed in adults.
