Simvastatin

7 DRUG INTERACTIONS Drug Interactions Associated with increased Risk of Risk of Myopathy/Rhabdomyolysis ( 2.3 , 2.4 , 4 , 5.1 , 7.1 , 7.2 , 7.3 , 12.3 ) Interacting Agents Prescribing Recommendations Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole,posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin Niacin (≥1 g/day) For Chinese patients, notrecommended with simvastatin Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily* Daptomycin Temporarily suspend simvastatin Grapefruit juice Avoid grapefruit juice *For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide. 7.3 Amiodarone, Dronedarone, Ranolazine, or Calcium Channel Blockers The risk of myopathy, including rhabdomyolysis, is increased by concomitant administration of amiodarone, dronedarone, ranolazine, or calcium channel blockers such as verapamil, diltiazem, or amlodipine [see Dosage and Administration (2.3) and Warnings and Precautions (5.1) , and Table 3 in Clinical Pharmacology (12.3) ].

Lipid-modifying agents HMG-CoA reductase inhibitors: lovastatin, simvastatin ↑ lovastatin ↑ simvastatin Coadministration of REYATAZ with lovastatin or simvastatin is contraindicated.

HMG-CoA reductase inhibitors : lovastatin simvastatin ↑lovastatin ↑simvastatin Coadministration with lovastatin or simvastatin is contraindicated due to the potential for serious reactions such as myopathy, including rhabdomyolysis [see Contraindications (4) ] .

Lipid-modifying agents HMG-CoA reductase inhibitors: lovastatin, simvastatin ↑ lovastatin ↑ simvastatin Coadministration of atazanavir with lovastatin or simvastatin is contraindicated.

7 DRUG INTERACTIONS Drug Interactions Associated with increased Risk of Risk of Myopathy/Rhabdomyolysis ( 2.3 , 2.4 , 4 , 5.1 , 7.1 , 7.2 , 7.3 , 12.3 ) Interacting Agents Prescribing Recommendations Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole,posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin Niacin (≥1 g/day) For Chinese patients, notrecommended with simvastatin Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily* Daptomycin Temporarily suspend simvastatin Grapefruit juice Avoid grapefruit juice *For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.

Gastroprokinetic Agents: Cisapride Contraindicated Cisapride : [See Contraindications (4.2) ] Lipid-lowering agents: Lomitapide Lovastatin Simvastatin Atorvastatin Pravastatin Fluvastatin Contraindicated Use With Caution No Dose Adjustment Lomitapide, Lovastatin, Simvastatin: Clarithromycin may increase the exposure of these drugs by inhibition of CYP3A metabolism, thereby increasing the risk of toxicities from these drugs [see Contraindications (4.5) and Warnings and Precautions (5.4) ] Atorvastatin, Pravastatin, Fluvastatin: [See Warnings and Precautions (5.4) ] Hypoglycemic Agents: Nateglinide Pioglitazone Repaglinide Rosiglitazone Insulin Use With Caution Nateglinide, Pioglitazone, Repaglinide, Rosiglitazone : [See Warnings and Precautions (5.4) and Adverse Reactions (6.2) ] Insulin : [See Warnings and Precautions (5.4) and Adverse Reactions (6.2) ] Immunosuppressants: Cyclosporine Tacrolimus Use With Caution Cyclosporine : There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with cyclosporine.

Lipid-modifying Agents: HMG-CoA reductase inhibitors: lovastatin simvastatin ↑ lovastatin ↑ simvastatin Coadministration with lovastatin or simvastatin is contraindicated due to potential for serious reactions such as myopathy including rhabdomyolysis.

Increases risk of myopathy and rhabdomyolysis when used with simvastatin. Concomitant use is contraindicated.

Increases risk of myopathy and rhabdomyolysis when used with simvastatin. Concomitant use is contraindicated.

7 DRUG INTERACTIONS Drug Interactions Associated with increased Risk of Risk of Myopathy/Rhabdomyolysis ( 2.3 , 2.4 , 4 , 5.1 , 7.1 , 7.2 , 7.3 , 12.3 ) Interacting Agents Prescribing Recommendations Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole,posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin Niacin (≥1 g/day) For Chinese patients, notrecommended with simvastatin Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily* Daptomycin Temporarily suspend simvastatin Grapefruit juice Avoid grapefruit juice *For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide. 7.8 Daptomycin Cases of rhabdomyolysis have been reported with simvastatin administered with daptomycin. Both simvastatin and daptomycin can cause myopathy and rhabdomyolysis when given alone and the risk of myopathy and rhabdomyolysis may be increased by coadministration.

Lipid Modifying Agents: HMG-CoA reductase inhibitors: lovastatin, simvastatin atorvastatin, pravastatin, rosuvastatin Other lipid modifying agents: lomitapide ↑ lovastatin ↑ simvastatin ↑ HMG-CoA reductase inhibitors ↑ lomitapide Co-administration is contraindicated due to potential for serious reactions such as myopathy including rhabdomyolysis.

Lipid Modifying Agents: HMG-CoA reductase inhibitors : lovastatin, simvastatin atorvastatin, pravastatin, rosuvastatin Other lipid modifying agents: lomitapide ↑ lovastatin ↑ simvastatin ↑ HMG-CoA reductase inhibitors ↑ lomitapide Co-administration is contraindicated due to potential for serious reactions such as myopathy including rhabdomyolysis.

Lipid Modifying Agents HMG-CoA reductase inhibitors: lovastatin, simvastatin ↑ lovastatin ↑ simvastatin Co-administration is contraindicated due to potential for serious reactions such as myopathy including rhabdomyolysis.

Lipid modifying agents: HMG-CoA reductase inhibitors: lovastatin, simvastatin ↑ lovastatin ↑ simvastatin Co-administration is contraindicated due to potential for serious reactions such as myopathy including rhabdomyolysis.

Lipid-modifying Agents: HMG-CoA Reductase Inhibitors: lovastatin simvastatin ↑ lovastatin ↑ simvastatin Coadministration with lovastatin or simvastatin is contraindicated due to potential for serious reactions such as myopathy including rhabdomyolysis.

Lipid-modifying Agents: HMG-CoA Reductase Inhibitors: lovastatin simvastatin ↑ lovastatin ↑ simvastatin Coadministration with lovastatin or simvastatin is contraindicated due to potential for serious reactions such as myopathy including rhabdomyolysis.

7 DRUG INTERACTIONS Drug Interactions Associated with increased Risk of Risk of Myopathy/Rhabdomyolysis ( 2.3 , 2.4 , 4 , 5.1 , 7.1 , 7.2 , 7.3 , 12.3 ) Interacting Agents Prescribing Recommendations Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole,posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin Niacin (≥1 g/day) For Chinese patients, notrecommended with simvastatin Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily* Daptomycin Temporarily suspend simvastatin Grapefruit juice Avoid grapefruit juice *For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide. If treatment with itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with simvastatin must be suspended during the course of treatment.

Increased risk of myopathy, including rhabdomyolysis when used with erythromycin due to CYP3A4 metabolism inhibition.

] Ezetimibe and Simvastatin Tablets Drug Interactions Associated With Increased Risk of Myopathy/Rhabdomyolysis ( 2.3 , 2.4 , 4 , 5.1 , 7.1 , 7.2 , 7.3 , 7.8 , 12.3 ) Interacting Agents Prescribing Recommendations Strong CYP3A4 Inhibitors, (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with ezetimibe and simvastatin tablets Niacin (≥1 g/day) For Chinese patients, not recommended with ezetimibe and simvastatin tablets Verapamil, diltiazem, dronedarone Do not exceed 10 mg/10 mg ezetimibe and simvastatin tablets, daily Amiodarone, amlodipine, ranolazine Do not exceed 10 mg/20 mg ezetimibe and simvastatin tablets, daily Lomitapide For patients with HoFH, do not exceed 10 mg/20 mg ezetimibe and simvastatin tablets 1 Daptomycin Temporally suspend ezetimibe and simvastatin tablets Grapefruit juice Avoid grapefruit juice 1. For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 10 mg/40 mg ezetimibe and simvastatin tablets when taking lomitapide. • Coumarin anticoagulants: simvastatin prolongs INR.

Lipid Modifying Agents: HMG-CoA reductase inhibitors : Atorvastatin a Lovastatin, simvastatin Other lipid modifying agents : Lomitapide ↑Atorvastatin ↑Lovastatin ↑Simvastatin ↑Lomitapide Titrate atorvastatin dose carefully and use the lowest necessary dose; do not exceed atorvastatin 20 mg/day. Coadministration with lovastatin or simvastatin is contraindicated due to potential for serious reactions such as risk of myopathy including rhabdomyolysis [see Contraindications (4)] .

Drug Interactions ( A) HMG-CoA Reductase Inhibitors: The concomitant administration of gemfibrozil with simvastatin is contraindicated (see CONTRAINDICATIONS and WARNINGS ). Combination therapy of gemfibrozil with simvastatin or with repaglinide, which are OATP1B1 substrates, is contraindicated (see CONTRAINDICATIONS ).

7 DRUG INTERACTIONS Drug Interactions Associated with increased Risk of Risk of Myopathy/Rhabdomyolysis ( 2.3 , 2.4 , 4 , 5.1 , 7.1 , 7.2 , 7.3 , 12.3 ) Interacting Agents Prescribing Recommendations Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole,posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin Niacin (≥1 g/day) For Chinese patients, notrecommended with simvastatin Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily* Daptomycin Temporarily suspend simvastatin Grapefruit juice Avoid grapefruit juice *For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide. If treatment with itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with simvastatin must be suspended during the course of treatment.

7 DRUG INTERACTIONS Drug Interactions Associated with increased Risk of Risk of Myopathy/Rhabdomyolysis ( 2.3 , 2.4 , 4 , 5.1 , 7.1 , 7.2 , 7.3 , 12.3 ) Interacting Agents Prescribing Recommendations Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole,posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin Niacin (≥1 g/day) For Chinese patients, notrecommended with simvastatin Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily* Daptomycin Temporarily suspend simvastatin Grapefruit juice Avoid grapefruit juice *For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide. If treatment with itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with simvastatin must be suspended during the course of treatment.

HMG-CoA Reductase Inhibitors: Lovastatin Simvastatin Contraindicated Lovastatin, Simvastatin, Atorvastatin, Pravastatin, Fluvastatin : (see CONTRAINDICATIONS , WARNINGS ).

pitavastatin, simvastatin ↑ HMG-CoA reductase inhibitors Co-administration of PREVYMIS and pitavastatin or simvastatin is not recommended. When PREVYMIS is co-administered with cyclosporine, use of either pitavastatin or simvastatin is contraindicated due to significantly increased pitavastatin or simvastatin concentrations and risk of myopathy or rhabdomyolysis [see Contraindications (4) ] .

Prevention or Management HMG CoA reductase inhibitors (“Statins”) Coadministration of ZOKINVY with lovastatin, simvastatin, or atorvastatin is contraindicated [see Contraindications ( 4 )] . As noted above, use with lovastatin, simvastatin, or atorvastatin, and midazolam is contraindicated [see Contraindications ( 4 )] ).

Lipid-modifying agents HMG-CoA Reductase Inhibitors: lovastatin simvastatin atorvastatin rosuvastatin Microsomal triglyceride transfer protein (MTTP) Inhibitor: lomitapide ↑ lovastatin ↑ simvastatin ↑ atorvastatin ↑ rosuvastatin ↑ lomitapide Contraindicated due to potential for myopathy including rhabdomyolysis [see Contraindications (4)].

Mifepristone increased the exposure to simvastatin and simvastatin acid significantly in healthy subjects. Concomitant use of simvastatin or lovastatin is contraindicated because of the increased risk of myopathy and rhabdomyolysis.

Strong CYP3A4 inhibitor that increases simvastatin exposure and risk of myopathy and rhabdomyolysis. Concomitant use is contraindicated.

Strong CYP3A4 inhibitor (HIV protease inhibitor) that increases simvastatin exposure and risk of myopathy and rhabdomyolysis. Concomitant use is contraindicated.

HMG-CoA reductase inhibitors lovastatin, simvastatin ↑ lovastatin ↑ simvastatin Co-administration contraindicated due to potential for myopathy including rhabdomyolysis [see Contraindications (4) ] . If treatment with PAXLOVID is considered medically necessary, discontinue use of lovastatin and simvastatin at least 12 hours prior to initiation of PAXLOVID, during the 5 days of PAXLOVID treatment, and for 5 days after completing PAXLOVID.

7 DRUG INTERACTIONS Drug Interactions Associated with increased Risk of Risk of Myopathy/Rhabdomyolysis ( 2.3 , 2.4 , 4 , 5.1 , 7.1 , 7.2 , 7.3 , 12.3 ) Interacting Agents Prescribing Recommendations Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole,posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin Niacin (≥1 g/day) For Chinese patients, notrecommended with simvastatin Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily* Daptomycin Temporarily suspend simvastatin Grapefruit juice Avoid grapefruit juice *For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide. If treatment with itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with simvastatin must be suspended during the course of treatment.

Strong CYP3A4 inhibitors that increase simvastatin plasma levels, elevating risk of myopathy and rhabdomyolysis.

Lipid-modifying agents HMG-CoA Reductase Inhibitor: lovastatin simvastatin atorvastatin rosuvastatin Microsomal triglyceride transfer protein (MTTP) Inhibitor: lomitapide ↑ lovastatin ↑ simvastatin ↑ atorvastatin ↑ rosuvastatin ↑ lomitapide Contraindicated due to potential for myopathy including rhabdomyolysis [see Contraindications ( 4 ) ] .

Lipid-modifying agents HMG-CoA Reductase Inhibitor: lovastatin simvastatin atorvastatin rosuvastatin Microsomal triglyceride transfer protein (MTTP) Inhibitor: lomitapide ↑ lovastatin ↑ simvastatin ↑ atorvastatin ↑ rosuvastatin ↑ lomitapide Contraindicated due to potential for myopathy including rhabdomyolysis [see Contraindications ( 4 )] .

7 DRUG INTERACTIONS Drug Interactions Associated with increased Risk of Risk of Myopathy/Rhabdomyolysis ( 2.3 , 2.4 , 4 , 5.1 , 7.1 , 7.2 , 7.3 , 12.3 ) Interacting Agents Prescribing Recommendations Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole,posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin Niacin (≥1 g/day) For Chinese patients, notrecommended with simvastatin Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily* Daptomycin Temporarily suspend simvastatin Grapefruit juice Avoid grapefruit juice *For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.

7 DRUG INTERACTIONS Drug Interactions Associated with increased Risk of Risk of Myopathy/Rhabdomyolysis ( 2.3 , 2.4 , 4 , 5.1 , 7.1 , 7.2 , 7.3 , 12.3 ) Interacting Agents Prescribing Recommendations Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole,posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin Niacin (≥1 g/day) For Chinese patients, notrecommended with simvastatin Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily* Daptomycin Temporarily suspend simvastatin Grapefruit juice Avoid grapefruit juice *For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide. If treatment with itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with simvastatin must be suspended during the course of treatment.

7 DRUG INTERACTIONS Drug Interactions Associated with increased Risk of Risk of Myopathy/Rhabdomyolysis ( 2.3 , 2.4 , 4 , 5.1 , 7.1 , 7.2 , 7.3 , 12.3 ) Interacting Agents Prescribing Recommendations Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole,posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin Niacin (≥1 g/day) For Chinese patients, notrecommended with simvastatin Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily* Daptomycin Temporarily suspend simvastatin Grapefruit juice Avoid grapefruit juice *For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide. If treatment with itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with simvastatin must be suspended during the course of treatment.

Increases risk of myopathy and rhabdomyolysis. Do not exceed simvastatin 20 mg daily.

Increases plasma concentration of HMG-CoA reductase inhibitor. Limit dose to 20 mg.

Co-administration increases systemic exposure of simvastatin. Do not exceed 20 mg daily of simvastatin in patients on amlodipine.

Co-administration increases systemic exposure of simvastatin. Limit simvastatin dose to 20 mg daily in patients on amlodipine.

Avacopan increases simvastatin systemic exposure. Limit simvastatin to 10 mg daily (or 20 mg daily if previously tolerated 80 mg daily).

Clinically Important Drug Interactions with NEXLETOL Simvastatin Clinical Impact: Concomitant use of NEXLETOL with simvastatin causes an increase in simvastatin concentration and may increase the risk of simvastatin-related myopathy [see Clinical Pharmacology (12.3) ] . Intervention : Avoid concomitant use of NEXLETOL with simvastatin greater than 20 mg. Simvastatin: Avoid concomitant use of NEXLETOL with simvastatin greater than 20 mg.

Clinically Important Drug Interactions with NEXLIZET Simvastatin Clinical Impact: Concomitant use of NEXLIZET with simvastatin causes an increase in simvastatin concentration and may increase the risk of simvastatin-related myopathy [see Clinical Pharmacology (12.3) ] . Intervention: Avoid concomitant use of NEXLIZET with simvastatin greater than 20 mg. Simvastatin: Avoid concomitant use of NEXLIZET with simvastatin greater than 20 mg.

Other Potentially Significant Drug Interactions Concomitant Drug Class or Food Noted or Anticipated Outcome Clinical Comment HMG-CoA Reductase Inhibitors: atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin Pharmacokinetic and/or pharmacodynamic interaction: the addition of one drug to a stable long-term regimen of the other has resulted in myopathy and rhabdomyolysis (including a fatality) Weigh the potential benefits and risks and carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy; monitoring CPK (creatine phosphokinase) will not necessarily prevent the occurrence of severe myopathy.

Calcium channel blocker that increases risk of myopathy and rhabdomyolysis. Do not exceed simvastatin 10 mg daily.

( 7.2 ) Statins: Avoid simvastatin doses greater than 10 mg daily. 7.3 Effects of Dronedarone on Other Drugs Simvastatin Dronedarone increased simvastatin/simvastatin acid exposure. Avoid doses greater than 10 mg once daily of simvastatin [see Clinical Pharmacology (12.3) ] .

Erythromycin has been reported to increase concentrations of simvastatin, an HMG-CoA reductase inhibitor.

Avoid grapefruit juice due to increased simvastatin plasma levels and risk of myopathy and rhabdomyolysis.

Approximately doubles simvastatin exposure and increases risk of myopathy and rhabdomyolysis.

Lomitapide doubles simvastatin exposure, increasing myopathy and rhabdomyolysis risk. Reduce simvastatin dose by 50% when initiating JUXTAPID; limit to 20 mg daily.

Niacin ≥1 g/day is not recommended with simvastatin in Chinese patients; increases risk of myopathy.

Concomitant use prolongs INR. Achieve stable INR prior to starting simvastatin and monitor INR frequently during therapy initiation or changes.

Do not exceed simvastatin 20 mg once daily; concomitant use increases simvastatin acid exposure two-fold, which may be clinically meaningful.

Concomitant use increases risk of alanine aminotransferase (ALT) elevations. Requires weekly monitoring of liver function and may require dose reduction or discontinuation based on hepatotoxicity severity.

Concomitant use increases risk of alanine aminotransferase (ALT) elevations. Increase to weekly monitoring of liver function; withhold pazopanib and resume at reduced dose or discontinue based on hepatotoxicity severity.

Increases risk of myopathy and rhabdomyolysis. Do not exceed simvastatin 20 mg daily.

REZDIFFRA increases plasma concentrations of simvastatin; limit daily dosage to 20 mg to reduce risk of statin-related adverse reactions.

Decrease AUC by 56% Narcotic Analgesics Oxycodone Decrease AUC by 86% Morphine Decrease exposure Selective 5-HT3 Receptor Antagonists Ondansetron Decrease exposure Statins Metabolized by CYP3A4 Simvastatin Decrease exposure Thiazolidinediones Rosiglitazone Decrease AUC by 66% Tricyclic Antidepressants Nortriptyline i Decrease exposure Other Drugs Enalapril Decrease active metabolite exposure Chloramphenicol j Decrease exposure Clarithromycin Decrease exposure Dapsone Decrease exposure Doxycycline k Decrease exposure Irinotecan l Prevention or Management: Avoid the use of rifampin, strong CYP3A4 inducer, if possible.

( 7.3) • Patients receiving more than 40 mg per day of simvastatin or lovastatin may be at increased risk of statin-related adverse effects. 7.4 Simvastatin, Lovastatin , Rosuvastatin Ticagrelor increases serum concentrations of simvastatin and lovastatin because these drugs are metabolized by CYP3A4. Avoid simvastatin and lovastatin doses greater than 40 mg [see Clinical Pharmacology ( 12.3 )].

Calcium channel blocker that increases risk of myopathy and rhabdomyolysis. Do not exceed simvastatin 10 mg daily.

CYP3A4 substrate combination associated with myopathy/rhabdomyolysis. Verapamil increases simvastatin exposure 2.5-fold. Limit simvastatin dose to 10 mg daily.

OATP1B1 substrate; voclosporin increases simvastatin acid exposure 3.1-fold (Cmax) and 1.8-fold (AUC). Monitor for myopathy and rhabdomyolysis; limit simvastatin to 20 mg daily.

Co-administration increases systemic exposure of simvastatin. Do not exceed 20 mg daily of simvastatin in patients on amlodipine.

7 DRUG INTERACTIONS Potassium supplements/potassium-sparing diuretics: hyperkalemia (7.1) Lithium: Increased serum lithium levels; toxicity symptoms (7.1) Injectable gold: facial flushing, nausea, vomiting, hypotension (7.1) Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Risk of renal dysfunction, loss of antihypertensive effect (7.1) Do not exceed doses greater than 20 mg daily of simvastatin (7.1) mTOR inhibitors: increased risk of angioedema (7.1) Dual inhibition of the RAS: Increased risk of renal impairment, hypotension, and hyperkalemia (7.1) Neprilysin inhibitors: increased risk of angioedema (7.1) 7.1 Drug/Drug Interactions Amlodipine Simvastatin: Co-administration of simvastatin with amlodipine increases the systemic exposure of simvastatin. Limit the dose of simvastatin in patients on amlodipine to 20 mg daily.

Impact of Amlodipine on Other Drugs: Simvastatin: Coadministration of simvastatin with amlodipine increases the systemic exposure of simvastatin. Limit the dose of simvastatin in patients on amlodipine to 20 mg daily [see Clinical Pharmacology (12.3) ] . • If simvastatin is coadministered with amlodipine, do not exceed doses greater than 20 mg daily of simvastatin ( 7 ) • Non-Steroidal Anti-Inflammatory Drug (NSAID) use may lead to increased risk of renal impairment and loss of anti-hypertensive effect ( 7 ) • Dual inhibition of the renin-angiotensin system: Increased risk of renal impairment, hypotension, and hyperkalemia ( 7 ) • Lithium: Increases in serum lithium level and lithium toxicity ( 7 ) Drug Interactions Sildenafil When amlodipine and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect [see Drug Interactions (7) ] .

Closely monitor patients for signs of reduced effectiveness when deferasirox is administered with drugs metabolized by CYP3A4 (e.g., alfentanil, aprepitant, budesonide, buspirone, conivaptan, cyclosporine, darifenacin, darunavir, dasatinib, dihydroergotamine, dronedarone, eletriptan, eplerenone, ergotamine, everolimus, felodipine, fentanyl, hormonal contraceptive agents, indinavir, fluticasone, lopinavir, lovastatin, lurasidone, maraviroc, midazolam, nisoldipine, pimozide, quetiapine, quinidine, saquinavir, sildenafil, simvastatin, sirolimus, tacrolimus, tolvaptan, tipranavir, triazolam, ticagrelor, and vardenafil) [ see Clinical Pharmacology (12.3)].

Monitor digoxin levels during simvastatin initiation.

7.2 Transporters Use caution when concomitantly administering eltrombopag and drugs that are substrates of OATP1B1 (e.g., atorvastatin, bosentan, ezetimibe, fluvastatin, glyburide, olmesartan, pitavastatin, pravastatin, rosuvastatin, repaglinide, rifampin, simvastatin acid, SN-38 [active metabolite of irinotecan], valsartan) or breast cancer resistance protein (BCRP) (e.g., imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, rosuvastatin, sulfasalazine, topotecan).

7.2 Transporters Use caution when concomitantly administering PROMACTA and drugs that are substrates of OATP1B1 (e.g., atorvastatin, bosentan, ezetimibe, fluvastatin, glyburide, olmesartan, pitavastatin, pravastatin, rosuvastatin, repaglinide, rifampin, simvastatin acid, SN-38 [active metabolite of irinotecan], valsartan) or breast cancer resistance protein (BCRP) (e.g., imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, rosuvastatin, sulfasalazine, topotecan).

Eslicarbazepine acetate can induce CYP3A4, decreasing plasma concentrations of simvastatin. Dose adjustment may be needed if clinically significant change in lipids is noted.

7.2 Pharmacokinetic Drug Interactions Table 3: Effect of Fexinidazole on other Drugs Drugs Metabolized by Cytochrome P450 (CYP) 3A4/5 Examples (not fully inclusive): Lovastatin, simvastatin, nisoldipine, saquinavir, midazolam, certain hormonal contraceptives (e.g., birth control pills, skin patches, implant) Clinical Impact Fexinidazole is considered a moderate CYP3A4/5 inducer [see Clinical Pharmacology (12.3) ] .

Caution should be used when prescribing other fibrate products with simvastatin; increases risk of adverse skeletal muscle effects.

Statins: Rosuvastatin b Atorvastatin Fluvastatin Pitavastatin Simvastatin ↑Rosuvastatin ↑Atorvastatin ↑Fluvastatin ↑Pitavastatin ↑Simvastatin Use the lowest possible starting dose for statins and monitor for statin-associated adverse events.

For other substrates of BCRP (e.g., mitoxantrone) and drugs in the OATP family (e.g., methotrexate, rifampin), especially HMG-Co reductase inhibitors (e.g., atorvastatin, nateglinide, pravastatin, repaglinide, and simvastatin), consider reducing the dose of these drugs and monitor patients closely for signs and symptoms of increased exposures to the drugs while patients are taking leflunomide [see Clinical Pharmacology (12.3) ].

For other substrates of BCRP (e.g., mitoxantrone) and drugs in the OATP family (e.g., methotrexate, rifampin), especially HMG- Co reductase inhibitors (e.g., atorvastatin, nateglinide, pravastatin, repaglinide, and simvastatin), consider reducing the dose of these drugs and monitor patients closely for signs and symptoms of increased exposures to the drugs while patients are taking leflunomide tablets [see Clinical Pharmacology (12.3)].

HMG-CoA Reductase Inhibitors – When single 40 mg doses of simvastatin or atorvastatin, both substrates of CYP3A4, were given to healthy adult volunteers who had received nefazodone hydrochloride, 200 mg BID for 6 days, approximately 20 fold increases in plasma concentrations of simvastatin and simvastatin acid and 3 to 4 fold increases in plasma concentrations of atorvastatin and atorvastatin lactone were seen. There have been rare reports of rhabdomyolysis involving patients receiving the combination of nefazodone and either simvastatin or lovastatin, also a substrate of CYP3A4 (see ADVERSE REACTIONS , Postintroduction Clinical Experience ). Caution should be used if nefazodone is administered in combination with HMG-CoA reductase inhibitors that are metabolized by CYP3A4, such as simvastatin, atorvastatin, and lovastatin, and dosage adjustments of these HMG-CoA reductase inhibitors are recommended.

Limit simvastatin to 20 mg daily when coadministered with amlodipine.

Limit simvastatin to 20 mg daily when coadministered with amlodipine.

Use with caution as concomitant use increases risk of adverse skeletal muscle effects.

Caution should be exercised when paclitaxel is concomitantly administered with known substrates (e.g., midazolam, buspirone, felodipine, lovastatin, eletriptan, sildenafil, simvastatin, and triazolam), inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin), and inducers (e.g., rifampin and carbamazepine) of CYP3A4.

7 DRUG INTERACTIONS NSAIDS: Increased risk of renal impairment and loss of antihypertensive effect (7) If simvastatin is co-administered with amlodipine, do not exceed doses greater than 20 mg daily of simvastatin (7) Do not co-administer aliskiren with telmisartan and amlodipine tablets in patients with diabetes (7.2) 7.1 Drug Interactions with Telmisartan and Amlodipine Tablets The pharmacokinetics of amlodipine and telmisartan are not altered when the drugs are co-administered. Other Drugs: Co-administration of telmisartan did not result in a clinically significant interaction with acetaminophen, amlodipine, glyburide, simvastatin, hydrochlorothiazide, warfarin, or ibuprofen. Simvastatin: Co-administration of multiple doses of 10 mg of amlodipine with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone.

7 DRUG INTERACTIONS NSAIDs: Increased risk of renal impairment and loss of anti-hypertensive effect ( 7.1 ) If simvastatin is co-administered with Widaplik, do not exceed doses greater than 20 mg daily of simvastatin ( 7.2 ) Do not co-administer aliskiren with Widaplik in patients with diabetes ( 7.1 ) 7.1 Drug Interactions with Telmisartan Aliskiren and other renin-angiotensin-aldosterone system (RAAS) inhibitors: Do not co-administer aliskiren with Widaplik in patients with diabetes. Impact of amlodipine on other drugs Simvastatin: Co-administration of simvastatin with amlodipine increases the systemic exposure of simvastatin. Limit the dose of simvastatin in patients on Widaplik to 20 mg daily.

For other substrates of BCRP (e.g., mitoxantrone) and drugs in the OATP family (e.g., methotrexate, rifampin), especially HMG-Co reductase inhibitors (e.g., atorvastatin, nateglinide, pravastatin, repaglinide, and simvastatin), consider reducing the dose of these drugs and monitor patients closely for signs and symptoms of increased exposures to the drugs while patients are taking teriflunomide tablets [see Clinical Pharmacology (12.3) ] .

Tocilizumab may decrease simvastatin exposure by up to 57% due to increased CYP3A4 metabolism. Dose adjustment may be needed.

Tocilizumab may decrease simvastatin exposure by up to 57%; monitor and adjust dose as needed.

Vadadustat increases statin Cmax and AUC. Monitor for statin-related adverse reactions.

Impact of Amlodipine on Other Drugs Simvastatin: Coadministration of simvastatin with amlodipine increases the systemic exposure of simvastatin. Limit the dose of simvastatin in patients on amlodipine to 20 mg daily [ see Clinical Pharmacology ( 12.3 ) ]. If simvastatin is coadministered with amlodipine, do not exceed doses greater than 20 mg daily of simvastatin ( 7 ) Antidiabetic drugs: Dosage adjustment of antidiabetic may be required ( 7 ) Cholestyramine and colestipol: Reduced absorption of thiazides ( 12.3 ) Lithium: Increased risk of lithium toxicity.

Lovastatin Simvastatin Atorvastatin Use VOQUEZNA TRIPLE PAK with caution.

Coumarin anticoagulant. Obtain INR before simvastatin initiation and monitor INR during simvastatin dosage initiation or adjustment.

Co-administration with tesamorelin had no significant impact on simvastatin pharmacokinetics in healthy subjects.

No dosing adjustments required for the following: Oral Antidiabetic Agents Metformin (1000 mg) 20 mg ↔ ↔ Pioglitazone (45 mg) 50 mg ↔ ↔ Sitagliptin (100 mg) 20 mg ↔ ↔ Glimepiride (4 mg) 20 mg ↔ ↔ Voglibose (0.2 mg three times daily) 10 mg ↔ ↔ Other Medications Hydrochlorothiazide (25 mg) 50 mg ↔ ↔ Bumetanide (1 mg) 10 mg once daily for 7 days ↔ ↔ Valsartan (320 mg) 20 mg ↓12% [↓3%, ↓20%] ↔ Simvastatin (40 mg) 20 mg ↔ ↔ Anti-infective Agent Rifampin (600 mg once daily for 6 days) 10 mg ↓7% [↓22%, ↑11%] ↓22% [↓27%, ↓17%] Nonsteroidal Anti-inflammatory Agent Mefenamic Acid (loading dose of 500 mg followed by 14 doses of 250 mg every 6 hours) 10 mg ↑13% [↑3%, ↑24%] ↑51% [↑44%, ↑58%] ↔ = no change (geometric mean ratio of test: reference within 0.80 to 1.25); ↓ or ↑ = parameter was lower or higher, respectively, with coadministration compared to dapagliflozin administered alone (geometric mean ratio of test: reference was lower than 0.80 or higher than 1.25) Effects of Dapagliflozin on Other Drugs Table 7 shows the effect of dapagliflozin on other coadministered drugs. No dosing adjustments required for the following: Oral Antidiabetic Agents Metformin (1000 mg) 20 mg ↔ ↔ Pioglitazone (45 mg) 50 mg ↓7% [↓25%, ↑15%] ↔ Sitagliptin (100 mg) 20 mg ↔ ↔ Glimepiride (4 mg) 20 mg ↔ ↑13% [0%, ↑29%] Other Medications Hydrochlorothiazide (25 mg) 50 mg ↔ ↔ Bumetanide (1 mg) 10 mg once daily for 7 days ↑13% [↓2%, ↑31%] ↑13% [↓1%, ↑30%] Valsartan (320 mg) 20 mg ↓6% [↓24%, ↑16%] ↑5% [↓15%, ↑29%] Simvastatin (40 mg) 20 mg ↔ ↑19% Digoxin (0.25 mg) 20 mg loading dose then 10 mg once daily for 7 days ↔ ↔ Warfarin (25 mg) 20 mg loading dose then 10 mg once daily for 7 days ↔ ↔ ↔ = no change (geometric mean ratio of test: reference within 0.80 to 1.25); ↓ or ↑ = parameter was lower or higher, respectively, with coadministration compared to the other medicine administered alone (geometric mean ratio of test: reference was lower than 0.80 or higher than 1.25).

midazolam, pimozide, simvastatin) is necessary when XELSTRYM is co-administered [see CLINICAL PHARMACOLOGY (12.3) ].

In a healthy volunteer crossover study (N=10), coadministration of a single 20 mg dose of simvastatin at the end of a 14-day regimen with 120 mg BID diltiazem SR resulted in a 5-fold increase in mean simvastatin AUC versus simvastatin alone. Subjects with increased average steady-state exposures of diltiazem showed a greater fold increase in simvastatin exposure. Computer-based simulations showed that at a daily dose of 480 mg of diltiazem, an 8- to 9-fold mean increase in simvastatin AUC can be expected.

7.2 Influence of SLYND on other Medicinal Products Based on in vitro studies and in vivo interaction studies in female volunteers using omeprazole, simvastatin and midazolam as marker substrate, an interaction of drospirenone with the metabolism of other active substances is unlikely.

Two further clinical drug-drug interaction studies using simvastatin and midazolam as marker substrates for CYP3A4, respectively, were performed and the results of these studies demonstrated that pharmacokinetics of the CYP3A4 substrates were not influenced by steady-state DRSP concentrations.

Two additional clinical drug-drug interaction studies using simvastatin and midazolam as marker substrates for CYP3A4 were each performed in 24 healthy postmenopausal women.

HMG-CoA reductase inhibitors: Atorvastatin Pravastatin Simvastatin ↓ atorvastatin * ↓ pravastatin * ↓ simvastatin * Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased.

HMG-CoA reductase inhibitors: atorvastatin pravastatin simvastatin ↓ atorvastatin ↓ pravastatin ↓ simvastatin Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased with EFV.

HMG-CoA reductase inhibitors: Atorvastatin Pravastatin Simvastatin ↓atorvastatin* ↓pravastatin* ↓simvastatin* Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased.

Fluvastatin Lovastatin Simvastatin ↑ fluvastatin ↑ lovastatin ↑ simvastatin Statin-associated adverse events such as myopathy should be closely monitored.

Lovastatin simvastatin fluvastatin pitavastatin ↓ lovastatin ↓ simvastatin ↑ fluvastatin ↑ pitavastatin Lovastatin and simvastatin are CYP3A substrates and co-administration with etravirine tablets may result in lower plasma concentrations of the HMG-CoA reductase inhibitor. Lovastatin simvastatin fluvastatin pitavastatin ↓ lovastatin ↓ simvastatin ↑ fluvastatin ↑ pitavastatin Lovastatin and simvastatin are CYP3A substrates and co-administration with etravirine tablets may result in lower plasma concentrations of the HMG-CoA reductase inhibitor.

7.7 Simvastatin and Lovastatin Due to an interaction with cyclosporine, clinical studies of everolimus with cyclosporine conducted in kidney transplant patients strongly discouraged patients with receiving HMG-CoA reductase inhibitors such as simvastatin and lovastatin [see Warnings and Precautions ( 5.11 )] .

7.7 Simvastatin and Lovastatin Due to an interaction with cyclosporine, clinical studies of everolimus with cyclosporine conducted in kidney transplant patients strongly discouraged patients with receiving HMG-CoA reductase inhibitors such as simvastatin and lovastatin [see Warnings and Precautions (5.11) ] .

HMG-CoA reductase inhibitors : The risk of myopathy and rhabdomyolysis increases when fluconazole is coadministered with HMG-CoA reductase inhibitors metabolized through CYP3A4, such as atorvastatin and simvastatin, or through CYP2C9, such as fluvastatin.

Carbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine, lacosamide Antiplatelets Ticagrelor Antilipidemic agents Atorvastatin, fluvastatin, simvastatin Antiviral agents Efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir Fosamprenavir: phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite.

HMG-CoA Reductase Inhibitors: Atorvastatin Lovastatin Simvastatin ↑ atorvastatin ↑ lovastatin ↑ simvastatin Coadministration may increase the concentration of atorvastatin, lovastatin, and simvastatin.

Interactions with Drugs Metabolized by CYP3A4 Imatinib mesylate tablets increase the mean C max and AUC of simvastatin (CYP3A4 substrate) 2- and 3.5-fold, respectively, suggesting an inhibition of the CYP3A4 by imatinib mesylate tablets.

HMG-CoA Reductase Inhibitors: lovastatin simvastatin ↑ lovastatin ↑ simvastatin Initiate lovastatin and simvastatin with the lowest starting dose and titrate carefully while monitoring for safety (e.g., myopathy).

Examples Alfentanil, avanafil, buspirone, conivaptan b , dabigatran etexilate, darifenacin, darunavir, digoxin, ebastine, everolimus, fexofenadine, ibrutinib, lomitapide, lovastatin, lurasidone, midazolam, naloxegol, nisoldipine, saquinavir, simvastatin, sirolimus, tacrolimus, tipranavir b , triazolam, and vardenafil.

From a pharmacokinetic perspective, no dose adjustment for drugs that are substrates of CYP1A2 (e.g., theophylline, duloxetine, melatonin), CYP2D6 (e.g., atomoxetine, desipramine, venlafaxine), CYP2C19 (e.g., omeprazole, lansoprazole, clobazam), and CYP3A4 (e.g., midazolam, pimozide, simvastatin) is necessary when lisdexamfetamine dimesylate is co-administered [see Clinical Pharmacology (12.3) ] .

From a pharmacokinetic perspective, no dose adjustment for drugs that are substrates of CYP1A2 (e.g., theophylline, duloxetine, melatonin), CYP2D6 (e.g., atomoxetine, desipramine, venlafaxine), CYP2C19 (e.g., omeprazole, lansoprazole, clobazam), and CYP3A4 (e.g., midazolam, pimozide, simvastatin) is necessary when VYVANSE is co-administered [see Clinical Pharmacology (12.3) ] .

From a pharmacokinetic perspective, no dose adjustment for drugs that are substrates of CYP1A2 (e.g., theophylline, duloxetine, melatonin), CYP2D6 (e.g., atomoxetine, desipramine, venlafaxine), CYP2C19 (e.g., omeprazole, lansoprazole, clobazam), and CYP3A4 (e.g., midazolam, pimozide, simvastatin) is necessary when lisdexamfetamine dimesylate capsules are co-administered [see Clinical Pharmacology ( 12.3 )] .

HMG-CoA Reductase Inhibitors: Limit the dose of simvastatin in patients on amiodarone to 20 mg daily.

Warfarin Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin Other Corticosteroids, doxycycline, estrogens, furosemide, oral contraceptives, paroxetine, quinidine, rifampin, sertraline, theophylline, and vitamin D Drugs whose level is decreased by phenytoin Anticoagulants Apixaban, dabigatran, edoxaban, rivaroxaban Antiepileptic drugs The effect of phenytoin on phenobarbital, valproic acid and sodium valproate serum levels is unpredictable Carbamazepine, felbamate, lacosamide, lamotrigine, topiramate, oxcarbazepine Antilipidemic agents Atorvastatin, fluvastatin, simvastatin Antiplatelets Ticagrelor Antiviral agents Efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir Fosamprenavir: phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite.

Warfarin Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin Other Corticosteroids, doxycycline, estrogens, furosemide, oral contraceptives, paroxetine, quinidine, rifampin, sertraline, theophylline, and vitamin D Drugs whose level is decreased by phenytoin Antiepileptic drugs a Carbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine Antilipidemic agents Atorvastatin, fluvastatin, simvastatin Antiviral agents Efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir Fosamprenavir: phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite.

7.3 HMG-CoA Reductase Inhibitors (Statins) Primarily Metabolized Through CYP3A4 Concomitant administration of posaconazole with simvastatin increases the simvastatin plasma concentrations by approximately 10-fold.

Thus, clinicians considering combined therapy of quinine sulfate with atorvastatin or other HMG-CoA reductase inhibitors (“statins”) that are CYP3A4 substrates (e.g., simvastatin, lovastatin) should carefully weigh the potential benefits and risks of each medication.

Thus, clinicians considering combined therapy of quinine sulfate with atorvastatin or other HMG-CoA reductase inhibitors ("statins") that are CYP3A4 substrates (e.g., simvastatin, lovastatin) should carefully weigh the potential benefits and risks of each medication.

7.6 Other Neither ramipril nor its metabolites have been found to interact with food, digoxin, antacid, furosemide, cimetidine, indomethacin, and simvastatin.

atorvastatin fluvastatin lovastatin simvastatin ↑ atorvastatin ↑ fluvastatin ↑ lovastatin ↑ simvastatin Coadministration with VOSEVI may increase the concentrations of atorvastatin, fluvastatin, lovastatin, and simvastatin.

Other Drugs: Co-administration of telmisartan did not result in a clinically significant interaction with acetaminophen, amlodipine, glyburide, simvastatin, hydrochlorothiazide, warfarin, or ibuprofen.

Other Drugs : Co-administration of telmisartan did not result in a clinically significant interaction with acetaminophen, amlodipine, glibenclamide, simvastatin, hydrochlorothiazide or ibuprofen.

Co-administration of multiple doses of 10 mg of verapamil with 80 mg simvastatin resulted in exposure to simvastatin 2.5-fold that following simvastatin alone. Limit the dose of simvastatin in patients on verapamil to 10 mg daily.