| Usual starting dose* | Metabolism¶ | Selected drug interactionsΔ | Adverse effects | |
| HMG CoA reductase inhibitors ("statins") | ||||
| Pravastatin | 10 or 20 mg once per day | Approximately 50% is renally cleared as unchanged drug. Smaller amounts are cleared by biliary excretion or undergo non-CYP and CYP 3A4 hepatic transformation. Pravastatin is a substrate of P-gp. | Cyclosporine: increased risk of myopathy due to additive toxicity and elevation of statin serum level by competitive inhibition of CYP 3A4 and/or P-gp. Pravastatin and fluvastatin are less likely than other statins to interact significantly with cyclosporine. Sirolimus, everolimus: increased serum levels of sirolimus and everolimus in combination with atorvastatin due to inhibition of P-gp. | Gastrointestinal intolerance, CK elevations, transaminase elevations, muscle toxicity, rhabdomyolysis (rare). Close monitoring of transaminases may provide early evidence of elevated statin levels and toxicity. |
| Fluvastatin | 10 or 20 mg once per day | Approximately 75% undergoes hepatic transformation by CYP 2C9 and 20% by CYP 3A4. Fluvastatin inhibits, and can interact with other drugs metabolized by CYP 2C9. | ||
| Rosuvastatin | 5 or 10 mg once per day. Maximum 5 mg per day with cyclosporine. | Most clearance occurs as unchanged drug. Approximately 10% undergoes CYP 2C9 transformation to a partially active metabolite. | ||
| Atorvastatin | 5 or 10 mg once per day. Maximum 10 mg per day with cyclosporine. | Undergoes extensive CYP 3A4 transformation to active metabolites. Atorvastatin is a substrate and inhibitor of P-gp. | ||
| Simvastatin | 5 or 10 mg once per day. Avoid use with cyclosporine. | Undergoes extensive CYP 3A4 transformation to active and inactive metabolites. | ||
| Cholesterol absorption inhibitor | ||||
| Ezetimibe | 10 mg once per day | Undergoes glucuronide conjugation in small intestine and liver to form active metabolite. Most clearance occurs by enterohepatic recycling and fecal excretion. | Statins: useful for added LDL lowering in combination with a statin or as single agent if statin not tolerated. Fibrate: increased serum level of ezetimibe; theoretic increased risk of cholelithiasis. Cyclosporine: increased serum level of ezetimibe and possible alteration of cyclosporine level. 5 mg ezetimibe daily may suffice for LDL lowering effect in combination with cyclosporine. | Gastrointestinal intolerance, headache. In combination with statin, slightly higher incidence of serum transaminase elevations than statin monotherapy. |
| Refractory severe hypertriglyceridemia (≥500 mg/dL [5.6 mmol/L]) | ||||
| Gemfibrozil | 600 mg twice per day | Undergoes non CYP transformation by glucuronide conjugation with small amount of CYP 3A4 transformation. Gemfibrozil inhibits and can interact with other drugs metabolized by CYP 2C8, 2C9, 2C19 and OATP1B1. | Statins: increased risks of hepatotoxicity, myopathy, and rhabdomyolysis due to additive toxicity and elevation of statin serum level. Avoid combining gemfibrozil with statins. Cyclosporine: additive risk of nephrotoxicity and altered serum concentration of cyclosporine. | Gastrointestinal intolerance, muscle toxicity, cholelithiasis, rhabdomyolysis (rare). |
| Fenofibrate | 30 to 67 mg once per day depending on preparation | Hydrolysed to active intermediary by plasma and tissue esterases. Undergoes non CYP metabolism by glucuronide conjugation. | Statins: increased risk of myopathy and rhabdomyolysis due to additive toxicity. If combination with a statin is unavoidable, fenofibrate with fluvastatin or pravastatin may be less likely to interact significantly than gemfibrozil with a statin. Cyclosporine: additive risk of nephrotoxicity and altered serum concentration of cyclosporine. | |
| Omega-3-acid ethyl esters◊ | 1 to 2 grams twice per day | Inadequately defined. | CYP mediated interactions with immunosuppressive agents, statins, fibrates or ezetimibe are not expected based on in vitro data. | Dyspepsia, fishy taste, modest increase in LDL-C (5%). Modest increase in bleeding time that is insignificant for patients with functional hemostasis. |
CYP: cytochrome P450; OATP1B1: organic anion transporting polypeptide 1B1; P-gp: P-glycoprotein transporter.
* Adult doses, oral administration. Post liver transplant patients with compromised renal function are at elevated risk of adverse effects due to statins and other hypolipidemic drugs. Limited dose titration or dose reduction may be necessary.
¶ Shows metabolism and disposition of drug reaching systemic circulation. Statins undergo extensive pre-systemic clearance in gastric mucosa and/or liver. Patients with hepatic insufficiency may have increased systemic exposure.
Δ For additional information, refer to Lexi-Interact™ drug interactions application included with UpToDate.
◊ Potential option. Inadequate data and experience in patients with hepatic insufficiency and/or post liver transplant. If used, a licensed standardized preparation (eg, Lovaza®) appears to be preferable.