Fenofibrate (fenofibrate)

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Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Fibrates/Cerivastatin

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The mechanism of action may involve multiple pathways and may be different depending on which fibrate is involved. Both statins and fibric acid derivatives can cause myalgia and can produce an additive effect when taken together. Fenofibrate and derivatives are known inhibitors of CYP2A6, CYP2C8, and CYP2C9 which could increase plasma concentration of several statins including cerivastatin, rosuvastatin, and fluvastatin. Interactions between statins and gemfibrozil are not likely due to gemfibrozil's inhibitory effect on the CYP system, but rather by its impairment of the hepatic glucuronidation pathway. Gemfibrozil is a strong inhibitor of the glucuronidation-mediated lactonization of several statins thereby increasing the concentration of active statin acid.(12-16)

CLINICAL EFFECTS: The concurrent administration of cerivastatin with a fibric acid derivative may result in rhabdomyolysis and/or renal failure. Symptoms of rhabdomyolysis include muscle pain, tenderness, weakness, elevated creatine kinase levels, and reddish-brown, hemepositive urine.

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis.

PATIENT MANAGEMENT: The concurrent administration of cerivastatin with gemfibrozil is contraindicated.(1,2) The concurrent administration of cerivastatin with other fibrates should be avoided.(1) Consider the use of an alternative statin in patients whom require fibric acid derivative therapy. If concurrent therapy is deemed medically necessary, monitor patients for signs and symptoms of myopathy/rhabdomyolysis, including muscle pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of urine, and/or discolored urine.

DISCUSSION: Rhabdomyolysis(3-7) and renal failure(3,4) have been reported in patients receiving concurrent cerivastatin and gemfibrozil. Rhabdomyolysis and renal failure have also been reported with the combination of cerivastatin and bezafibrate(8). In a retrospective cohort study of 252,460 patients, cerivastatin in combination with fibrate resulted in a rhabdomyolysis risk of 1 in 10 treated patients per year. The risk of hospitalization due to rhabdomyolysis for patients aged 65 or older with diabetes treated with a statin and a fibrate increased 1411-fold compared to stain monotherapy.(9) A case-crossover study consisting of 93,831 patients evaluated statin and statin/fibrate use and their association with myopathy. The study showed that cerivastatin had an increased relative risk (2.05, 95% CI 1.2-3.5) for myopathy over atorvastatin at 12 weeks.(10) A review of case reports submitted to the FDA's AERS database for statin- and statin/gemfibrozil-associated rhabdomyolysis and showed that the reporting rates for patients taking cerivastatin were higher than other statins at 4.24/100,000 prescriptions vs. < 1/100,000 prescriptions, respectively.(11) The ACCORD trial was a randomized trial of 5518 patients with type 2 diabetes receiving simvastatin (40 mg per day or less) and either fenofibrate (initial dose of 160 mg per day, dose adjusted for renal function) or placebo. At the mean follow up of 4.7 years, the primary efficacy endpoint of first occurrence of a major cardiovascular event, including nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes, occurred at an annual rate of 2.2% in the fenofibrate group and 2.4 % in the placebo group (p=0.32).(17)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Agents That Increase Cpk/Aumolertinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Aumolertinib may increase blood CPK levels leading to myopathy and rhabdomyolysis. Other agents that also increase CPK may contribute to additive effects on CPK levels.(1) In addition, aumolertinib may prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1) Taletrectinib and zidesamtinib may prolong the QTc interval.

CLINICAL EFFECTS: Concurrent use of aumolertinib and other agents that also increase CPK levels may increase the risk of myopathy or rhabdomyolysis, which is characterized by progressive muscle weakness and pain in the presence of a normal neurological exam.(1) In addition, the concurrent use of aumolertinib with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1) Taletrectinib and zidesamtinib may prolong the QTc interval.

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may also be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. Patients on fluvastatin who are CYP2C9 intermediate or poor metabolizers may have increased fluvastatin concentrations and risk of myopathy. Patients on rosuvastatin with ABCG2 polymorphisms leading to decreased or poor BCRP transporter function may have increased rosuvastatin concentrations and risk of myopathy. The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, and advanced age.(1,2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: Concurrent use of aumolertinib and other agents that increase CPK levels should be avoided. Prior to initiation of aumolertinib, blood CPK levels should be obtained and periodically monitored during treatment and as clinically indicated.(1) If the patient develops elevated CPK levels or rhabdomyolysis, the following is recommended: For Grade 3 with muscular symptoms: - Withhold aumolertinib for up to 2 weeks. - If muscular symptoms resolve and CPK increase is <= Grade 3, resume at 110 mg dose for the first occurrence; resume at 55 mg for the second occurrence. - Permanently discontinue aumolertinib if symptoms/signs recur at anytime while on the reduced dose. - If muscular symptoms do not resolve and CPK increase does not improve to <= Grade 2, permanently discontinue aumolertinib. For Grade 4 with or without muscular symptoms: - Withhold aumolertinib for up to 2 weeks. - If muscular symptoms resolve and CPK increase is <= Grade 3, resume at 55 mg for the first occurrence. - Permanently discontinue aumolertinib if symptoms/signs recur at anytime while on the reduced dose. - If muscular symptoms do not resolve and CPK remains >= Grade 3, permanently discontinue aumolertinib. If rhabdomyolysis occurs, hold aumolertinib and initiate treatment for rhabdomyolysis.(1) In concurrent use is warranted, carefully monitor for myopathy or rhabdomyolysis. Patients should be instructed to report any symptoms of myopathy such as unexplained muscle aches, tenderness, weakness, or the onset of tingling/numbness in the fingers or toes.(1) The manufacturer of aumolertinib states that concurrent use of other drugs that are known to prolong the QTc interval should be avoided. Taletrectinib and zidesamtinib may also prolong the QTc interval. If a suitable alternative is not available, consider increasing the frequency of ECG and electrolyte monitoring.(1) Consider obtaining serum calcium, magnesium, and potassium levels and correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. If QTc prolongation occurs, follow recommended dose modifications: - Grade 2 (QTc interval >480 to 500 ms): Withhold aumolertinib for up to 2 weeks. If QTc interval has not recovered to <= 480 ms, permanently discontinue aumolertinib. If QTc interval recovers to <= 480 ms or within 30 ms of baseline, resume aumolertinib treatment at 110 mg. Monitor ECGs at least weekly for 2 weeks following return to <= 480 ms. Monitor and correct electrolytes and/or change concomitant medications. - Grade 3 (QTc interval > 500 ms or QTc interval increase of > 60 ms from baseline): Withhold aumolertinib for up to 2 weeks. If QTc interval has not recovered to <= 480 ms or within 30 ms of baseline, permanently discontinue aumolertinib. If QTc interval recovers to <= 480 ms and it is the first occurrence, resume treatment at 110 mg dose. If QTc interval recovers to <= 480 ms and it is the second occurrence or the first occurrence in patients with risk factors, resume treatment at 55 mg dose. Permanently discontinue aumolertinib if signs or symptoms recur at any time on the 55 mg dose. Monitor ECGs at least weekly for 2 weeks following return to <= 480 ms. Monitor and correct electrolytes and/or change concomitant medications. - QT interval prolongation associated with torsade de pointes, polymorphic ventricular tachycardia, or signs/symptoms of other serious arrhythmia: permanently discontinue aumolertinib.(1)

DISCUSSION: Aumolertinib increased blood CPK levels in 31.7% of patients in clinical studies at recommended doses. Patients developed Grade 3 CPK elevations with muscular symptoms (7.5% of patients) and Grade 4 CPK elevations with or without muscular symptoms. Elevated CPK levels led to interruption or dose reduction in 6.1% and 2.0% of patients, respectively. Rhabdomyolysis occurred in 2.6% of patients.(1) A concentration-QT analysis predicted a QTc interval prolongation at 110 mg aumolertinib of 9.06 ms (upper confidence interval = 11.01 ms) in 49 subjects.(1) In clinical studies (n=545), QT prolongation was reported in 51 patients (9.4%) treated with aumolertinib 110 mg. Seven patients (1.3%) had symptomatic events, including cardiac arrest, syncope, and ventricular arrhythmia. One patient with cardio-respiratory arrest and one patient with sudden cardiac death died. QTcF increase >60 ms occurred in 4.2% of patients, and increase in QTcF to >500 ms occurred in 0.9% of patients.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)

Bezafibrate; Fenofibrate/Rosiglitazone

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The exact mechanism is unknown.

CLINICAL EFFECTS: Concurrent use of rosiglitazone with bezafibrate or fenofibrate may result in severe paradoxical decreases in high-density lipoprotein (HDL) in some patients.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor HDL levels in patients receiving combination therapy with rosiglitazone with bezafibrate or fenofibrate. One or both agents may need to be discontinued.

DISCUSSION: There have been numerous reports of severe paradoxical decreases in HDL levels (defined as <0.52 mmol/L or 20 mg/dL) with concurrent pioglitazone or rosiglitazone with bezafibrate or fenofibrate.(1-10) In some patients, discontinuation of the antidiabetic agent alone increased HDL levels. In others, both agents were discontinued.

Fibrates/Selected Anticoagulants (Vit K Antagonists)

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The exact mechanism is unknown. Fibric acid derivatives may displace anticoagulants from their plasma protein binding sites or may affect anticoagulant receptor sites. It has also been suggested that the effect may be related to the hypolipidemic action of the fibric acid derivatives.

CLINICAL EFFECTS: Concurrent use of selected anticoagulants and fibric acid derivatives may increase the risk for bleeding.

PREDISPOSING FACTORS: Severe hyperlipidemia, larger doses of the fibric acid derivative, and older age may predispose patients to this interaction. The risk for bleeding episodes may also be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Patients receiving concurrent therapy with selected anticoagulants and a fibric acid derivative should be closely monitored for excessive anticoagulant effects. The dose of the anticoagulant may need to be adjusted if the fibric acid derivative is added to or discontinued from stabilized anticoagulant therapy. The time of highest risk for an anticoagulant drug interaction is when the precipitant drug is initiated or discontinued. When concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: There have been case reports of bezafibrate,(1) clofibrate, (2-5) fenofibrate,(6-8) and gemfibrozil(9-11) interacting with warfarin. The interactions between clofibrate(12-14) and and warfarin and gemfibrozil(15) and warfarin have also been documented in clinical trials. There are also case reports of bezafibrate(16) and clofibrate(17) interacting with dicumarol. A study showed that bezafibrate increased the effects of phenprocoumon.(18)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Fenofibrate/Atorvastatin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Unknown.

CLINICAL EFFECTS: Concurrent administration of atorvastatin and fibric acid derivatives has been associated with severe myopathy, rhabdomyolysis and acute renal failure.

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis.

PATIENT MANAGEMENT: When possible, avoid administration of atorvastatin and fibric acid derivatives concomitantly unless patients require aggressive therapy. Instruct patients to report any unexplained muscle pain, tenderness or weakness. If muscular symptoms develop, monitor serum creatine kinase levels and renal function. One or both agents may need to be discontinued. The American College of Cardiology and American Heart Association Guidelines state that fenofibrate may be considered concomitantly with a low- or moderate-intensity statin only if the benefits from atherosclerotic cardiovascular risk reduction or triglyceride lowering when triglycerides are greater than or equal to 500 mg/dL are judged to outweigh the potential risk for adverse effects.(20) The European Society of Cardiology and European Atherosclerosis Society recommend concomitant statin-fenofibrate therapy in patients with atherogenic combined dyslipidemia, especially patients with metabolic syndrome and/or diabetes.(21) The US manufacturer of fenofibrate states that concurrent therapy with HMG CO-A reductase inhibitors should be avoided unless the benefit of further decreases in lipid levels is likely to outweigh the increased risk. Fenofibrate may be preferred over gemfibrozil in patients who do require concurrent statin and fibrate therapy.(9)

DISCUSSION: Concurrent fenofibrate (145 mg) with atorvastatin (20 mg) decreased the atorvastatin area-under-curve (AUC) by 17% (range from 67% decrease to 44% increase). Atorvastatin maximum concentration (Cmax) and the kinetics of fenofibrate were not significantly affected. The risk of rhabdomyolysis with concurrent fibrate and HMG CoA reductase inhibitor therapy appears to be greater with gemfibrozil. Analysis of the FDA Adverse Event Report database indicates that the rate is 30 times higher with gemfibrozil than with fenofibrate. In an analysis of data from the Veteran's Administration over a 2 year period, there were 149 reports of rhabdomyolysis in 93,677 (0.016%) patients receiving concurrent gemfibrozil and statin therapy compared with no reports in 1,830 patients receiving concurrent fenofibrate and statin therapy. In a study in 66 healthy volunteers, concomitant administration of fenofibrate (160 mg for 7 days) and atorvastatin (40 mg single dose) did not result in a clinically significant change in the atorvastatin AUC.(22) A meta-analysis of 6 randomized controlled trials (including approximately 1600 patients) found no cases of myopathy or rhabdomyolysis in combination therapy of fenofibrate with simvastatin, fluvastatin, or atorvastatin. A comparison of the incidence of creatine kinase greater than 5 times the ULN between combination statin-fenofibrate and statin monotherapy was found to be not significant.(23) A meta-analysis of 13 randomized controlled trials (including approximately 7000 patients) found no significant difference in the incidence of elevated creatine kinase or muscle-associated adverse effects between single-drug statin therapy or combination fenofibrate-statin therapy.(24)

Fenofibrate/Selected Hmg-Coa Reductase Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Unknown.

CLINICAL EFFECTS: Concurrent administration of HMG-CoA reductase inhibitors and fibric acid derivatives has been associated with severe myopathy, rhabdomyolysis and acute renal failure.

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. Patients on fluvastatin who are CYP2C9 intermediate or poor metabolizers may have increased fluvastatin concentrations and risk of myopathy. Patients on rosuvastatin with ABCG2 polymorphisms leading to decreased or poor BCRP transporter function may have increased rosuvastatin concentrations and risk of myopathy.

PATIENT MANAGEMENT: When possible, avoid administration of these drugs concomitantly unless patients require aggressive therapy. Instruct patients to report any unexplained muscle pain, tenderness or weakness. If muscular symptoms develop, monitor serum creatine kinase levels and renal function. One or both agents may need to be discontinued. The American College of Cardiology and American Heart Association Guidelines state that fenofibrate may be considered concomitantly with a low- or moderate-intensity statin only if the benefits from atherosclerotic cardiovascular risk reduction or triglyceride lowering when triglycerides are greater than or equal to 500 mg/dL are judged to outweigh the potential risk for adverse effects.(20) The European Society of Cardiology and European Atherosclerosis Society recommend concomitant statin-fenofibrate therapy in patients with atherogenic combined dyslipidemia, especially patients with metabolic syndrome and/or diabetes.(21) The US manufacturer of fenofibrate states that concurrent therapy with HMG CO-A reductase inhibitors should be avoided unless the benefit of further decreases in lipid levels is likely to outweigh the increased risk. Fenofibrate may be preferred over gemfibrozil in patients who do require concurrent statin and fibrate therapy.(9) The manufacturer of pravastatin states that concurrent therapy should be avoided unless the benefits of combination therapy outweigh the risks.(6) The Canadian manufacturer of rosuvastatin states that concurrent therapy with other fibrates should be approached with caution. The Australian and UK manufacturers of rosuvastatin state that rosuvastatin 40 mg is contraindicated with concomitant use of fibrates.(27,28) The risks of concurrent use of fibrates should be carefully weighed against the benefits. Patients taking a fibrate should start rosuvastatin therapy with the 5 mg dose. The US manufacturer of rosuvastatin states that the concurrent use of fenofibrate should be carefully weighed against the benefits. In patients receiving concurrent fenofibrate, a dosage reduction of rosuvastatin should be considered.(5) The manufacturer of simvastatin states that concurrent therapy with other fibrates should be approached with caution.(7)

DISCUSSION: Concurrent fenofibrate (160 mg daily) increased the AUC and Cmax of pitavastatin (4 mg daily) by 18% and 11%, respectively. Concurrent fenofibrate (145 mg) with pravastatin (40 mg) increased pravastatin Cmax and AUC by 36% (range from 69% decrease to 321% increase) and 28% (range from 54% decrease to 128% increase), respectively, and the 3-alpha-hydroxy-iso-pravastatin Cmax and AUC by 55% (range from 32% decrease to 314% increase) and by 39% (range from 24% decrease to 261% increase), respectively. A single dose of pravastatin had no effect on the kinetics of fenofibrate. In a study in 24 healthy subjects, concurrent fenofibrate (160 mg daily) increased the average AUC of pravastatin (40 mg daily) by 19-28%; however, individual changes were variable and not statistically significant. Concurrent fenofibrate and rosuvastatin resulted in no significant changes in rosuvastatin or fenofibrate levels; however, rhabdomyolysis has been reported during concurrent therapy. Concurrent fenofibrate and simvastatin resulted in no significant changes in simvastatin or fenofibrate levels; however, rhabdomyolysis has been reported during concurrent therapy. In a study in 29 patients, 4 patients reported myalgia during concurrent simvastatin and fenofibrate, compared with no reports during concurrent simvastatin and cholestyramine. The risk of rhabdomyolysis with concurrent fibrate and HMG CoA reductase inhibitor therapy appears to be greater with gemfibrozil. Analysis of the FDA Adverse Event Report database indicates that the rate is 30 times higher with gemfibrozil than with fenofibrate. In an analysis of data from the Veteran's Administration over a 2 year period, there were 149 reports of rhabdomyolysis in 93,677 (0.016%) patients receiving concurrent gemfibrozil and statin therapy compared with no reports in 1,830 patients receiving concurrent fenofibrate and statin therapy. In a study in 66 healthy volunteers, concomitant administration of fenofibrate (160 mg for 7 days) and atorvastatin (40 mg single dose) did not result in a clinically significant change in the atorvastatin AUC.(22) A meta-analysis of 6 randomized controlled trials (including approximately 1600 patients) found no cases of myopathy or rhabdomyolysis in combination therapy of fenofibrate with simvastatin, fluvastatin, or atorvastatin. A comparison of the incidence of creatine kinase greater than 5 times the ULN between combination statin-fenofibrate and statin monotherapy was found to be not significant.(23) A meta-analysis of 13 randomized controlled trials (including approximately 7000 patients) found no significant difference in the incidence of elevated creatine kinase or muscle-associated adverse effects between single-drug statin therapy or combination fenofibrate-statin therapy.(24) The ACCORD trial showed that fenofibrate-simvastatin concomitant therapy had similar rates as simvastatin alone for myopathy, myositis, or rhabdomyolysis.(25) The ACCORD trial was a randomized trial of 5518 patients with type 2 diabetes receiving simvastatin (40 mg per day or less) and either fenofibrate (initial dose of 160 mg per day, dose adjusted for renal function) or placebo. At the mean follow up of 4.7 years, the primary efficacy endpoint of first occurrence of a major cardiovascular event, including nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes, occurred at an annual rate of 2.2% in the fenofibrate group and 2.4 % in the placebo group (p=0.32).(26) Selected HMG-CoA reductase inhibitors linked to this monograph include: fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.

Fenofibrate; Gemfibrozil/Bile Acid Sequestrants

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Bile acid sequestrants may bind to fenofibrate and gemfibrozil resulting in decreased absorption of fenofibrate and gemfibrozil.(1,2)

CLINICAL EFFECTS: Concurrent use of fenofibrate and gemfibrozil with bile acid sequestrants may result in decreased fenofibrate absorption and clinical effects.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer states that fenofibrate should be administered 1 hour before or 4-6 hours after administration of bile acid sequestrants.(1) The US manufacturer states that gemfibrozil should be administered 2 hours apart from bile acid sequestrants.(2)

DISCUSSION: Bile acid sequestrants are known to bind to drugs when given concurrently. Administration with fenofibrate and gemfibrozil may result in decreased systemic absorption.(1,2)

Fibrates/Bempedoic Acid

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism for this interaction is unknown.

CLINICAL EFFECTS: Concomitant use of bempedoic acid with fibrates may increase triglycerides and decrease high-density lipoprotein cholesterol (HDL-C).(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of bempedoic acid states monitor triglycerides and HDL-C four weeks after initial concomitant use of bempedoic acid and a fibrate and periodically thereafter. If increased triglycerides or decreased HDL-C levels are detected, discontinue bempedoic acid or fibrate therapy based on clinical judgment. Monitor triglycerides and HDL-C levels until levels return to baseline.(1,2)

DISCUSSION: In some patients in clinical studies and post-marketing reports, concomitant administration of fibrates with bempedoic acid resulted in increased triglycerides and decreased HDL-C. Reversibility of both increased triglycerides and decreased HDL-C levels was observed when either bempedoic acid or fibrate therapy was discontinued.(1,2)

Fibrates/Colchicine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism of action is not clear. Concurrent use of colchicine and fibrates may result in additive or synergistic risk for myopathy or rhabdomyolysis.(1-2)

CLINICAL EFFECTS: Concurrent use of colchicine and fibrates have been associated with myopathy and rhabdomyolysis.(1-2)

PREDISPOSING FACTORS: This interaction is expected to be more severe in the elderly and in patients with renal impairment.(1-3)

PATIENT MANAGEMENT: The risks and benefits of colchicine should be carefully weighed in patients who are currently taking fibrates. Assure that colchicine dosage has been reduced in patients with a creatinine clearance < 30 mL/min. Patients should be monitored and instructed to report any signs or symptoms of unexpected muscle pain, tenderness or weakness.(1)

DISCUSSION: Neuromyopathy was reported in a patient maintained on bezafibrate who received colchicine for recurrent gout.(4) Rhabdomyolysis was reported in a patient following the addition of gemfibrozil to colchicine therapy. The patient had pre-existing mild renal failure, hepatitis B-related chronic liver disease, and amyloidosis, which may have contributed.(3)

Fibrates/Ezetimibe

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Both ezetimibe and fibrates may increase cholesterol excretion in the bile. Fibrates may inhibit the metabolism of ezetimibe.(1)

CLINICAL EFFECTS: Concurrent administration of ezetimibe may result in cholelithiasis, elevated levels of ezetimibe, and toxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of ezetimibe states that the concurrent use of ezetimibe and fibrates other than fenofibrate is not recommended.(1) The Australian manufacturer of ezetimibe states that concurrent use with fenofibrate in patients with gallbladder disease is contraindicated.(2) The US manufacturer of bempedoic acid-ezetimibe (Nexlizet) states monitor triglycerides and high-density lipoprotein cholesterol (HDL-C) four weeks after initial concomitant use of bempedoic acid-ezetimibe (Nexlizet) and a fibrate and periodically thereafter. If increased triglycerides or decreased HDL-C levels are detected, discontinue bempedoic acid-ezetimibe (Nexlizet) or fibrate therapy based on clinical judgment. Monitor triglycerides and HDL-C levels until levels return to baseline.(3) Patients receiving concurrent therapy with any fibrate should be monitored for cholelithiasis and increased ezetimibe side effects. If cholelithiasis is suspected, gallbladder studies are indicated and alternative therapy may need to be utilized.(1)

DISCUSSION: Fibrates have been shown to increase cholesterol excretion into the bile, leading to cholelithiasis. Ezetimibe has been shown in dogs to increase cholesterol in the gallbladder bile.(1) In a study in 32 subjects, concurrent fenofibrate and ezetimibe increased the maximum concentration (Cmax) and area-under-curve (AUC) of total ezetimibe by 64% and 48%, respectively. There was no significant effect on fenofibrate pharmacokinetics. Concomitant fenofibrate increased total ezetimibe concentrations by 1.5-fold.(1) In a study in 625 patients for up to 12 weeks and 576 patients for up to an additional 48 weeks, concurrent ezetimibe and fenofibrate was effective at lowering total cholesterol, LDL-C, Apo B, and non-HDL-C. The number of patients was inadequate to assess gallbladder risk; however, 0.6% of patients in the fenofibrate monotherapy group experienced cholecystectomy versus 1.7% during concurrent therapy.(1) In a study in 12 healthy subjects, concurrent gemfibrozil and ezetimibe increased the bioavailability of ezetimibe by 1.7-fold. There was no significant effect on gemfibrozil pharmacokinetics.(1)

Selected Fibrates/Cyclosporine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Concurrent use of cyclosporine and fibrates may result in additive nephrotoxicity.(1)

CLINICAL EFFECTS: Concurrent use of cyclosporine and fibrates may result in additive nephrotoxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Use concurrent cyclosporine and fibrates with caution. If concurrent use is warranted, use the lowest effective dose of the fibrate and monitor patients for decreased renal function.

DISCUSSION: In a study in heart-transplant patients, concurrent fenofibrate had no effect on cyclosporine levels, but patients developed increased serum concentration.(2) Two studies in transplant patients found that gemfibrozil had no effect on cyclosporine levels or renal function.(3,4)

Fenofibrate and fenofibric acid are contraindicated in patients with severe renal impairment (including those undergoing dialysis), active liver disease (including primary biliary cirrhosis and unexplained and persistent liver function abnormality), or preexisting gallbladder disease. The drugs also are contraindicated in nursing women and in patients with known hypersensitivity to fenofibrate or fenofibric acid.

• Child-pugh class A hepatic impairment
• Child-pugh class B hepatic impairment
• Child-pugh class C hepatic impairment
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Lactation

• Acute pancreatitis
• Chronic kidney disease stage 2 (mild) GFR 60-89 ml/min
• Chronic kidney disease stage 3A (moderate) GFR 45-59 ml/min
• Chronic kidney disease stage 3B (moderate) GFR 30-44 ml/min
• Disease of liver
• Gallbladder disease
• Myopathy
• Myositis
• Rhabdomyolysis

• Agranulocytosis
• Anemia
• Hypothyroidism
• Kidney disease with likely reduction in glomerular filtration rate (GFr)
• Leukopenia
• Thrombocytopenic disorder

Adverse effects occurring in 2% or more of patients receiving fenofibrate include abnormal liver function tests (e.g., increased ALT and/or AST), respiratory disorder, abdominal pain, back pain, headache, increased CK concentrations, diarrhea, nausea, rhinitis, constipation, asthenia, and flu syndrome.

Adverse effects occurring in 2% or more of patients receiving fenofibric acid include abnormal liver function tests, including increased AST/ALT; increased CPK; and rhinitis.

More Frequent

• Abnormal hepatic function tests
• Increased alanine transaminase
• Increased aspartate transaminase

Less Frequent

• Infection
• Myalgia
• Pruritus of skin
• Skin rash
• Thrombophlebitis
• Urticaria

Rare or Very Rare

• Acute pancreatitis
• Acute renal failure
• Agranulocytosis
• Anaphylaxis
• Angioedema
• Biliary calculus
• Cholecystitis
• Cholestatic hepatitis
• DRESS syndrome
• Eczema
• Hepatic cirrhosis
• Hepatic failure
• Hepatitis
• Hepatocellular damage
• Hyperbilirubinemia
• Hypersensitivity pneumonitis
• Interstitial lung disease
• Jaundice
• Muscle weakness
• Myositis
• Pulmonary thromboembolism
• Respiration changes
• Rhabdomyolysis
• Stevens-johnson syndrome
• Thrombocytopenic disorder
• Toxic epidermal necrolysis
• Venous thrombosis

More Frequent

• Rhinitis

Less Frequent

• Acute abdominal pain
• Back pain
• Constipation
• Dizziness
• Eructation
• Flatulence
• Flu-like symptoms
• General weakness
• Headache disorder
• Libido changes
• Myopathy
• Nausea
• Ocular irritation
• Pharyngitis
• Skin photosensitivity
• Upper respiratory infection

Rare or Very Rare

• Anemia
• Arthralgia
• Cough
• Diarrhea
• Dyspepsia
• High density lipoprotein deficiency
• Increased creatine kinase level
• Insomnia
• Muscle spasm

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Safety and efficacy of fenofibrate and fenofibric acid have not been established in pediatric patients.

There are insufficient data in pregnant women to determine whether fenofibrate is associated with a risk of developmental adverse effects. In animal reproduction studies, no evidence of embryofetal toxicity was observed with dose exposures up to the maximum recommended clinical dose.

Fenofibrate should be used during pregnancy only if the potential benefits justify the potential risks to the fetus.

Because of the potential for serious adverse effects in nursing infants, fenofibrate and fenofibric acid should not be used in nursing women; a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman. (See Cautions: Contraindications.)

Because fenofibric acid is substantially excreted by the kidneys, and geriatric patients are more likely to have decreased renal function, dosage of fenofibrate and fenofibric acid for geriatric patients should be selected based on renal function. (See Dosage and Administration: Special Populations.) Renal function monitoring should be considered in geriatric patients receiving fenofibrate or fenofibric acid therapy.