Gemfibrozil (gemfibrozil)

Dosage of gemfibrozil must be carefully adjusted according to individual requirements and response. Serum lipoprotein concentrations should be determined regularly during gemfibrozil therapy. (See Cautions: Precautions and Contraindications.)

For the management of hypertriglyceridemia or other hyperlipoproteinemias+, the usual adult dosage of gemfibrozil is 600 mg twice daily. The drug should be discontinued after 3 months if serum lipoprotein concentrations do not improve substantially.

Gemfibrozil is administered orally, 30 minutes before the morning and evening meals.

There is no enhanced messaging for this drug.

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)

Gemfibrozil/Asunaprevir

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: Asunaprevir is a substrate for the OATP1B1 transporter. OATP1B1-facilitated transport into the liver is thought to be associated with asunaprevir efficacy. Gemfibrozil is a strong OATP1B1 inhibitor and so may decrease asunaprevir efficacy by inhibiting its transport into the liver.(1,2)

CLINICAL EFFECTS: The combination of asunaprevir with gemfibrozil may result in decreased liver concentrations of asunaprevir and loss of efficacy for treatment of hepatitis C.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Because of the risk for treatment failure, the manufacturer of asunaprevir states that concomitant use with gemfibrozil is contraindicated.(1)

DISCUSSION: A study of 20 healthy subjects found that rifampin (a strong CYP3A4 inducer and OATP1B1 inhibitor) 600 mg daily decreased the maximum concentration (Cmax) and area-under-curve (AUC) of asunaprevir (600 mg twice daily) by 5% and 21%, respectively. The expected decrease in asunaprevir concentrations was thought to be attenuated by the inhibition of liver uptake by OATP1B1. Hepatic asunaprevir exposure was thought to be significantly reduced.(3) There have been no studies with the concurrent use of asunaprevir and gemfibrozil. Unlike rifampin, gemfibrozil does not induce CYP3A4, but it is expected to decrease hepatic exposure to asunaprevir via OATP1B1 inhibition.

Gemfibrozil/Atorvastatin

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: 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.

PATIENT MANAGEMENT: According to 2018 ACC/AHA Blood Cholesterol Guidelines, gemfibrozil is contraindicated in patients on statin therapy. According to the 2016 AHA Scientific Statement Recommendations for Management of Clinically Significant Drug-Drug Interactions with Statins and Select Agents Used in Patients with Cardiovascular Disease, atorvastatin dose should be initiated at 10 mg daily and should not exceed 20 mg daily when used concurrently with gemfibrozil. According to 2013 ACC/AHA Blood Cholesterol Guidelines, gemfibrozil should not be initiated in patients on statin therapy. Fenofibrate may be considered with low or moderate intensity statin therapy only if benefits outweigh the risks. The US, Australian, Canadian, and UK manufacturers of gemfibrozil state that use with HMG CO-A reductase inhibitors does not outweigh the risks of severe myopathy, rhabdomyolysis, and acute renal failure. The Canadian manufacturer of gemfibrozil states that HMG CO-A reductase inhibitors should not be used concurrently. The US, Canadian, and UK manufacturers of atorvastatin state that concurrent use of gemfibrozil should be avoided. Instruct patients receiving concurrent therapy 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.

DISCUSSION: Gemfibrozil has been shown to increase levels of cerivastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin. Administration of gemfibrozil with cerivastatin, lovastatin, and simvastatin has been associated with myolysis and rhabdomyolysis (muscle pain, tenderness, and weakness). Although the reaction has been reported with the statins alone, the incidence increases dramatically with concurrent administration of gemfibrozil. 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 (0.16%) patients receiving concurrent gemfibrozil and statin therapy compared with no reports in 1,830 patients receiving concurrent fenofibrate and statin therapy. In a retrospective cohort study of 252,460 patients, concurrent use of statins and fibrates increased the risk of rhabdomyolysis, especially in patients with diabetes mellitus. The risk of hospitalization for patients aged 65 or older with diabetes mellitus, treated with a statin and fibrate, increased 48-fold compared to statin monotherapy. In a retrospective study, of 468 patients with a diagnosis of myopathy, 61 received a statin prior to their diagnosis. Forty-one of these patients developed confirmed myopathy, creatinine kinase more than or equal to 1000 IU/L.

Gemfibrozil/Bexarotene

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 exact mechanism is unknown.

CLINICAL EFFECTS: Concurrent use of gemfibrozil may result in elevated levels of and toxicity from bexarotene, including hypertriglyceridemia, pancreatitis, liver problems, and neutropenia.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the concurrent use of bexarotene and gemfibrozil.(1) If concurrent use is warranted, monitor patients for signs of toxicity, including hypertriglyceridemia, pancreatitis, liver problems, and neutropenia.

DISCUSSION: In a clinical trial of bexarotene in patients with cutaneous T-cell lymphoma, a small subset of patients who also received gemfibrozil experienced elevated bexarotene levels and toxicity.(1,2)

Gemfibrozil/Fluvastatin

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: 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.

PATIENT MANAGEMENT: According to the 2018 ACC/AHA Blood Cholesterol Guidelines, gemfibrozil is contraindicated in patients on statin therapy. According to the 2016 AHA Scientific Statement Recommendations for Management of Clinically Significant Drug-Drug Interactions with Statins and Select Agents Used in Patients with Cardiovascular Disease, fluvastatin dose does not require a dose adjustment when used concurrently with gemfibrozil. According to 2013 ACC/AHA Blood Cholesterol Guidelines, gemfibrozil should not be initiated in patients on statin therapy. Fenofibrate may be considered with low or moderate intensity statin therapy only if benefits outweigh the risks. The US, Australian, Canadian, and UK manufacturers of gemfibrozil state that use with HMG CO-A reductase inhibitors does not outweigh the risks of severe myopathy, rhabdomyolysis, and acute renal failure. The Canadian manufacturer of gemfibrozil states that HMG CO-A reductase inhibitors should not be used concurrently. The US manufacturer of fluvastatin states that concurrent use of gemfibrozil should be avoided. The Australian, Canadian, and UK manufacturers state concurrent use should be approached with caution. Instruct patients receiving concurrent therapy 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.

DISCUSSION: Gemfibrozil has been shown to increase levels of cerivastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin. Administration of gemfibrozil with cerivastatin, lovastatin, and simvastatin has been associated with myolysis and rhabdomyolysis (muscle pain, tenderness, and weakness). Although the reaction has been reported with the statins alone, the incidence increases dramatically with concurrent administration of gemfibrozil. 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 (0.16%) patients receiving concurrent gemfibrozil and statin therapy compared with no reports in 1,830 patients receiving concurrent fenofibrate and statin therapy. In a retrospective cohort study of 252,460 patients, concurrent use of statins and fibrates increased the risk of rhabdomyolysis, especially in patients with diabetes mellitus. The risk of hospitalization for patients aged 65 or older with diabetes mellitus, treated with a statin and fibrate, increased 48-fold compared to statin monotherapy. In a retrospective study, of 468 patients with a diagnosis of myopathy, 61 received a statin prior to their diagnosis. Forty-one of these patients developed confirmed myopathy, creatinine kinase more than or equal to 1000 IU/L.

Gemfibrozil/Lovastatin; Pravastatin

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: 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.

PATIENT MANAGEMENT: According to 2013 ACC/AHA Blood Cholesterol Guidelines, gemfibrozil should not be initiated in patients on statin therapy. Fenofibrate may be considered with low or moderate intensity statin therapy only if benefits outweigh the risks. According to 2016 AHA guidelines on the management of drug-drug interactions with statins, concurrent use of gemfibrozil with lovastatin, pravastatin, or simvastatin should be avoided and concurrent use with atorvastatin, pitavastatin, or rosuvastatin may be considered if fenofibrate or fenofibric acid is not an option. Concurrent therapy with atorvastatin should be initiated at 10 mg daily and increased to 20 mg daily if tolerated and necessary. Concurrent therapy with pitavastatin should be initiated at 1 mg daily and increased to 2 mg daily if tolerated and necessary. Concurrent therapy with rosuvastatin should be initiated at 5 mg daily and increased to 10 mg daily if tolerated and necessary. The US, Australian, Canadian, and UK manufacturers of gemfibrozil state that use with HMG CO-A reductase inhibitors does not outweigh the risks of severe myopathy, rhabdomyolysis, and acute renal failure. The US and UK manufacturers of gemfibrozil state that concurrent use of simvastatin is contraindicated. The Canadian manufacturer of gemfibrozil states that HMG CO-A reductase inhibitors should not be used concurrently. The US and Canadian manufacturers of lovastatin state concurrent use of gemfibrozil should be avoided. The US, Canadian, and UK manufacturers of pravastatin state that concurrent use of gemfibrozil should be avoided. Instruct patients receiving concurrent therapy 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.

DISCUSSION: Gemfibrozil has been shown to increase levels of cerivastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin. Administration of gemfibrozil with cerivastatin, lovastatin, and simvastatin has been associated with myolysis and rhabdomyolysis (muscle pain, tenderness, and weakness). Although the reaction has been reported with the statins alone, the incidence increases dramatically with concurrent administration of gemfibrozil. 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. Concurrent fenofibrate (160 mg daily) increased the AUC and Cmax of pitavastatin (4 mg daily) by 18% and 11%, respectively. Concurrent gemfibrozil (600 mg twice daily) increased the AUC and Cmax of pitavastatin (4 mg daily) by 45% and 31%, 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. Concurrent fenofibrate and rosuvastatin resulted in no significant changes in rosuvastatin or fenofibrate levels. Concurrent gemfibrozil 600 mg twice daily for 3 days, followed by lovastatin 40 mg increased the AUC of the active metabolite of lovastatin 2.8 fold. Concurrent gemfibrozil (600 mg twice daily) and rosuvastatin (80 mg) increased the rosuvastatin AUC and Cmax by 90% and 120%, respectively. In healthy subjects, gemfibrozil increased the Cmax and AUC of a single dose of rosuvastatin by 2.2-fold and 1.9-fold, respectively. 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 (0.16%) patients receiving concurrent gemfibrozil and statin therapy compared with no reports in 1,830 patients receiving concurrent fenofibrate and statin therapy. In a retrospective cohort study of 252,460 patients, concurrent use of statins and fibrates increased the risk of rhabdomyolysis, especially in patients with diabetes mellitus. The risk of hospitalization for patients aged 65 or older with diabetes mellitus, treated with a statin and fibrate, increased 48-fold compared to statin monotherapy. In a retrospective study, of 468 patients with a diagnosis of myopathy, 61 received a statin prior to their diagnosis. Forty-one of these patients developed confirmed myopathy, creatinine kinase more than or equal to 1000 IU/L.

Gemfibrozil/Pitavastatin

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: 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.

PATIENT MANAGEMENT: According to the 2018 ACC/AHA Blood Cholesterol Guidelines, gemfibrozil is contraindicated in patients on statin therapy. According to the 2016 AHA Scientific Statement Recommendations for Management of Clinically Significant Drug-Drug Interactions with Statins and Select Agents Used in Patients with Cardiovascular Disease, pitavastatin dose should be initiated at 1 mg daily and should not exceed 2 mg daily when used concurrently with gemfibrozil. According to 2013 ACC/AHA Blood Cholesterol Guidelines, gemfibrozil should not be initiated in patients on statin therapy. Fenofibrate may be considered with low or moderate intensity statin therapy only if benefits outweigh the risks. The US, Australian, Canadian, and UK manufacturers of gemfibrozil state that use with HMG CO-A reductase inhibitors does not outweigh the risks of severe myopathy, rhabdomyolysis, and acute renal failure. The Canadian manufacturer of gemfibrozil states that HMG CO-A reductase inhibitors should not be used concurrently. The US manufacturer of pitavastatin states concurrent use of gemfibrozil should be avoided. Instruct patients receiving concurrent therapy 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.

DISCUSSION: Gemfibrozil has been shown to increase levels of cerivastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin. Administration of gemfibrozil with cerivastatin, lovastatin, and simvastatin has been associated with myolysis and rhabdomyolysis (muscle pain, tenderness, and weakness). Although the reaction has been reported with the statins alone, the incidence increases dramatically with concurrent administration of gemfibrozil. Concurrent fenofibrate (160 mg daily) increased the AUC and Cmax of pitavastatin (4 mg daily) by 18% and 11%, respectively. Concurrent gemfibrozil (600 mg twice daily) increased the AUC and Cmax of pitavastatin (4 mg daily) by 45% and 31%, respectively. 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 (0.16%) patients receiving concurrent gemfibrozil and statin therapy compared with no reports in 1,830 patients receiving concurrent fenofibrate and statin therapy. In a retrospective cohort study of 252,460 patients, concurrent use of statins and fibrates increased the risk of rhabdomyolysis, especially in patients with diabetes mellitus. The risk of hospitalization for patients aged 65 or older with diabetes mellitus, treated with a statin and fibrate, increased 48-fold compared to statin monotherapy. In a retrospective study, of 468 patients with a diagnosis of myopathy, 61 received a statin prior to their diagnosis. Forty-one of these patients developed confirmed myopathy, creatinine kinase more than or equal to 1000 IU/L.

Gemfibrozil/Repaglinide

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: Gemfibrozil inhibits the OATP1B1 transporter and is a strong inhibitor of CYP2C8, leading to inhibition of repaglinide transport and metabolism by these pathways.(1,6)

CLINICAL EFFECTS: Concurrent use of gemfibrozil and repaglinide may result in elevated levels and clinical effects of repaglinide.(1)

PREDISPOSING FACTORS: Concurrent administration of itraconazole may further increase repaglinide levels.(1,3)

PATIENT MANAGEMENT: The US manufacturers of gemfibrozil(2) and repaglinide,(3) and the Canadian manufacturer of repaglinide(4) state that concurrent use of gemfibrozil and repaglinide is contraindicated. Consider the use of fenofibrate in patients treated with repaglinide who require fibrate therapy.

DISCUSSION: In a randomized, cross-over study in 12 healthy subjects, gemfibrozil (600 mg twice daily) increased the area-under-curve (AUC) and half-life of repaglinide by 8.1-fold and 1.8-fold, respectively.(1,3) At seven hours post dose, gemfibrozil increased plasma repaglinide levels by 28.6-fold. The blood-glucose lowering effects of repaglinide were also increased by gemfibrozil.(1) In a study, concurrent administration of gemfibrozil (600 mg twice daily) and itraconazole (100 mg twice daily) for three days increased repaglinide AUC and Cmax by 19-fold and 2.8-fold, respectively.(2) In a randomized, cross-over study in 9 healthy subjects, concurrent gemfibrozil (600 mg twice daily) and itraconazole (200 mg once, then 100 mg twice daily) increased the AUC and maximum concentration (Cmax) of nateglinide (30 mg) by 47% and 30%, respectively. The AUC and Cmax of a nateglinide metabolite were also increased by 166% and 92%, respectively. However, the blood-glucose lowering effects of nateglinide were not significantly altered.(5) An in vitro study used human liver subcellular fractions, fresh human hepatocytes, and recombinant enzymes to study repaglinide metabolism. This study concluded that repaglinide undergoes direct glucuronidation and that gemfibrozil inhibited both glucuronide and M4 formation with minor M2 inhibition. This resulted in a 80% decrease in turnover of repaglinide.(8) In a randomized crossover study, ten healthy volunteers were given 0.25 mg orally of repaglinide then, 1 hour later, a single oral 30 mg, 100 mg, 300 mg, or 900 mg dose of gemfibrozil or placebo. The mean AUC of repaglinide was increased 1.9-fold,4.5-fold, 6.7-fold, or 8.3-fold after a single dose of gemfibrozil 30 mg, 100 mg, 300 mg, or 900 mg, respectively (p<0.001). The Cmax of repaglinide increased 1.4-fold, 1.7-fold, 2.1-fold, and 2.4-fold, respectively, after the single oral dose of gemfibrozil (p<0.05).(8) In a randomized cross-over study, 12 healthy patients received bezafibrate (400 mg daily), fenofibrate (200 mg daily), or placebo (once daily) for 5 days. On day 5, the patient also took a single dose of repaglinide (0.25 mg) one hour after the fibrate dose. Bezafibrate and fenofibrate had no statistically significant effects on the Cmax, Tmax, AUC, or T1/2 of repaglinide, nor did it affect blood glucose concentrations.(9)

Gemfibrozil/Rosuvastatin

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: Unknown.

CLINICAL EFFECTS: Concurrent administration of HMG-CoA reductase inhibitors and gemfibrozil 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 rosuvastatin with ABCG2 polymorphisms leading to decreased or poor BCRP transporter function may have increased rosuvastatin concentrations and risk of myopathy.

PATIENT MANAGEMENT: According to the 2018 ACC/AHA Blood Cholesterol Guidelines, gemfibrozil is contraindicated in patients on statin therapy. According to the 2016 AHA Scientific Statement Recommendations for Management of Clinically Significant Drug-Drug Interactions with Statins and Select Agents Used in Patients with Cardiovascular Disease, rosuvastatin dose should be initiated at 5 mg daily and should not exceed 10 mg daily when used concurrently with gemfibrozil. The manufacturer of gemfibrozil states that concurrent therapy with gemfibrozil and HMG CO-A reductase inhibitors does not outweigh the risks of severe myopathy, rhabdomyolysis, and acute renal failure. The Canadian manufacturer of rosuvastatin states that patients receiving concurrent gemfibrozil should not receive more than 20 mg of rosuvastatin daily and that the concurrent use of gemfibrozil and 40 mg of rosuvastatin is contraindicated. The Australian and US manufacturers of rosuvastatin state that the concurrent use of gemfibrozil and rosuvastatin should be avoided and that the risks of concurrent use of other fibrates should be carefully weighed against the benefits. In patients requiring concurrent gemfibrozil, the dosage of rosuvastatin should be limited to 10 mg daily. When possible, avoid administration of these drugs concomitantly unless patients require aggressive therapy. If possible, consider the use of fenofibrate over gemfibrozil for concurrent therapy with a statin. 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.

DISCUSSION: Gemfibrozil has been shown to increase levels of cerivastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin. Administration of gemfibrozil with cerivastatin, lovastatin, and simvastatin has been associated with myolysis and rhabdomyolysis (muscle pain, tenderness, and weakness). Although the reaction has been reported with the statins alone, the incidence increases dramatically with concurrent administration of gemfibrozil. Concurrent gemfibrozil (600 mg twice daily) and rosuvastatin (80 mg) increased the rosuvastatin AUC and Cmax by 90% and 120%, respectively. In healthy subjects, gemfibrozil increased the Cmax and AUC of a single dose of rosuvastatin by 2.2-fold and 1.9-fold, respectively. 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 retrospective cohort study of 252,460 patients, concurrent use of statins and fibrates increased the risk of rhabdomyolysis, especially in patients with diabetes mellitus. The risk of hospitalization for patients aged 65 or older with diabetes mellitus, treated with a statin and fibrate, increased 48-fold compared to statin monotherapy. In a retrospective study, of 468 patients with a diagnosis of myopathy, 61 received a statin prior to their diagnosis. Forty-one of these patients developed confirmed myopathy, creatinine kinase more than or equal to 1000 IU/L.

Gemfibrozil/Simvastatin

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: Unknown.

CLINICAL EFFECTS: Concurrent administration of HMG-CoA reductase inhibitors and gemfibrozil 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: According to the 2018 ACC/AHA Blood Cholesterol Guidelines, gemfibrozil is contraindicated in patients on statin therapy. According to the 2016 AHA Scientific Statement Recommendations for Management of Clinically Significant Drug-Drug Interactions with Statins and Select Agents Used in Patients with Cardiovascular Disease, simvastatin is contraindicated with gemfibrozil. The manufacturers of gemfibrozil and simvastatin both contraindicate concurrent use. When possible, avoid administration of these drugs concomitantly unless patients require aggressive therapy. If possible, consider the use of fenofibrate over gemfibrozil for concurrent therapy with a statin. 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.

DISCUSSION: Gemfibrozil has been shown to increase levels of cerivastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin. Administration of gemfibrozil with cerivastatin, lovastatin, and simvastatin has been associated with myolysis and rhabdomyolysis (muscle pain, tenderness, and weakness). Although the reaction has been reported with the statins alone, the incidence increases dramatically with concurrent administration of gemfibrozil. 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 retrospective cohort study of 252,460 patients, concurrent use of statins and fibrates increased the risk of rhabdomyolysis, especially in patients with diabetes mellitus. The risk of hospitalization for patients aged 65 or older with diabetes mellitus, treated with a statin and fibrate, increased 48-fold compared to statin monotherapy. In a retrospective study, of 468 patients with a diagnosis of myopathy, 61 received a statin prior to their diagnosis. Forty-one of these patients developed confirmed myopathy, creatinine kinase more than or equal to 1000 IU/L.

Oatp1b1-3 Inhibitors/Atrasentan

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: OATP1B1 and 1B3 inhibitors may increase the absorption and/or decrease the hepatic uptake of atrasentan.(1)

CLINICAL EFFECTS: Concurrent use of OATP1B1 or 1B3 inhibitors may result in elevated levels of and side effects from atrasentan, including fluid retention and hepatotoxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of atrasentan states that concurrent use of OATP1B1 or 1B3 inhibitors should be avoided.(1)

DISCUSSION: In a clinical study, atrasentan maximum concentration (Cmax) was 4.3 times higher and area-under-curve (AUC) was 3.8 times higher following coadministration of a single dose of 0.75 mg atrasentan with cyclosporine (OATP1B1 and 1B3 inhibitor) compared to atrasentan alone. OATP1B1 and OATP1B3 inhibitors include: atazanavir, belumosudil, boceprevir, clarithromycin, cobicistat, cyclosporine, eltrombopag, erythromycin, fostemsavir, gemfibrozil, glecaprevir-pibrentasvir, leflunomide, leniolisib, letermovir, lopinavir, nirmatrelvir, ombitasvir-paritaprevir, resmetirom, ritonavir, roxadustat, saquinavir, simeprevir, telaprevir, teriflunomide, tipranavir, vadadustat, velpatasvir, voclosporin, and voxilaprevir.(1,2)

Strong Cyp2c8 Inhibitors/Daprodustat

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: Strong inhibitors of CYP2C8 may impair the CYP2C8-mediated metabolism of daprodustat.(1)

CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP2C8 may result in elevated levels of and clinical effects of daprodustat, including the risk for thromboembolic events and hypertension.

PREDISPOSING FACTORS: Patients with a history of myocardial infarction, cerebrovascular event, or acute coronary syndrome within the past 3 months may be at increased risk of thromboembolic events. Other risk factors for thromboembolic events include thrombophilia, malignancy, hyperlipidemia, hypertension, heart failure, diabetes mellitus, chronic kidney disease, COPD, obesity, tobacco smoking, major surgery with prolonged post-operative immobilization, and being bed-ridden.

PATIENT MANAGEMENT: The manufacturer of daprodustat states that concomitant administration of strong CYP2C8 inhibitors is contraindicated.(1)

DISCUSSION: In an interaction study, gemfibrozil 600 mg twice daily for 5 days increased the area-under-curve (AUC) and maximum concentration (Cmax) of daprodustat (single 100 mg dose) by 18.6-fold and 3.9-fold respectively.(1) Strong inhibitors of CYP2C8 include gemfibrozil.(2,3)

Strong Cyp2c8 Inhibitors/Dasabuvir

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: Strong inhibitors of CYP2C8 may impair the CYP2C8 mediated metabolism of dasabuvir.(1)

CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP2C8 may result in elevated levels of and clinical effects of dasabuvir, including the risk for QT prolongation.

PREDISPOSING FACTORS: 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, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of a 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, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The manufacturer of Viekira Pak (ombitasvir, paritaprevir, ritonavir, dasabuvir sodium) states that concurrent use of strong CYP2C8 inhibitors is contraindicated due to an increased risk for dasabuvir associated QT prolongation.(1) If concurrent therapy is deemed medically necessary, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In an interaction study with 11 subjects, gemfibrozil 600 mg twice daily increased the area-under-curve (AUC) and maximum concentration (Cmax) of dasabuvir 11.25-fold and 2.01-fold respectively.(1) Strong inhibitors of CYP2C8 include gemfibrozil.(3,4)

Strong Cyp2c8 Inhibitors/Pioglitazone (> 15 Mg)

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: Strong inhibitors of CYP2C8 may inhibit the metabolism of pioglitazone.(1-5)

CLINICAL EFFECTS: Concurrent use of strong CYP2C8 inhibitors may result in elevated levels of and clinical effects, including severe hypoglycemia, from pioglitazone.(1-5)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The maximum recommended dosage of pioglitazone is 15 mg daily when used concurrently with strong CYP2C8 inhibitors.(2)

DISCUSSION: In a randomized, cross-over study in 10 healthy subjects, pretreatment with gemfibrozil (600 mg daily for 3 days) increased the the area-under-curve (AUC) of a single dose of pioglitazone (30 mg) by 3.4-fold. The AUC of the ratios of the M-III metabolite/pioglitazone and M-IV metabolite/pioglitazone were reduced by 71% and by 65%, respectively. (1,2) In a randomized, double-blind, cross-over study in 12 healthy subjects, pretreatment with gemfibrozil (600 mg daily for 3 days) increased the AUC and half-life (T1/2) of a single dose of pioglitazone (15 mg) by 3.2-fold (range 2.3-fold to 6.5-fold) and by 1.7-fold, respectively. There was no significant effect on pioglitazone maximum concentration (Cmax). The 0-48 hour AUC of the M-III and M-IV metabolites were decreased by 42% and by 45%, respectively; however, there was no significant effect on their 0-infinity AUC.(3) In a randomized, cross-over study, gemfibrozil (600 mg twice daily for 4 days) increased the AUC of a single dose of pioglitazone (15 mg) by 4.3-fold. The increase was variable between CYP2C8 genotypes. Individuals who were CYP2C8*3 carriers had a 5.2-fold increase in pioglitazone, while CYP2C8*1 homozygotes had a 3.3-fold increase in pioglitazone.(5) Strong inhibitors of CYP2C8 include: gemfibrozil.(8,9)

Strong Cyp2c8 Inhibitors/Selexipag

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: Strong CYP2C8 inhibitors may inhibit the metabolism of selexipag.(1,2)

CLINICAL EFFECTS: Concurrent use of a strong CYP2C8 inhibitor may increase levels and effects of selexipag, including headache, diarrhea, jaw pain, nausea, myalgia, vomiting, pain in extremity, flushing, decreased hemoglobin, and hyperthyroidism.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of strong CYP2C8 inhibitors and selexipag is contraindicated.(1,2) If concurrent use is warranted, monitor patients closely for increased effects of selexipag, including headache, diarrhea, jaw pain, nausea, myalgia, vomiting, pain in extremity, flushing, decreased hemoglobin, and hyperthyroidism.

DISCUSSION: Gemfibrozil doubled the area-under-curve (AUC) of selexipag and increased the AUC of its active metabolite 11-fold.(1,2) Strong inhibitors of CYP2C8 include gemfibrozil.(3,4)

Strong Cyp2c8 Inhibitors/Tolebrutinib

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: Strong inhibitors of CYP2C8 may inhibit the metabolism of tolebrutinib.(1-2)

CLINICAL EFFECTS: Concurrent use of strong CYP2C8 inhibitors may result in elevated levels and clinical effects of tolebrutinib, including immunosuppression and hepatotoxicity.(1-2)

PREDISPOSING FACTORS: This interaction is expected to be more severe in patients with hepatic impairment.(1)

PATIENT MANAGEMENT: The manufacturer of tolebrutinib states that use of concomitant strong CYP2C8 inhibitors should be avoided. If the use of strong CYP2C8 inhibitors will be short-term, treatment with tolebrutinib should be interrupted.(1)

DISCUSSION: In a study of healthy participants, concurrent use of gemfibrozil (strong inhibitor of CYP2C8) 600 mg BID for 6 days increased tolebrutinib area-under-curve (AUC) by 8.4-fold.(2) Strong inhibitors of CYP2C8 include gemfibrozil.(3,4)

Strong Oatp1b1 Inhibitors/Elagolix

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: Strong inhibitors of OATP1B1 may decrease the hepatic uptake of elagolix.(1,2)

CLINICAL EFFECTS: Concurrent use of an inhibitor of OATP1B1 may result in elevated levels of and side effects from elagolix, including an increased risk of ALT elevations.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of elagolix and strong OATP1B1 inhibitors is contraindicated.(1)

DISCUSSION: Strong OATP1B1 inhibitors linked to this monograph include: belumosudil, cyclosporine, encorafenib, gemfibrozil, letermovir, paritaprevir, resmetirom, roxadustat, and vadadustat.(1,2)

Ugt Inhibitors/Lorazepam Extended Release

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: Inhibitors of UDP-glucuronosyltransferases (UGT) may inhibit the metabolism of lorazepam.(1)

CLINICAL EFFECTS: Concurrent use of UGT inhibitors may result in increased exposure to and toxicity from lorazepam, including profound sedation, respiratory depression, and coma.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of lorazepam extended release capsules states the initiating a UGT inhibitor during therapy with lorazepam extended release capsules should be avoided. If a UGT inhibitor is initiated, discontinue lorazepam extended release capsules and switch patient to a reduced dose of lorazepam tablets during concurrent therapy.(1)

DISCUSSION: In a study in 8 healthy males, pretreatment with valproate (250 mg twice daily for 3 days) decreased the total clearance of a single dose of lorazepam (2 mg intravenously) by 40% in 6 subjects. The formation rate of lorazepam glucuronide was decreased by 55% in these subjects. Lorazepam concentrations were about 2-fold higher for at least 12 hours post-dose during concurrent valproate.(2,4) In a randomized, double-blind, placebo-controlled study in 16 healthy males, concurrent divalproex (500 mg every 12 hours for 12 days) increased the area-under-curve (AUC), maximum concentration (Cmax), and minimum concentration (Cmin) of lorazepam (1 mg every 12 hours, Days 6-10) by 20%, 8%, and 31%, respectively. Lorazepam clearance was decreased by 31% during concurrent divalproex.(5) There is one case report of coma following the injection of 6 mg of lorazepam over 24 hours in a patient maintained on valproate (1000 mg). The patient remained in a coma for between 48 and 72 hours.(6) In a study in 9 healthy subjects, pretreatment with probenecid (500 mg every 6 hours) increased the half-life (T1/2) of a single intravenous dose of lorazepam (2 mg) by 130%. Lorazepam clearance was decreased by 45%. There was no change in lorazepam apparent volume of distribution.(2,7) UGT inhibitors linked to this monograph include: atazanavir, belumosudil, capivasertib, erlotinib, gemfibrozil, indinavir, ketoconazole, lapatinib, mefenamic acid, nilotinib, pazopanib, probenecid, regorafenib, sorafenib, and valproic acid.

Ugt1a1 Inhibitors/Irinotecan

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: Inhibitors of UGT1A1 may inhibit the metabolism of SN-38, the active metabolite of irinotecan.(1) Atazanavir may inhibit the metabolism of irinotecan by UGT1A1.(1,2) This increases the system exposure to SN-38, the active metabolite of irinotecan.(3)

CLINICAL EFFECTS: Concurrent use of UGT1A1 inhibitors may result in increased exposure to and toxicity from irinotecan.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of irinotecan states do not administer UGT1A1 inhibitors with irinotecan unless there are no therapeutic alternatives. The increased exposure to the active metabolite should be taken into consideration when co-administering these agents.(1) The US manufacturer of atazanavir states that concurrent use of irinotecan is contraindicated.(2) The Australian manufacturer of atazanavir states that irinotecan should not be administered with atazanavir.(3)

DISCUSSION: Because atazanavir inhibits UGT1A1 at therapeutic concentrations, it is expected to interfere with the metabolism of irinotecan. Therefore, the manufacturer of atazanavir states that irinotecan should not be administered with atazanavir.(1,2) UGT1A1 inhibitors linked to this monograph include: atazanavir, capivasertib, belumosudil, erlotinib, gemfibrozil, lapatinib, nilotinib, pazopanib, probenecid, regorafenib, and sorafenib. One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Ugt1a1 Inhibitors/Sacituzumab Govitecan

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: Inhibitors of UGT1A1 may inhibit the metabolism of SN-38, the topoisomerase inhibitor which is the antineoplastic component of sacituzumab govitecan.(1)

CLINICAL EFFECTS: Concurrent use of UGT1A1 inhibitors may result in increased exposure to and toxicity from sacituzumab govitecan. Toxicities from sacituzumab govitecan include neutropenia, severe diarrhea, nausea, and vomiting.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the use of inhibitors of UGT1A1 in patients receiving sacituzumab govitecan.(1)

DISCUSSION: SN-38, the small molecule moiety of sacituzumab govitecan, is metabolized by UGT1A1, and inhibitors of UGT1A1 are expected to increase SN-38 levels and dose limiting toxicities.(1) In a clinical trial, patients homozygous for decreased function UGT1A1*28 allele had a 26% incidence of Grade 4 neutropenia, compared to 13% of patients heterozygous for the UGT1A1*28 allele and 11% of patients homozygous for the wild type allele.(1) Coadministration of ketoconazole (a CYP3A4 and UGT1A1 inhibitor) with irinotecan, has been reported to result in increased exposure to SN-38, an active metabolite of irinotecan.(2) UGT1A1 inhibitors linked to this monograph include: atazanavir, belumosudil, capivasertib, erlotinib, gemfibrozil, indinavir, ketoconazole, lapatinib, nilotinib, pazopanib, probenecid, regorafenib, and sorafenib.

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)

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)

Oatp1b1 Inhibitors/Eluxadoline

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

MECHANISM OF ACTION: OATP1B1 inhibitors may decrease the hepatic uptake of eluxadoline.(1)

CLINICAL EFFECTS: Concurrent use of OATP1B1 inhibitors may result in elevated levels of and side effects from eluxadoline, including constipation, nausea, abdominal pain, and impaired mental and physical abilities.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent OATP1B1 inhibitors should receive a dose of eluxadoline of 75 mg twice daily. Monitor patients for impaired mental or physical abilities, abdominal pain, nausea, and constipation.(1)

DISCUSSION: Concurrent administration of a single dose (600 mg) of cyclosporine, an OATP1B1 inhibitor, increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of eluxadoline (100 mg) by 4.4-fold and 6.2-fold, respectively.(1) OATP1B1 inhibitors include: atazanavir, belumosudil, boceprevir, cyclosporine, darunavir, encorafenib, eltrombopag, erythromycin, gemfibrozil, leflunomide, leniolisib, letermovir, lopinavir, paritaprevir, resmetirom, rifampin, ritonavir, roxadustat, saquinavir, simeprevir, telaprevir, teriflunomide, tipranavir, vadadustat, and voclosporin.(1,2)

Oatp1b1-3 Inhibitors/Brincidofovir

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

MECHANISM OF ACTION: OATP1B1 and 1B3 inhibitors may increase the absorption and/or decrease the hepatic uptake of brincidofovir.(1)

CLINICAL EFFECTS: Concurrent use of OATP1B1 or 1B3 inhibitors may result in elevated levels of and side effects from brincidofovir.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of brincidofovir states that alternative medications that are not OATP1B1 or 1B3 inhibitors should be considered. If concurrent use is necessary, instruct the patient to take the OATP1B1 or 1B3 inhibitor at least 3 hours after brincidofovir and increase monitoring for side effects, including transaminase and bilirubin elevations and GI side effects like diarrhea.(1)

DISCUSSION: In a clinical trial, single-dose oral cyclosporine (600 mg, an OATP1B1 and 1B3 inhibitor) increased the mean brincidofovir area-under-curve (AUC) and maximum concentration (Cmax) by 374% and 269%, respectively.(1) OATP1B1 and 1B3 inhibitors include: atazanavir, belumosudil, boceprevir, clarithromycin, cyclosporine, darunavir, eltrombopag, encorafenib, erythromycin, gemfibrozil, glecaprevir-pibrentasvir, ledipasvir, leflunomide, leniolisib, letermovir, lopinavir, ombitasvir-paritaprevir, paritaprevir, resmetirom, rifampin, ritonavir, roxadustat, saquinavir, simeprevir, sofosbuvir, telaprevir, teriflunomide, tipranavir, vadadustat, velpatasvir, and voclosporin.(1,2)

Strong Cyp2c8 Inhibitor/Pioglitazone (<=15Mg); Rosiglitazone

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

MECHANISM OF ACTION: Strong CYP2C8 inhibitors may inhibit the metabolism of pioglitazone(1-5) and rosiglitazone.(6)

CLINICAL EFFECTS: Concurrent use of strong CYP2C8 inhibitors may result in elevated levels of and clinical effects, including severe hypoglycemia, from pioglitazone(1-5) or rosiglitazone.(6,7)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Consider avoiding strong inhibitors of CYP2C8 in patients maintained on pioglitazone or rosiglitazone. The maximum recommended dosage of pioglitazone is 15 mg daily when used concurrently with gemfibrozil or other strong CYP2C8 inhibitors.(2) The dosage of pioglitazone(2) or rosiglitazone(7) may need to be adjusted if gemfibrozil is initiated or discontinued. If concurrent therapy is warranted, patients should be closely monitored for increased response to pioglitazone or rosiglitazone.

DISCUSSION: In a randomized, cross-over study in 10 healthy subjects, pretreatment with gemfibrozil (600 mg daily for 3 days) increased the the area-under-curve (AUC) of a single dose of pioglitazone (30 mg) by 3.4-fold. The AUC of the ratios of the M-III metabolite/pioglitazone and M-IV metabolite/pioglitazone were reduced by 71% and by 65%, respectively. (1,2) In a randomized, double-blind, cross-over study in 12 healthy subjects, pretreatment with gemfibrozil (600 mg daily for 3 days) increased the AUC and half-life (T1/2) of a single dose of pioglitazone (15 mg) by 3.2-fold (range 2.3-fold to 6.5-fold) and by 1.7-fold, respectively. There was no significant effect on pioglitazone maximum concentration (Cmax). The 0-48 hour AUC of the M-III and M-IV metabolites were decreased by 42% and by 45%, respectively; however, there was no significant effect on their 0-infinity AUC.(3) In a randomized, cross-over study, gemfibrozil (600 mg twice daily for 4 days) increased the AUC of a single dose of pioglitazone (15 mg) by 4.3-fold. The increase was variable between CYP2C8 genotypes. Individuals who were CYP2C8*3 carriers had a 5.2-fold increase in pioglitazone, while CYP2C8*1 homozygotes had a 3.3-fold increase in pioglitazone.(5) In a randomized crossover study in 10 subjects, gemfibrozil (600 mg twice daily) increased the rosiglitazone (4 mg single dose) AUC by 2.3-fold and increased rosiglitazone T1/2 from 3.6 hours to 7.6 hours. Rosiglitazone Cmax increased 1.2-fold. At 24 hours post dose, the rosiglitazone concentration was 9.8-fold greater when it was taken with gemfibrozil. Gemfibrozil increased the time to Cmax (Tmax) of N-desmethylrosiglitazone from 7 hours to 12 hours and decreased its AUC by 38%.(6) Concurrent use of gemfibrozil (600 mg twice daily) with rosiglitazone (4 mg daily) increased rosiglitazone AUC by 127%.(7) Strong inhibitors of CYP2C8 include: gemfibrozil.(8,9)

Strong Cyp2c8 Inhibitors/Dabrafenib

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

MECHANISM OF ACTION: Strong inhibitors of CYP2C8 may inhibit the metabolism of dabrafenib.(1)

CLINICAL EFFECTS: Concurrent use of strong inhibitors of CYP2C8 may result in elevated levels of and toxicity from dabrafenib.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of strong inhibitors of CYP2C8 with dabrafenib is not recommended. If possible, choose an alternative agent. If concurrent use is required, monitor patients closely for toxicity.(1)

DISCUSSION: Concurrent use of gemfibrozil (600 mg BID for 4 days), a strong inhibitor of CYP2C8, increased dabrafenib (75 mg BID) area-under-curve (AUC) by 47%.(1) Strong inhibitors of CYP2C8 include gemfibrozil.(2,3)

Strong Cyp2c8 Inhibitors/Elafibranor

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

MECHANISM OF ACTION: Strong inhibitors of CYP2C8 may inhibit the metabolism of elafibranor.(1)

CLINICAL EFFECTS: Concomitant use of a strong CYP2C8 inhibitor may increase elafibranor plasma concentrations, which may increase the risk of elafibranor toxicity, including hepatotoxicity, rhabdomyolysis, myopathy, and bone fractures.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of elafibranor recommends avoiding concomitant use of elafibranor with strong CYP2C8 inhibitors.(1)

DISCUSSION: Strong CYP2C8 inhibitors are predicted to increase elafibranor and GFT1007 (metabolite) exposure.(1) Strong CYP2C8 inhibitors linked to this monograph include gemfibrozil.(2)

Strong Cyp2c8 Inhibitors/Enzalutamide

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

MECHANISM OF ACTION: Strong inhibitors of CYP2C8 may inhibit the metabolism of enzalutamide.(1)

CLINICAL EFFECTS: Concurrent use of strong inhibitors of CYP2C8 may result in elevated levels of and toxicity from enzalutamide.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid concurrent use of strong inhibitors of CYP2C8 with enzalutamide. If concurrent use is required, reduce the dosage of enzalutamide to 80 mg once daily. If the strong CYP2C8 inhibitor is discontinued, return the dosage of enzalutamide to the dosage used prior to initiation of the strong CYP2C8 inhibitor.(1)

DISCUSSION: In a clinical trial in healthy subjects, administration of gemfibrozil (a strong inhibitor of CYP2C8, 600 mg BID) increased the area-under-curve (AUC of enzalutamide by 2.2-fold. There was no significant effect on enzalutamide maximum concentration (Cmax).(1) Strong inhibitors of CYP2C8 include gemfibrozil.(2,3)

Strong Cyp2c8 Inhibitors/Iptacopan

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

MECHANISM OF ACTION: Strong inhibitors of CYP2C8 may impair the CYP2C8-mediated metabolism of iptacopan.(1)

CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP2C8 may result in elevated levels of and clinical effects of iptacopan, including the risk of serious infections caused by encapsulated bacteria and hyperlipidemia.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of iptacopan states that concomitant administration of strong CYP2C8 inhibitors is not recommended.(1)

DISCUSSION: No studies have been done evaluating the effects of strong CYP2C8 inhibitors on iptacopan. A Phase 1 drug-drug interaction study with clopidogrel 300 mg x 1 then 75 mg daily (moderate CYP2C8 inhibitor) in healthy volunteers demonstrated no clinically relevant effects on the plasma pharmacokinetics of iptacopan 100 mg daily. In the presence of clopidogrel, the geometric mean maximum concentration (Cmax) of iptacopan increased by 5% and the area-under-curve (AUC) increased by 36%.(2) Strong inhibitors of CYP2C8 include gemfibrozil.(3,4)

Strong Cyp2c8 Inhibitors/Ozanimod

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

MECHANISM OF ACTION: Strong CYP2C8 inhibitors may inhibit the metabolism of ozanimod.(1)

CLINICAL EFFECTS: Concurrent use of a strong CYP2C8 inhibitor may increase levels and effects of ozanimod, including increased infection risk, bradyarrhythmias, atrioventricular conduction delays, liver injury, and hypertension.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of strong CYP2C8 inhibitors and ozanimod is not recommended.(1) If concurrent use is warranted, monitor patients closely for increased effects of ozanimod, including increased infection risk, bradyarrhythmias, atrioventricular conduction delays, liver injury, and hypertension.

DISCUSSION: Concurrent use of ozanimod with gemfibrozil increased the area-under-curve (AUC) of active metabolites CC112273 and CC1084037 by 47% and 69%, respectively. There were no clinically significant changes in the AUC of ozanimod.(1) Strong inhibitors of CYP2C8 include gemfibrozil.(2,3)

Strong Cyp2c8 Inhibitors/Resmetirom

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

MECHANISM OF ACTION: Strong inhibitors of CYP2C8 may inhibit the metabolism of resmetirom.(1)

CLINICAL EFFECTS: Concomitant use of a strong CYP2C8 inhibitor may increase resmetirom plasma concentrations, which may increase the risk of resmetirom toxicity, including hepatotoxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concomitant use of resmetirom with strong CYP2C8 inhibitors is not recommended.(1)

DISCUSSION: Multiple doses of resmetirom 100 mg daily were given with clopidogrel, a moderate CYP2C8 inhibitor, and the resmetirom area-under-curve (AUC) and maximum concentration (Cmax) increased 1.7-fold and 1.3-fold, respectively.(1) Strong CYP2C8 inhibitors linked to this monograph include gemfibrozil.(2)

Strong Cyp2c8 Inhibitors/Tovorafenib

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

MECHANISM OF ACTION: Strong inhibitors of CYP2C8 may inhibit the metabolism of tovorafenib.(1)

CLINICAL EFFECTS: Concomitant use of a strong CYP2C8 inhibitor may increase tovorafenib plasma concentrations, which may increase the risk of tovorafenib toxicity, including hepatotoxicity, bleeding, and photosensitivity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of tovorafenib recommends avoiding concomitant use of tovorafenib with strong CYP2C8 inhibitors.(1)

DISCUSSION: Strong CYP2C8 inhibitors are predicted to increase tovorafenib exposure.(1) Strong CYP2C8 inhibitors linked to this monograph include gemfibrozil.(2)

Strong Cyp2c8 Inhibitors/Tucatinib

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

MECHANISM OF ACTION: Strong inhibitors of CYP2C8 may inhibit the metabolism of tucatinib.(1)

CLINICAL EFFECTS: Concomitant use of a strong CYP2C8 inhibitor may increase tucatinib plasma concentrations, which may increase the risk of tucatinib toxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid concomitant use of tucatinib with strong CYP2C8 inhibitors. If concomitant use with a strong CYP2C8 inhibitor cannot be avoided, reduce the recommended dosage to 100 mg twice daily. After discontinuation of the strong CYP2C8 inhibitor for 3 elimination half-lives, resume the tucatinib dose that was taken prior to initiating the inhibitor.(1)

DISCUSSION: A single dose of tucatinib 300 mg was given with gemfibrozil (600 mg twice daily), a strong CYP2C8 inhibitor, and the tucatinib area-under-curve (AUC) and maximum concentration (Cmax) increased 3-fold and 1.6-fold, respectively.(1) Strong CYP2C8 inhibitors linked to this monograph include gemfibrozil.(2)

Ugt1a1 Inhibitors/Belinostat

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

MECHANISM OF ACTION: Inhibitors of UGT1A1 may inhibit the metabolism of belinostat.(1)

CLINICAL EFFECTS: Concurrent use of UGT1A1 inhibitor may result in increased exposure to and toxicity from belinostat. Toxicities from belinostat include thrombocytopenia, neutropenia, anemia, infections, hepatotoxicity, and gastrointestinal toxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the use of UGT1A1 inhibitors in patients receiving belinostat. If concurrent use cannot be avoided, a dose reduction by 25% is recommended as follows: -If starting dose is 1,000 mg/m2 - reduce dose to 750 mg/m2 -If starting dose is 750 mg/m2 - reduce dose to 562.5 mg/m2 -If starting dose is 500 mg/m2 - interrupt belinostat treatment for the duration of the UGT1A1 inhibitor. After discontinuation of the UGT1A1 inhibitor for 5 half-lives, resume belinostat at the dosage that was taken prior to the UGT1A1 inhibitor.(1) If concurrent use is required, the dose of belinostat may need to be reduced in response to dose-limiting toxicities. The manufacturer of belinostat recommends a 25% dose reduction (to 750 mg/m2) in patients who are homozygous for the UGT1A1*28 allele.(1)

DISCUSSION: Belinostat is primarily metabolized by UGT1A1 and inhibitors of UGT1A1 are expected to increase belinostat levels and dose limiting toxicities.(1) In a PKPB model, belinostat half-life increased by 1.5-fold, area-under-curve (AUC) increased by 1.4-fold, concentration maximum (Cmax) decreased by 33%, and renal excretion increased by 2.5-fold following administration with atazanavir (UGT1A1 inhibitor).(1) UGT1A1 inhibitors linked include: atazanavir, belumosudil, capivasertib, erlotinib, gemfibrozil, indinavir, ketoconazole, lapatinib, nilotinib, pazopanib, probenecid, regorafenib, and sorafenib.

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

Cyp3a4; Cyp2c8; P-Glycoprotein (P-Gp) Inhibitors/Loperamide

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

MECHANISM OF ACTION: Inhibitors of CYP3A4, CYP2C8, and/or P-gp may increase loperamide systemic absorption and facilitate entry into central nervous system (CNS).(1)

CLINICAL EFFECTS: Concurrent use of inhibitors of CYP3A4, CYP2C8, and/or P-gp may increase levels of loperamide, resulting in respiratory depression.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Use loperamide with caution in patients receiving inhibitors of CYP3A4, CYP2C8, and/or P-gp. Consider lower doses of loperamide in these patients and monitor for adverse effects. The manufacturer of lonafarnib recommends starting loperamide at a dose of 1 mg and slowly increasing the dose as needed.(2)

DISCUSSION: In a randomized, cross-over study in 12 healthy subjects, itraconazole (100 mg twice daily for 5 days - first dose 200 mg), gemfibrozil (600 mg twice daily), and the combination of itraconazole and gemfibrozil (same dosages) increased the area-under-curve (AUC) of single doses of loperamide (4 mg) by 2.9-fold, 1.6-fold, and 4.2-fold, respectively.(3) In a study of healthy subjects, lonafarnib (100 mg twice daily for 5 days) increased the AUC and maximum concentration (Cmax) of single dose loperamide (2 mg) by 299% and 214%, respectively.(3) In a study in 18 healthy males, quinidine increased the AUC of a single dose of loperamide by 2.2-fold and markedly decreased pupil size.(4) In a study in 8 healthy subjects, subjects experienced respiratory depression when a single dose of loperamide (16 mg) was administered with a single dose of quinidine (600 mg) but not when loperamide was administered alone.(6) Loperamide plasma levels increased 2-fold to 3-fold.(5) Coadministration of trofinetide 12,000 mg twice daily with 4 mg of loperamide increased the AUC of loperamide by 1.73-fold and the Cmax by 1.95-fold. Administration of trofinetide 2 hours prior to loperamide increased the AUC of loperamide by 1.22-fold and the Cmax by 1.44-fold.(7)

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)

Oatp1b1-3 Inhibitors/Atogepant

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

MECHANISM OF ACTION: Atogepant is a substrate of OATP1B1 and 1B3. Inhibitors of these transporters may increase the GI absorption and/or decrease the hepatic uptake of atogepant.(1)

CLINICAL EFFECTS: Concurrent use of OATP1B1 or 1B3 inhibitors may result in elevated levels of and side effects from atogepant, including nausea, constipation and fatigue.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of atogepant states that, when used concurrently with an OATP inhibitor for prevention of episodic migraine, the atogepant dose should be limited to 10 mg or 30 mg once daily. When used concurrently with an OATP inhibitor for prevention of chronic migraines, the atogepant dose should be limited to 30 mg once daily.(1)

DISCUSSION: In a clinical trial of healthy subjects, single-dose rifampin, an OATP inhibitor, increased the atogepant area-under-curve (AUC) and maximum concentration (Cmax) by 2.85-fold and 2.23-fold, respectively.(1) OATP1B1 and 1B3 inhibitors include: atazanavir, belumosudil, cyclosporine, darunavir, eltrombopag, erythromycin, gemfibrozil, glecaprevir-pibrentasvir, ledipasvir, leflunomide, leniolisib, letermovir, paritaprevir, resmetirom, ritonavir, roxadustat, simeprevir, sofosbuvir, teriflunomide, vadadustat, velpatasvir, and voclosporin.(1,2)

Oatp1b1-3 Inhibitors/Momelotinib

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

MECHANISM OF ACTION: OATP1B1 and 1B3 inhibitors may decrease the hepatic uptake of momelotinib.(1)

CLINICAL EFFECTS: Concurrent use of OATP1B1 and 1B3 inhibitors may result in elevated levels of and side effects from momelotinib, including myelosuppression and hepatotoxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of momelotinib with OATP1B1 and 1B3 inhibitors should be approached with caution. Monitor patients closely for adverse reactions and consider dose modifications per momelotinib prescribing recommendations.(1)

DISCUSSION: Concurrent administration of a single dose rifampin, an OATP1B1/1B3 inhibitor, increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of momelotinib by 40% and 57%, respectively. The M21 metabolite Cmax increased 6% and AUC increased 12%.(1) OATP1B1 inhibitors include: atazanavir, belumosudil, boceprevir, cobicistat, cyclosporine, darolutamide, darunavir, eltrombopag, enasidenib, encorafenib, erythromycin, fostemsavir, gemfibrozil, glecaprevir-pibrentasvir, ledipasvir, letermovir, lopinavir, nirmatrelvir, paritaprevir, resmetirom, rifampin, roxadustat, saquinavir, simeprevir, telaprevir, tipranavir, vadadustat, velpatasvir, and voclosporin.(1,2)

Selected Strong And Moderate Cyp2c8 Inhibitors/Paclitaxel

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

MECHANISM OF ACTION: Inhibitors of CYP2C8 may inhibit paclitaxel metabolism by this pathway. Clopidogrel and gemfibrozil are strong inhibitors of CYP2C8. Deferasirox is a moderate inhibitor of CYP2C8.(1-3)

CLINICAL EFFECTS: Concurrent use of CYP2C8 inhibitors and paclitaxel may result in elevated levels and clinical effects of paclitaxel.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturers of paclitaxel recommend combination use CYP2C8 inhibitors with caution. If concomitant use is necessary, paclitaxel dose reduction may be required.(1,2)

DISCUSSION: The US manufacturer of paclitaxel recommends use with CYP2C8 inhibitors with caution.(1,2)

Strong And Moderate Cyp2c8 Inhibitors/Etrasimod

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

MECHANISM OF ACTION: Strong and moderate inhibitors of CYP2C8 may impair the CYP2C8-mediated metabolism of etrasimod.(1) Etrasimod is metabolized by CYP2C8, CYP2C9, and CYP3A4.(1)

CLINICAL EFFECTS: In patients who are poor metabolizers of CYP2C9, concurrent use of a strong or moderate inhibitor of CYP2C8 may result in elevated levels of and clinical effects from etrasimod including immunosuppression, decreased lung function, bradycardia, and AV conduction delays.

PREDISPOSING FACTORS: CYP2C9 poor metabolizers (e.g., *2/*3, *3/*3) may have decreased clearance of etrasimod when etrasimod is used concomitantly with strong or moderate inhibitors of CYP2C8.(1)

PATIENT MANAGEMENT: Concomitant use of etrasimod with strong or moderate CYP2C8 inhibitors in patients who are CYP2C9 poor metabolizers is not recommended.(1)

DISCUSSION: CYP2C9 activity is decreased in individuals with genetic variants such as CYP2C9*2 and CYP2C9*3 alleles. The impact of CYP2C9 genetic variants on the pharmacokinetics of etrasimod has not been directly evaluated. Increased exposure of etrasimod in patients who are CYP2C9 poor metabolizers is expected with concomitant use of strong or moderate inhibitors of CYP2C8.(1) Concomitant use of etrasimod with steady-state fluconazole (a moderate CYP2C9 and CYP3A4 inhibitor) increased etrasimod area-under-curve (AUC) by 84%.(1) Strong inhibitors of CYP2C8 include: clopidogrel and gemfibrozil.(2,3) Moderate inhibitors of CYP2C8 include: deferasirox.(2,3)

Strong Cyp2c8 Inhibitors/Treprostinil

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

MECHANISM OF ACTION: Strong CYP2C8 inhibitors may inhibit the metabolism of treprostinil.(1)

CLINICAL EFFECTS: Concurrent use of a strong CYP2C8 inhibitor may increase levels and effects of treprostinil, including severe headache, nausea, diarrhea, and hypotension.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: When initiating oral treprostinil in patient maintained on a strong CYP2C8 inhibitor, the initial dose should be 0.125 mg twice daily, with dosage increases limited to 0.125 mg twice daily every 3 to 4 days.(1) When initiating a strong CYP2C8 inhibitor in patients maintained on oral treprostinil, consider halving the dose of oral treprostinil.(1) Since it is unknown how strong CYP2C8 inhibitors will affect treprostinil administered intravenously or via inhalation, it would be prudent to initiate and titrate treprostinil doses cautiously in patients maintained on CYP2C8 inhibitors and monitor patients maintained on treprostinil in whom CYP2C8 inhibitors are discontinued.

DISCUSSION: Concurrent use of a strong CYP2C8 inhibitor (gemfibrozil, 600 mg twice daily for 4 days) doubled the maximum concentration (Cmax) and area-under-curve (AUC) of treprostinil (1 mg).(1) The extent to which intravenous(2) and inhaled treprostinil(3) would be affected by a CYP2C8 inhibitor is unknown. Strong inhibitors of CYP2C8 includes gemfibrozil.(4,5)

Ugt Inhibitors/Lorazepam; Mexazolam

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

MECHANISM OF ACTION: Inhibitors of UDP-glucuronosyltransferases (UGT) may inhibit the metabolism of lorazepam.(1-4) One of the active metabolites of mexazolam is lorazepam.

CLINICAL EFFECTS: Concurrent use of UGT inhibitors may increase levels of and clinical effects from lorazepam, including profound sedation, respiratory depression, and coma.(1-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturers of lorazepam state that the dosage of lorazepam should be reduced by 50% in patients receiving UGT inhibitors.(1,2)

DISCUSSION: In a study in 9 healthy subjects, pretreatment with probenecid (500 mg every 6 hours) increased the half-life (T1/2) of a single intravenous dose of lorazepam (2 mg) by 130%. Lorazepam clearance was decreased by 45%. There was no change in lorazepam apparent volume of distribution.(1,4) In 7 patients given probenecid 1G orally one hour prior to induction anesthesia with midazolam, there was no significant change in plasma protein binding due to probenecid pretreatment. The mean free midazolam fractions were 3.31% prior and 3.34% following pretreatment.(5) UGT inhibitors linked to this monograph include: atazanavir, belumosudil, capivasertib, erlotinib, gemfibrozil, indinavir, ketoconazole, lapatinib, mefenamic acid, nilotinib, pazopanib, probenecid, regorafenib, and sorafenib.

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• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Disease of liver
• Gallbladder disease
• Lactation

• Anemia

• Leukopenia
• Thrombocytopenic disorder

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Less Frequent

• Appendicitis

Rare or Very Rare

• Anemia
• Angioedema
• Atrial fibrillation
• Biliary calculus
• Bone marrow hypoplasia
• Exfoliative dermatitis
• Gallbladder disease
• Hyperbilirubinemia
• Increased alanine transaminase
• Increased alkaline phosphatase
• Increased aspartate transaminase
• Laryngeal edema
• Leukopenia
• Myopathy
• Myositis
• Obstructive hyperbilirubinemia
• Rhabdomyolysis
• Thrombocytopenic disorder

More Frequent

• Acute abdominal pain
• Dyspepsia

Less Frequent

• Constipation
• Diarrhea
• Dysgeusia
• Eczema
• Fatigue
• Headache disorder
• Nausea
• Pain in extremities
• Skin rash
• Vertigo
• Vomiting

Rare or Very Rare

• Arthralgia
• Blurred vision
• Depression
• Dizziness
• Drowsy
• Eosinophilia
• Erectile dysfunction
• Hypoesthesia
• Libido changes
• Muscle weakness
• Myalgia
• Paresthesia
• Peripheral neuritis
• Pruritus of skin
• Skin inflammation
• Synovitis
• Urticaria

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Gemfibrozil has been shown to produce adverse fetal and fertility effects in rats and rabbits at dosages 0.5-3 times the usual human dosage (based on surface area). There are no adequate and controlled studies using gemfibrozil in pregnant women; because the drug has been shown to be tumorigenic in some animals, gemfibrozil should be used during pregnancy only when the potential benefits clearly justify the possible risks to the woman and/or fetus. Currently, most experts recommend that hyperlipoproteinemias in pregnant women generally be managed with dietary measures; consultation with a lipid specialist may be indicated for pregnant women with severe forms of hyperlipidemia.

It is not known if gemfibrozil is distributed into milk. Because of the potential for serious adverse reactions to gemfibrozil in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

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