Lopid

Fibric Acid Derivatives/Fibrates

Oral Administration

Administer 30 minutes before the morning and evening meals.

Severe

atrial fibrillation / Early / 0.7-0.7
cholecystitis / Delayed / Incidence not known
pancreatitis / Delayed / Incidence not known
hepatoma / Delayed / Incidence not known
rhabdomyolysis / Delayed / Incidence not known
lupus-like symptoms / Delayed / Incidence not known
vasculitis / Delayed / Incidence not known
intracranial bleeding / Delayed / Incidence not known
exfoliative dermatitis / Delayed / Incidence not known
laryngeal edema / Rapid / Incidence not known
anaphylactic shock / Rapid / Incidence not known
angioedema / Rapid / Incidence not known
retinal edema / Delayed / Incidence not known

Moderate

cholelithiasis / Delayed / 7.5-7.5
constipation / Delayed / 1.4-1.4
cholestasis / Delayed / Incidence not known
jaundice / Delayed / Incidence not known
elevated hepatic enzymes / Delayed / Incidence not known
hyperbilirubinemia / Delayed / Incidence not known
colitis / Delayed / Incidence not known
impotence (erectile dysfunction) / Delayed / Incidence not known
depression / Delayed / Incidence not known
neuritis / Delayed / Incidence not known
confusion / Early / Incidence not known
synovitis / Delayed / Incidence not known
myopathy / Delayed / Incidence not known
myasthenia / Delayed / Incidence not known
leukopenia / Delayed / Incidence not known
eosinophilia / Delayed / Incidence not known
thrombocytopenia / Delayed / Incidence not known
anemia / Delayed / Incidence not known
cataracts / Delayed / Incidence not known
blurred vision / Early / Incidence not known

Mild

dyspepsia / Early / 19.6-19.6
abdominal pain / Early / 9.8-9.8
diarrhea / Early / 7.2-7.2
fatigue / Early / 3.8-3.8
nausea / Early / 2.5-2.5
rash / Early / 1.7-1.7
dizziness / Early / 1.5-1.5
headache / Early / 1.2-1.2
vomiting / Early / Incidence not known
weight loss / Delayed / Incidence not known
syncope / Early / Incidence not known
libido decrease / Delayed / Incidence not known
paresthesias / Delayed / Incidence not known
myalgia / Early / Incidence not known
arthralgia / Delayed / Incidence not known
infection / Delayed / Incidence not known
alopecia / Delayed / Incidence not known
photosensitivity / Delayed / Incidence not known
urticaria / Rapid / Incidence not known
pruritus / Rapid / Incidence not known

Lopid

Rx

Oral fibrate antilipemic; used for hypertriglyceridemia; effectively lowers serum triglycerides; the HMG-CoA reductase inhibitors are more effective for hypercholesterolemia; second-line therapy for type IIb hypercholesterolemia, used only in patients with HDL < 35 mg/dl and without evidence of CAD.

For the treatment of hypercholesterolemia or hyperlipoproteinemia and hypertriglyceridemia as an adjunct to diet. For the treatment of Type IV and V hypertriglyceridemia in patients who present a risk of pancreatitis and who do not respond adequately to dietary therapy.
NOTE: Gemfibrozil is not indicated for patients with Type I hyperlipoproteinemia, who have elevated chylomicrons and triglycerides, but who have normal VLDL concentrations.
Oral dosage Adults

600 mg PO twice daily. Monitor lipid concentrations periodically. Discontinue gemfibrozil if lipid response is inadequate after 3 months of therapy.

For the treatment of Type IIb hypercholesterolemia without history of or symptoms of existing coronary heart disease who have had an inadequate response to weight loss, dietary therapy, exercise, and other pharmacological agents and who have elevated LDL-C and triglycerides and low HDL-C to reduce the risk of developing coronary heart disease.
NOTE: Gemfibrozil is not indicated for the treatment of patients with low HDL-C as their only lipid abnormality.
Oral dosage Adults

600 mg PO twice daily. Monitor lipid concentrations periodically. Discontinue gemfibrozil if lipid response is inadequate after 3 months of therapy.

Hepatic Impairment

Gemfibrozil is contraindicated in patients with hepatic dysfunction, including primary biliary cirrhosis.

Renal Impairment

CrCl >= 50 mL/min: No dose adjustment is necessary.
CrCl 10—50 mL/min: Consider alternative therapy per the manufacturer, reports of worsening renal insufficiency have occurred during use of gemfibrozil in those with a baseline SCr > 2 mg/dL (i.e., estimated CrCl of < 50 mL/min based on a 70 kg adult male). Use with caution if gemfibrozil therapy is necessary.
CrCl < 10 mL/min: Per manufacturer recommendations contraindicated in severe renal dysfunction.
 
Intermittent hemodialysis
Not applicable; gemfibrozil is not recommended in patients with severe renal dysfunction (manufacturer information).

Acarbose: (Moderate) Dose reductions and increased frequency of glucose monitoring may be required when antidiabetic agents are administered with fibric acid derivatives (e.g., clofibrate, fenofibric acid, fenofibrate, gemfibrozil). Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion.
Alogliptin; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and fibric acid derivative use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Alogliptin; Pioglitazone: (Major) Do not exceed 15 mg/day of pioglitazone when coadministered with gemfibrozil. Coadministration may increase the exposure of pioglitazone, increasing the risk for hypoglycemia. Pioglitazone is a CYP2C8 substrate and gemfibrozil is a strong CYP2C8 inhibitor. The exposure to pioglitazone is increased approximately 3-fold when combined with gemfibrozil. Fibric acid derivatives may also enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion.
Alpha-glucosidase Inhibitors: (Moderate) Dose reductions and increased frequency of glucose monitoring may be required when antidiabetic agents are administered with fibric acid derivatives (e.g., clofibrate, fenofibric acid, fenofibrate, gemfibrozil). Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion.
Amlodipine; Atorvastatin: (Major) Use caution and the lowest atorvastatin dose necessary if coadministration with gemfibrozil is necessary due to an increased risk of myopathy and rhabdomyolysis. Clinical practice guidelines state the concurrent use of gemfibrozil and atorvastatin is acceptable if clinically indicated and fenofibrate or fenofibric acid is not an option. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy.
Amlodipine; Olmesartan: (Moderate) Coadministration may result in an increase in olmesartan exposure. A dose reduction of olmesartan may be required if used concomitantly with gemfibrozil. Use olmesartan and gemfibrozil together with caution. Olmesartan is a substrate of the OATP1B1 transporter. Gemfibrozil inhibits OATP1B1.
Amlodipine; Valsartan: (Minor) Coadministration of valsartan and gemfibrozil may increase systemic exposure to valsartan. Valsartan is a substrate of the hepatic uptake transporter OATP1B1 and gemfibrozil is an inhibitor of OATP. Patients should be monitored for adverse effects of valsartan.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Minor) Coadministration of valsartan and gemfibrozil may increase systemic exposure to valsartan. Valsartan is a substrate of the hepatic uptake transporter OATP1B1 and gemfibrozil is an inhibitor of OATP. Patients should be monitored for adverse effects of valsartan.
Apalutamide: (Moderate) Monitor for an increase in apalutamide-related adverse reactions if coadministration with gemfibrozil is necessary. Consider reducing the dose of apalutamide if necessary based on tolerability in patients experiencing grade 3 or higher adverse reactions or intolerable toxicities. Apalutamide is a CYP2C8 substrate and gemfibrozil is a strong CYP2C8 inhibitor. Coadministration with gemfibrozil decreased the Cmax of single-dose apalutamide by 21% but increased the AUC by 68%; strong CYP2C8 inhibition is expected to increase the steady-state apalutamide Cmax by 32% and AUC by 44%. The predicted steady-state exposure of the active moieties (unbound apalutamide plus potency-adjusted unbound N-desmethyl apalutamide) is predicted to increase by 23%.
Apixaban: (Moderate) Use apixaban and gemfibrozil together with caution. CYP2C8 plays a minor role in the metabolism of apixaban, and gemfibrozil is a strong CYP2C8 inhibitor. Coadministration may result in an increase in apixaban exposure. A dose reduction of apixaban may be required if used concomitantly with gemfibrozil.
Atogepant: (Major) Limit the dose of atogepant to 10 or 30 mg PO once daily for episodic migraine or 30 mg PO once daily for chronic migraine if coadministered with gemfibrozil. Concurrent use may increase atogepant exposure and the risk of adverse effects. Atogepant is a substrate of OATP1B1 and OATP1B3 and gemfibrozil is an OATP inhibitor. Coadministration with an OATP1B1/3 inhibitor resulted in a 2.85-fold increase in atogepant overall exposure and a 2.23-fold increase in atogepant peak concentration.
Atorvastatin: (Major) Use caution and the lowest atorvastatin dose necessary if coadministration with gemfibrozil is necessary due to an increased risk of myopathy and rhabdomyolysis. Clinical practice guidelines state the concurrent use of gemfibrozil and atorvastatin is acceptable if clinically indicated and fenofibrate or fenofibric acid is not an option. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy.
Atorvastatin; Ezetimibe: (Major) The safety and effectiveness of ezetimibe when coadministered with gemfibrozil have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. Coadministration of ezetimibe with gemfibrozil is not recommended. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. The incidence rates for cholecystectomy have been reported as 0.6% for fenofibrate monotherapy and 1.7% for combination therapy (ezetimibe plus fenofibrate), respectively. According to the manufacturer, the number of patients exposed to combination therapy versus fenofibrate or ezetimibe monotherapy has been inadequate to assess gallbladder disease risk. If cholelithiasis is suspected in a patient receiving ezetimibe and fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered. In a pharmacokinetic study, concomitant fenofibrate or gemfibrozil administration increased total ezetimibe concentrations by approximately 1.5- or 1.7-fold, respectively. However, ezetimibe does not affect the pharmacokinetics of fenofibrate or the bioavailability of gemfibrozil. (Major) Use caution and the lowest atorvastatin dose necessary if coadministration with gemfibrozil is necessary due to an increased risk of myopathy and rhabdomyolysis. Clinical practice guidelines state the concurrent use of gemfibrozil and atorvastatin is acceptable if clinically indicated and fenofibrate or fenofibric acid is not an option. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy.
Belinostat: (Moderate) Gemfibrozil may inhibit UGT1A1 in vitro; belinostat is primarily metabolized by UGT1A1. Use caution if coadministration of belinostat with gemfibrozil is necessary, as increased belinostat concentrations and toxicities may occur.
Bempedoic Acid; Ezetimibe: (Major) The safety and effectiveness of ezetimibe when coadministered with gemfibrozil have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. Coadministration of ezetimibe with gemfibrozil is not recommended. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. The incidence rates for cholecystectomy have been reported as 0.6% for fenofibrate monotherapy and 1.7% for combination therapy (ezetimibe plus fenofibrate), respectively. According to the manufacturer, the number of patients exposed to combination therapy versus fenofibrate or ezetimibe monotherapy has been inadequate to assess gallbladder disease risk. If cholelithiasis is suspected in a patient receiving ezetimibe and fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered. In a pharmacokinetic study, concomitant fenofibrate or gemfibrozil administration increased total ezetimibe concentrations by approximately 1.5- or 1.7-fold, respectively. However, ezetimibe does not affect the pharmacokinetics of fenofibrate or the bioavailability of gemfibrozil.
Bexarotene: (Major) Concomitant administration of bexarotene capsules and gemfibrozil is not recommended; concurrent administration results in increased bexarotene plasma concentrations. Due to low systemic exposure, clinically significant drug interactions are unlikely with bexarotene topical gel.
Bosentan: (Moderate) Use bosentan and gemfibrozil together with caution. Bosentan is a substrate of the OATP1B1 transporter. Gemfibrozil inhibits OATP1B1. Coadministration may result in an increase in bosentan exposure. A dose reduction of bosentan may be required if used concomitantly with gemfibrozil.
Brincidofovir: (Moderate) Postpone the administration of gemfibrozil for at least three hours after brincidofovir administration and increase monitoring for brincidofovir-related adverse reactions (i.e., elevated hepatic enzymes and bilirubin, diarrhea, other gastrointestinal adverse events) if concomitant use of brincidofovir and gemfibrozil is necessary. Brincidofovir is an OATP1B1 substrate and gemfibrozil is an OATP1B1 inhibitor. In a drug interaction study, the mean AUC and Cmax of brincidofovir increased by 374% and 269%, respectively, when administered with another OATP1B1 inhibitor.
Bupivacaine; Meloxicam: (Moderate) Consider a meloxicam dose reduction and monitor for adverse reactions if coadministration with gemfibrozil is necessary. Concurrent use may increase meloxicam exposure. Meloxicam is a CYP2C9 substrate and gemfibrozil is a weak CYP2C9 inhibitor.
Canagliflozin: (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and fibric acid derivative use; a SGLT2 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Canagliflozin; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and fibric acid derivative use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and fibric acid derivative use; a SGLT2 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Cannabidiol: (Moderate) Consider a dose reduction of gemfibrozil as clinically appropriate, if adverse reactions occur when administered with cannabidiol. Increased gemfibrozil exposure is possible. Gemfibrozil is a UGT2B7 substrate. In vitro data predicts inhibition of UGT2B7 by cannabidiol potentially resulting in clinically significant interactions.
Carbamazepine: (Moderate) Use carbamazepine and gemfibrozil together with caution. Carbamazepine is a substrate of CYP2C8, and gemfibrozil is a strong CYP2C8 inhibitor. Coadministration may result in a significant increase in carbamazepine exposure. A dose reduction of carbamazepine may be required if used concomitantly with gemfibrozil.
Chenodiol: (Major) Fibric acid derivatives (i.e., clofibrate and perhaps other lipid-lowering fibrate drugs) increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may counteract the effectiveness of chenodiol.
Cholestyramine: (Moderate) According to the manufacturer of gemfibrozil, the administration times of gemfibrozil and bile acid sequestrants should be separated by at least 2 hours. Coadministration with a bile acid resin resulted in a 30% reduction in gemfibrozil AUC; exposure to gemfibrozil was not significantly affected when the drugs were administed two hours apart.
Clofarabine: (Moderate) Concomitant use of clofarabine, a substrate of OAT1 and OAT3, and gemfibrozil, an inhibitor of OAT protein (OATP), may result in increased clofarabine levels. Therefore, monitor for signs of clofarabine toxicity such as gastrointestinal toxicity (e.g., nausea, vomiting, diarrhea, mucosal inflammation), hematologic toxicity, and skin toxicity (e.g., hand and foot syndrome, rash, pruritus) in patients also receiving OATP inhibitors.
Colchicine: (Moderate) Monitor for myopathy during concomitant colchicine and fibric acid derivative use. Cases of myopathy, including rhabdomyolysis, have been reported with fibric acid derivatives coadministered with colchicine.
Colesevelam: (Moderate) Separate the administration of gemfibrozil and colesevelam by at least 2 hours. Coadministration of bile acid resins such as colestipol resulted in a 30% reduction in gemfibrozil AUC; exposure to gemfibrozil was not significantly affected when the drugs were administed 2 hours apart.
Colestipol: (Moderate) Separate the administration of gemfibrozil and colestipol by at least 2 hours. Coadministration of bile acid resins such as colestipol results in a 30% reduction in gemfibrozil AUC; exposure to gemfibrozil was not significantly affected when the drugs were administed two hours apart.
Cyclosporine: (Moderate) The use of fibric acid derivatives, such as gemfibrozil, may potentiate the risk for renal dysfunction with cyclosporine. During the concomitant use of a drug that may exhibit additive or synergistic renal impairment with cyclosporine, close monitoring of renal function (in particular serum creatinine) and cyclosporine levels should be performed. If a significant impairment of renal function occurs, the dosage of the coadministered drug should be reduced or an alternative treatment considered.
Dabrafenib: (Major) Avoid the concomitant use of dabrafenib and gemfibrozil; dabrafenib exposure increased by 47% when these drugs were administered together in a drug interaction study. Use of an alternate agent in place of gemfibrozil is recommended. If concomitant use cannot be avoided, monitor patients for dabrafenib toxicity (e.g., skin toxicity, ocular toxicity, and cardiotoxicity). Dabrafenib is a CYP2C8 substrate; gemfibrozil is a strong CYP2C8 inhibitor. The dabrafenib AUC value increased by 47% when dabrafenib 75 mg PO twice daily was administered with gemfibrozil 600 mg twice daily for 4 days in a drug interaction study; there were no change in the AUC values of the metabolites, hydroxy-dabrafenib and desmethyl-dabrafenib.
Dapagliflozin: (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and fibric acid derivative use; a SGLT2 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Dapagliflozin; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and fibric acid derivative use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and fibric acid derivative use; a SGLT2 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Dapagliflozin; Saxagliptin: (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and fibric acid derivative use; a SGLT2 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Daprodustat: (Contraindicated) Concurrent use of daprodustat and gemfibrozil is contraindicated due the risk of increased daprodustat exposure which may increase the risk of daprodustat-related adverse reactions. Daprodustat is a CYP2C8 substrate and gemfibrozil is a strong CYP2C8 inhibitor. Concomitant use increased daprodustat exposure by 18.6-fold.
Diclofenac: (Moderate) If possible, avoid concurrent use of diclofenac with inhibitors of CYP2C9, such as gemfibrozil; if coadministration is required, do not exceed a total daily diclofenac dose of 100 mg. When used with a CYP2C9 inhibitor the systemic exposure to diclofenac (a CYP2C9 substrate) may increase, potentially resulting in adverse events.
Diclofenac; Misoprostol: (Moderate) If possible, avoid concurrent use of diclofenac with inhibitors of CYP2C9, such as gemfibrozil; if coadministration is required, do not exceed a total daily diclofenac dose of 100 mg. When used with a CYP2C9 inhibitor the systemic exposure to diclofenac (a CYP2C9 substrate) may increase, potentially resulting in adverse events.
Dipeptidyl Peptidase-4 Inhibitors: (Moderate) Monitor blood glucose during concomitant dipeptidyl peptidase-4 inhibitor (DPP-4) and fibric acid derivative use; a DPP-4 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Diphenhydramine; Naproxen: (Moderate) Use naproxen and gemfibrozil together with caution. Naproxen is a substrate of CYP2C8, and gemfibrozil is a strong CYP2C8 inhibitor. Coadministration may result in a significant increase in naproxen exposure. A dose reduction of naproxen may be required if used concomitantly with gemfibrozil.
Doxercalciferol: (Moderate) CYP450 enzyme inhibitors, like gemfibrozil, may inhibit the 25-hydroxylation of doxercalciferol, thereby decreasing the formation of the active metabolite and thus, decreasing efficacy. Patients should be monitored for a decrease in efficacy if CYP450 inhibitors are coadministered with doxercalciferol.
Dronabinol: (Moderate) Use caution if coadministration of dronabinol with gemfibrozil is necessary, and monitor for an increase in dronabinol-related adverse reactions (e.g., feeling high, dizziness, confusion, somnolence). Dronabinol is a CYP2C9 and 3A4 substrate; gemfibrozil is a weak inhibitor of CYP2C9. Concomitant use may result in elevated plasma concentrations of dronabinol.
Dulaglutide: (Moderate) Monitor blood glucose during concomitant incretin mimetic and fibric acid derivative use; an incretin mimetic dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Elagolix: (Contraindicated) Concomitant use of elagolix and strong organic anion transporting polypeptide (OATP) 1B1 inhibitors such as gemfibrozil is contraindicated. Use of elagolix with drugs that inhibit OATP1B1 may increase elagolix plasma concentrations. Elagolix is a substrate of CYP3A, P-gp, and OATP1B1. Another OATP1B1 potent inhibitor increased elagolix AUC in the range of 2- to 5.58-fold. Increased elagolix concentrations increase the risk for dose-related side effects, including loss of bone mineral density.
Elagolix; Estradiol; Norethindrone acetate: (Contraindicated) Concomitant use of elagolix and strong organic anion transporting polypeptide (OATP) 1B1 inhibitors such as gemfibrozil is contraindicated. Use of elagolix with drugs that inhibit OATP1B1 may increase elagolix plasma concentrations. Elagolix is a substrate of CYP3A, P-gp, and OATP1B1. Another OATP1B1 potent inhibitor increased elagolix AUC in the range of 2- to 5.58-fold. Increased elagolix concentrations increase the risk for dose-related side effects, including loss of bone mineral density.
Elbasvir; Grazoprevir: (Contraindicated) Concurrent administration of grazoprevir with gemfibrozil is contraindicated. Use of these drugs together is expected to significantly increase the plasma concentrations of grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations). Gemfibrozil is an inhibitor of the organic anion transporting polypeptide (OATP); grazoprevir is a substrate of OATP1B1/3.
Eltrombopag: (Moderate) Eltrombopag is metabolized by CYP2C8. The significance of administering inhibitors of CYP2C8, such as gemfibrozil, on the systemic exposure of eltrombopag has not been established. Monitor patients for signs of eltrombopag toxicity if these drugs are coadministered.
Eluxadoline: (Major) When administered concurrently with gemfibrozil, the dose of eluxadoline must be reduced to 75 mg PO twice daily, and the patient should be closely monitored for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity). Eluxadoline is a substrate of the organic anion-transporting peptide (OATP1B1); gemfibrozil is an OATP1B1/2B1 inhibitor. Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known.
Empagliflozin: (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and fibric acid derivative use; a SGLT2 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Empagliflozin; Linagliptin: (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and fibric acid derivative use; a SGLT2 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Empagliflozin; Linagliptin; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and fibric acid derivative use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and fibric acid derivative use; a SGLT2 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Empagliflozin; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and fibric acid derivative use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and fibric acid derivative use; a SGLT2 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Enzalutamide: (Major) Avoid coadministration of gemfibrozil with enzalutamide if possible due to increased enzalutamide exposure. If concomitant use is unavoidable, reduce the dose of enzalutamide to 80 mg once daily; the original dose of enzalutamide may be resumed when gemfibrozil is discontinued. Enzalutamide is a CYP2C8 substrate and gemfibrozil is a strong CYP2C8 inhibitor. Coadministration with gemfibrozil increased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 2.2-fold.
Ertugliflozin: (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and fibric acid derivative use; a SGLT2 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Ertugliflozin; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and fibric acid derivative use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and fibric acid derivative use; a SGLT2 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Ertugliflozin; Sitagliptin: (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and fibric acid derivative use; a SGLT2 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Exenatide: (Moderate) Monitor blood glucose during concomitant incretin mimetic and fibric acid derivative use; an incretin mimetic dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Ezetimibe: (Major) The safety and effectiveness of ezetimibe when coadministered with gemfibrozil have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. Coadministration of ezetimibe with gemfibrozil is not recommended. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. The incidence rates for cholecystectomy have been reported as 0.6% for fenofibrate monotherapy and 1.7% for combination therapy (ezetimibe plus fenofibrate), respectively. According to the manufacturer, the number of patients exposed to combination therapy versus fenofibrate or ezetimibe monotherapy has been inadequate to assess gallbladder disease risk. If cholelithiasis is suspected in a patient receiving ezetimibe and fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered. In a pharmacokinetic study, concomitant fenofibrate or gemfibrozil administration increased total ezetimibe concentrations by approximately 1.5- or 1.7-fold, respectively. However, ezetimibe does not affect the pharmacokinetics of fenofibrate or the bioavailability of gemfibrozil.
Ezetimibe; Simvastatin: (Contraindicated) The use of simvastatin with gemfibrozil is contraindicated due to an increased risk for myopathy and rhabdomyolysis. Gemfibrozil can cause myopathy when used alone, and the risk of myopathy and rhabdomyolysis is increased by concomitant use with simvastatin. In addition, the AUC and Cmax of simvastatin are increased with concomitant gemfibrozil use. This may be due to inhibition of OATP1B1 by gemfibrozil; simvastatin is a substrate of OATP1B1. (Major) The safety and effectiveness of ezetimibe when coadministered with gemfibrozil have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. Coadministration of ezetimibe with gemfibrozil is not recommended. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. The incidence rates for cholecystectomy have been reported as 0.6% for fenofibrate monotherapy and 1.7% for combination therapy (ezetimibe plus fenofibrate), respectively. According to the manufacturer, the number of patients exposed to combination therapy versus fenofibrate or ezetimibe monotherapy has been inadequate to assess gallbladder disease risk. If cholelithiasis is suspected in a patient receiving ezetimibe and fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered. In a pharmacokinetic study, concomitant fenofibrate or gemfibrozil administration increased total ezetimibe concentrations by approximately 1.5- or 1.7-fold, respectively. However, ezetimibe does not affect the pharmacokinetics of fenofibrate or the bioavailability of gemfibrozil.
Fluvastatin: (Major) Avoid the concomitant administration of fluvastatin and gemfibrozil. The risk of myopathy/rhabdomyolysis increases when HMG-CoA reductase inhibitors are administered concurrently with gemfibrozil. The serious risk of myopathy or rhabdomyolysis should be weighed carefully against the benefits of combined 'statin' and fibrate therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and gemfibrozil as coadministration may increase serum concentrations of glecaprevir and increase the risk of adverse effects. Glecaprevir is a substrate of organic anion transporting polypeptide (OATP)1B1; gemfibrozil is an inhibitor of OATP1B1.
Glipizide; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and fibric acid derivative use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Glyburide; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and fibric acid derivative use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Incretin Mimetics: (Moderate) Monitor blood glucose during concomitant incretin mimetic and fibric acid derivative use; an incretin mimetic dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Insulin Degludec; Liraglutide: (Moderate) Monitor blood glucose during concomitant incretin mimetic and fibric acid derivative use; an incretin mimetic dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Insulin Glargine; Lixisenatide: (Moderate) Monitor blood glucose during concomitant incretin mimetic and fibric acid derivative use; an incretin mimetic dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Insulins: (Moderate) Monitor blood glucose during concomitant fibric acid derivatives and insulin use; an insulin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Irinotecan Liposomal: (Major) Avoid administration of gemfibrozil during treatment with irinotecan unless there are no therapeutic alternatives. The active metabolite of irinotecan, SN-38, is a UGT1A1 substrate; gemfibrozil is a UGT1A1 inhibitor. Concomitant use of UGT1A1 inhibitors may increase systemic exposure to SN-38.
Irinotecan: (Major) Avoid administration of gemfibrozil during treatment with irinotecan unless there are no therapeutic alternatives. The active metabolite of irinotecan, SN-38, is a UGT1A1 substrate; gemfibrozil is a UGT1A1 inhibitor. Concomitant use of UGT1A1 inhibitors may increase systemic exposure to SN-38.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Coadministration may result in an increase in rifampin exposure. A dose reduction of rifampin may be required if used concomitantly with gemfibrozil. Use rifampin and gemfibrozil together with caution. Rifampin is a substrate of the OATP1B1 transporter. Gemfibrozil inhibits OATP1B1.
Isoniazid, INH; Rifampin: (Moderate) Coadministration may result in an increase in rifampin exposure. A dose reduction of rifampin may be required if used concomitantly with gemfibrozil. Use rifampin and gemfibrozil together with caution. Rifampin is a substrate of the OATP1B1 transporter. Gemfibrozil inhibits OATP1B1.
Lesinurad: (Moderate) Use lesinurad and gemfibrozil together with caution; gemfibrozil may increase the systemic exposure of lesinurad. Gemfibrozil is a mild inhibitor of CYP2C9, and lesinurad is a CYP2C9 substrate.
Lesinurad; Allopurinol: (Moderate) Use lesinurad and gemfibrozil together with caution; gemfibrozil may increase the systemic exposure of lesinurad. Gemfibrozil is a mild inhibitor of CYP2C9, and lesinurad is a CYP2C9 substrate.
Letermovir: (Moderate) Closely monitor for letermovir-related adverse events (i.e., tachycardia, atrial fibrillation, and gastrointestinal events) if administered with gemfibrozil, as use of these drugs together may result in increased letermovir plasma concentration. Letermovir is a substrate of the organic anion-transporting polypeptide (OATP1B1); gemfibrozil is an inhibitor of OATP1B1.
Linagliptin; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and fibric acid derivative use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Liraglutide: (Moderate) Monitor blood glucose during concomitant incretin mimetic and fibric acid derivative use; an incretin mimetic dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Lixisenatide: (Moderate) Monitor blood glucose during concomitant incretin mimetic and fibric acid derivative use; an incretin mimetic dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Lonafarnib: (Major) Avoid coadministration of lonafarnib and gemfibrozil; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. If coadministration is unavoidable, closely monitor patients for lonafarnib-related adverse reactions. Lonafarnib is a CYP2C9 substrate and gemfibrozil is a CYP2C9 inhibitor.
Loperamide: (Moderate) Monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest), if coadministered with gemfibrozil. Concurrent use may increase loperamide exposure. Loperamide is a CYP2C8 substrate and gemfibrozil is a strong CYP2C8 inhibitor. Coadministration with another strong CYP2C8 inhibitor increased loperamide exposure by 2.2-fold.
Loperamide; Simethicone: (Moderate) Monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest), if coadministered with gemfibrozil. Concurrent use may increase loperamide exposure. Loperamide is a CYP2C8 substrate and gemfibrozil is a strong CYP2C8 inhibitor. Coadministration with another strong CYP2C8 inhibitor increased loperamide exposure by 2.2-fold.
Lorazepam: (Moderate) Monitor for an increase in lorazepam-related adverse reactions and consider reducing the dose of lorazepam if concomitant use of lorazepam and gemfibrozil is necessary. Avoid lorazepam extended-release capsules and utilize lorazepam immediate-release dosage forms that can be easily titrated. Lorazepam is an UGT substrate and gemfibrozil is an UGT inhibitor.
Lovastatin: (Major) Avoid the concurrent use of gemfibrozil and lovastatin. The risk of myopathy and rhabdomyolysis is increased with combined gemfibrozil and HMG-CoA reductase inhibitor ("statin") therapy. Myopathy or rhabdomyolysis with or without acute renal failure have been reported as early as 3 weeks after initiation of combined therapy or after several months. There is no assurance that periodic monitoring of creatine kinase will prevent the occurrence of severe myopathy and kidney damage. In uncontrolled clinical studies of lovastatin, myopathy was reported more frequently in patients receiving concomitant therapy with gemfibrozil. Gemfibrozil may increase the risk of myopathy, rhabdomyolysis and acute renal failure in patients taking lovastatin. Data suggest that the addition of gemfibrozil to lovastatin therapy does not result in greater reductions in LDL-C than that achieved with lovastatin alone.
Lumateperone: (Major) Avoid coadministration of lumateperone and gemfibrozil as concurrent use may increase lumateperone exposure and the risk of adverse effects. Lumateperone is a UGT1A1 substrate; gemfibrozil is a UGT1A1 inhibitor.
Maraviroc: (Moderate) Use caution and closely monitor for increased adverse effects during concurrent administration of maraviroc and gemfibrozil as increased maraviroc concentrations may occur. Maraviroc is a substrate of organic anion-transporting polypeptide (OATP1B1); gemfibrozil is an inhibitor of OATP1B1. The effects of this transporter on the concentrations of maraviroc are unknown, although an increase in concentrations and thus, toxicity, are possible.
Meloxicam: (Moderate) Consider a meloxicam dose reduction and monitor for adverse reactions if coadministration with gemfibrozil is necessary. Concurrent use may increase meloxicam exposure. Meloxicam is a CYP2C9 substrate and gemfibrozil is a weak CYP2C9 inhibitor.
Metformin: (Moderate) Monitor blood glucose during concomitant metformin and fibric acid derivative use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Metformin; Repaglinide: (Contraindicated) Concurrent use of repaglinide and gemfibrozil is contraindicated, due to significantly increased repaglinide exposure and hypoglycemic risk. Gemfibrozil is a potent inhibitor of CYP2C8, the primary pathway by which repaglinide is metabolized. Concurrent administration resulted in an 8.1-fold increase in repaglinide AUC as well as a 28.6-fold higher repaglinide plasma concentration 7 hours post-dose. The repaglinide half-life increased from 1.3 to 3.7 hours. Fibric acid derivatives are also known to enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion. (Moderate) Monitor blood glucose during concomitant metformin and fibric acid derivative use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Metformin; Rosiglitazone: (Major) Dose reduction of rosiglitazone may be needed if given with gemfibrozil. Gemfibrozil results in increased rosiglitazone exposure and increases the risk for hypoglycemia. Gemfibrozil is a potent inhibitor of CYP2C8 and rosiglitazone is primarily metabolized via CYP2C8. Concomitant administration of gemfibrozil (600 mg twice daily) and rosiglitazone (4 mg once daily) for 7 days increased rosiglitazone AUC by 127%, compared to the administration of rosiglitazone (4 mg once daily) alone. Fibric acid derivatives also enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion. (Moderate) Monitor blood glucose during concomitant metformin and fibric acid derivative use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Metformin; Saxagliptin: (Moderate) Monitor blood glucose during concomitant metformin and fibric acid derivative use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Metformin; Sitagliptin: (Moderate) Monitor blood glucose during concomitant metformin and fibric acid derivative use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Miglitol: (Moderate) Dose reductions and increased frequency of glucose monitoring may be required when antidiabetic agents are administered with fibric acid derivatives (e.g., clofibrate, fenofibric acid, fenofibrate, gemfibrozil). Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion.
Montelukast: (Minor) Concentrations of montelukast may be increased with concomitant use of gemfibrozil; however, based on available clinical experience, no dosage adjustment of montelukast is required upon co-administration with gemfibrozil. At clinically relevant concentrations, CYP2C8 is the primary isozyme involved in the metabolism of montelukast; the drug is also metabolized by CYP2C9 and CYP3A4. Data from a clinical drug interaction study involving montelukast and gemfibrozil (a CYP2C8 and 2C9 inhibitor) demonstrated that gemfibrozil, at a therapeutic dose, increased the systemic exposure of montelukast by 4.4-fold. The addition of a potent CYP3A4 inhibitor did not further increase the inhibition of montelukast metabolism.
Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration of nab-paclitaxel with gemfibrozil is necessary due to the risk of increased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP2C8 substrate and gemfibrozil is a strong CYP2C8 inhibitor. In vitro, the metabolism of paclitaxel to 6-alpha-hydroxypaclitaxel was inhibited by another inhibitor of CYP2C8.
Naproxen: (Moderate) Use naproxen and gemfibrozil together with caution. Naproxen is a substrate of CYP2C8, and gemfibrozil is a strong CYP2C8 inhibitor. Coadministration may result in a significant increase in naproxen exposure. A dose reduction of naproxen may be required if used concomitantly with gemfibrozil.
Naproxen; Esomeprazole: (Moderate) Use naproxen and gemfibrozil together with caution. Naproxen is a substrate of CYP2C8, and gemfibrozil is a strong CYP2C8 inhibitor. Coadministration may result in a significant increase in naproxen exposure. A dose reduction of naproxen may be required if used concomitantly with gemfibrozil.
Naproxen; Pseudoephedrine: (Moderate) Use naproxen and gemfibrozil together with caution. Naproxen is a substrate of CYP2C8, and gemfibrozil is a strong CYP2C8 inhibitor. Coadministration may result in a significant increase in naproxen exposure. A dose reduction of naproxen may be required if used concomitantly with gemfibrozil.
Nateglinide: (Moderate) Dose reductions and increased frequency of glucose monitoring may be required when antidiabetic agents are administered with fibric acid derivatives (e.g., clofibrate, fenofibric acid, fenofibrate, gemfibrozil). Adjust nateglinide dosage if clinically indicated. Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion.
Nebivolol; Valsartan: (Minor) Coadministration of valsartan and gemfibrozil may increase systemic exposure to valsartan. Valsartan is a substrate of the hepatic uptake transporter OATP1B1 and gemfibrozil is an inhibitor of OATP. Patients should be monitored for adverse effects of valsartan.
Niacin; Simvastatin: (Contraindicated) The use of simvastatin with gemfibrozil is contraindicated due to an increased risk for myopathy and rhabdomyolysis. Gemfibrozil can cause myopathy when used alone, and the risk of myopathy and rhabdomyolysis is increased by concomitant use with simvastatin. In addition, the AUC and Cmax of simvastatin are increased with concomitant gemfibrozil use. This may be due to inhibition of OATP1B1 by gemfibrozil; simvastatin is a substrate of OATP1B1.
Olmesartan: (Moderate) Coadministration may result in an increase in olmesartan exposure. A dose reduction of olmesartan may be required if used concomitantly with gemfibrozil. Use olmesartan and gemfibrozil together with caution. Olmesartan is a substrate of the OATP1B1 transporter. Gemfibrozil inhibits OATP1B1.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Coadministration may result in an increase in olmesartan exposure. A dose reduction of olmesartan may be required if used concomitantly with gemfibrozil. Use olmesartan and gemfibrozil together with caution. Olmesartan is a substrate of the OATP1B1 transporter. Gemfibrozil inhibits OATP1B1.
Olmesartan; Hydrochlorothiazide, HCTZ: (Moderate) Coadministration may result in an increase in olmesartan exposure. A dose reduction of olmesartan may be required if used concomitantly with gemfibrozil. Use olmesartan and gemfibrozil together with caution. Olmesartan is a substrate of the OATP1B1 transporter. Gemfibrozil inhibits OATP1B1.
Ozanimod: (Major) Coadministration of ozanimod with gemfibrozil is not recommended. Coadministration may increase the exposure of the active metabolites of ozanimod, which may increase the risk of adverse reactions. Ozanimod is a CYP2C8 substrate and gemfibrozil is a strong CYP2C8 inhibitor. Coadministration with gemfibrozil increased the exposure of active metabolites CC112273 and CC1084037 by approximately 47% and 69%, respectively. No clinically significant differences in the exposure of ozanimod were observed when coadministered with gemfibrozil.
Paclitaxel: (Major) Paclitaxel is a substrate of CYP2C8 and gemfibrozil is a potent CYP2C8 inhibitor. Paclitaxel concentrations are expected to increase with the co-use of gemfibrozil. Consider alternative therapy to gemfibrozil. If coadministration is necessary, use caution and monitor for increased paclitaxel side effects, including myelosuppression and peripheral neuropathy.
Pexidartinib: (Major) Avoid concomitant use of pexidartinib and gemfibrozil due to the risk of increased pexidartinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pexidartinib dosage as follows: 500 mg/day or 375 mg/day of pexidartinib, reduce to 125 mg twice daily; 250 mg/day of pexidartinib, reduce to 125 mg once daily. If gemfibrozil is discontinued, increase the pexidartinib dose to the original dose after 3 plasma half-lives of gemfibrozil. Pexidartinib is a UGT substrate; gemfibrozil is a UGT inhibitor. Coadministration of another UGT inhibitor increased pexidartinib exposure by 60%.
Pioglitazone: (Major) Do not exceed 15 mg/day of pioglitazone when coadministered with gemfibrozil. Coadministration may increase the exposure of pioglitazone, increasing the risk for hypoglycemia. Pioglitazone is a CYP2C8 substrate and gemfibrozil is a strong CYP2C8 inhibitor. The exposure to pioglitazone is increased approximately 3-fold when combined with gemfibrozil. Fibric acid derivatives may also enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion.
Pioglitazone; Glimepiride: (Major) Do not exceed 15 mg/day of pioglitazone when coadministered with gemfibrozil. Coadministration may increase the exposure of pioglitazone, increasing the risk for hypoglycemia. Pioglitazone is a CYP2C8 substrate and gemfibrozil is a strong CYP2C8 inhibitor. The exposure to pioglitazone is increased approximately 3-fold when combined with gemfibrozil. Fibric acid derivatives may also enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion.
Pioglitazone; Metformin: (Major) Do not exceed 15 mg/day of pioglitazone when coadministered with gemfibrozil. Coadministration may increase the exposure of pioglitazone, increasing the risk for hypoglycemia. Pioglitazone is a CYP2C8 substrate and gemfibrozil is a strong CYP2C8 inhibitor. The exposure to pioglitazone is increased approximately 3-fold when combined with gemfibrozil. Fibric acid derivatives may also enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion. (Moderate) Monitor blood glucose during concomitant metformin and fibric acid derivative use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Pitavastatin: (Major) Although FDA approved labeling recommends avoiding coadministration of pitavastatin and gemfibrozil, clinical practice guidelines state the concurrent use of gemfibrozil and pitavastatin is acceptable to use if clinically indicated and fenofibrate or fenofibric acid is not an option. Initiate pitavastatin at a reduced dosage of 1 mg/day not to exceed 2 mg/day if coadministered with gemfibrozil. The risk of myopathy/rhabdomyolysis increases when HMG-CoA reductase inhibitors are administered concurrently with gemfibrozil. The serious risk of myopathy or rhabdomyolysis should be weighed carefully against the benefits of combined statin and gemfibrozil therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
Pramlintide: (Moderate) Dose reductions and increased frequency of glucose monitoring may be required when antidiabetic agents are administered with fibric acid derivatives (e.g., clofibrate, fenofibric acid, fenofibrate, gemfibrozil). Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion.
Pravastatin: (Major) Avoid concomitant use of pravastatin and gemfibrozil due to increased risk for rhabdomyolysis. The benefit of combined therapy with gemfibrozil and HMG-CoA reductase inhibitors does not outweigh the risks for most patients. If combination therapy with gemfibrozil and an HMG-CoA reductase inhibitor is necessary, consider an alternative statin. Coadministration has also been shown to increase the overall exposure of pravastatin by 2-fold; pravastatin is an OATP1B1 substrate and gemfibrozil is an OATP1B1 inhibitor.
Probenecid; Colchicine: (Moderate) Monitor for myopathy during concomitant colchicine and fibric acid derivative use. Cases of myopathy, including rhabdomyolysis, have been reported with fibric acid derivatives coadministered with colchicine.
Quinine: (Moderate) Coadministration may result in a significant increase in quinine exposure. A dose reduction of quinine may be required if used concomitantly with gemfibrozil. Use quinine and gemfibrozil together with caution. Quinine is a substrate of CYP2C8, and gemfibrozil is a strong CYP2C8 inhibitor.
Raltegravir: (Moderate) Raltegravir use has been associated with elevated creatinine kinase concentrations; myopathy and rhabdomyolysis have been reported. Use raltegravir cautiously with drugs that increase the risk of myopathy or rhabdomyolysis such as fibric acid derivatives.
Red Yeast Rice: (Major) Since compounds in red yeast rice are chemically similar to and possess actions similar to lovastatin, patients should avoid this dietary supplement if they currently take drugs known to increase the risk of myopathy (e.g., fibric acid derivatives (gemfibrozil, fenofibrate, clofibrate)) when coadministered with HMG-CoA reductase inhibitors.
Repaglinide: (Contraindicated) Concurrent use of repaglinide and gemfibrozil is contraindicated, due to significantly increased repaglinide exposure and hypoglycemic risk. Gemfibrozil is a potent inhibitor of CYP2C8, the primary pathway by which repaglinide is metabolized. Concurrent administration resulted in an 8.1-fold increase in repaglinide AUC as well as a 28.6-fold higher repaglinide plasma concentration 7 hours post-dose. The repaglinide half-life increased from 1.3 to 3.7 hours. Fibric acid derivatives are also known to enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion.
Revefenacin: (Major) Coadministration of revefenacin with gemfibrozil is not recommended because it could lead to an increase in systemic exposure of the active metabolite of revefenacin and an increased potential for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3; gemfibrozil is an inhibitor of OATP1B1.
Rifampin: (Moderate) Coadministration may result in an increase in rifampin exposure. A dose reduction of rifampin may be required if used concomitantly with gemfibrozil. Use rifampin and gemfibrozil together with caution. Rifampin is a substrate of the OATP1B1 transporter. Gemfibrozil inhibits OATP1B1.
Riociguat: (Moderate) Coadministration may result in a significant increase in riociguat exposure. A dose reduction of riociguat may be required if used concomitantly with gemfibrozil. Use riociguat and gemfibrozil together with caution. Riociguat is a substrate of CYP2C8, and gemfibrozil is a strong CYP2C8 inhibitor.
Rosiglitazone: (Major) Dose reduction of rosiglitazone may be needed if given with gemfibrozil. Gemfibrozil results in increased rosiglitazone exposure and increases the risk for hypoglycemia. Gemfibrozil is a potent inhibitor of CYP2C8 and rosiglitazone is primarily metabolized via CYP2C8. Concomitant administration of gemfibrozil (600 mg twice daily) and rosiglitazone (4 mg once daily) for 7 days increased rosiglitazone AUC by 127%, compared to the administration of rosiglitazone (4 mg once daily) alone. Fibric acid derivatives also enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion.
Rosuvastatin: (Major) Avoid concomitant use of gemfibrozil and rosuvastatin due to the increased risk of myopathy and rhabdomyolysis. If coadministration cannot be avoided, initiate rosuvastatin at a reduced dosage of 5 mg once daily; do not exceed a rosuvastatin dosage of 10 mg once daily. Clinical practice guidelines state the concurrent use of gemfibrozil and rosuvastatin is acceptable to use if clinically indicated and fenofibrate or fenofibric acid is not an option. The risk of myopathy/rhabdomyolysis increases when HMG-CoA reductase inhibitors are administered concurrently with gemfibrozil. The serious risk of myopathy or rhabdomyolysis should be weighed carefully against the benefits of combined statin and gemfibrozil therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
Rosuvastatin; Ezetimibe: (Major) Avoid concomitant use of gemfibrozil and rosuvastatin due to the increased risk of myopathy and rhabdomyolysis. If coadministration cannot be avoided, initiate rosuvastatin at a reduced dosage of 5 mg once daily; do not exceed a rosuvastatin dosage of 10 mg once daily. Clinical practice guidelines state the concurrent use of gemfibrozil and rosuvastatin is acceptable to use if clinically indicated and fenofibrate or fenofibric acid is not an option. The risk of myopathy/rhabdomyolysis increases when HMG-CoA reductase inhibitors are administered concurrently with gemfibrozil. The serious risk of myopathy or rhabdomyolysis should be weighed carefully against the benefits of combined statin and gemfibrozil therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage. (Major) The safety and effectiveness of ezetimibe when coadministered with gemfibrozil have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. Coadministration of ezetimibe with gemfibrozil is not recommended. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. The incidence rates for cholecystectomy have been reported as 0.6% for fenofibrate monotherapy and 1.7% for combination therapy (ezetimibe plus fenofibrate), respectively. According to the manufacturer, the number of patients exposed to combination therapy versus fenofibrate or ezetimibe monotherapy has been inadequate to assess gallbladder disease risk. If cholelithiasis is suspected in a patient receiving ezetimibe and fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered. In a pharmacokinetic study, concomitant fenofibrate or gemfibrozil administration increased total ezetimibe concentrations by approximately 1.5- or 1.7-fold, respectively. However, ezetimibe does not affect the pharmacokinetics of fenofibrate or the bioavailability of gemfibrozil.
Sacituzumab Govitecan: (Major) Avoid coadministration of sacituzumab govitecan and gemfibrozil due to the risk of increased sacituzumab govitecan exposure which may increase the risk of adverse reactions. The cytotoxic component of sacituzumab govitecan, SN-38, is metabolized by UGT1A1 and gemfibrozil is a UGT1A1 inhibitor. Formal drug interaction studies with sacituzumab govitecan have not been conducted but the concomitant use of UGT1A1 inhibitors is expected to increase SN-38 exposure.
Sacubitril; Valsartan: (Minor) Coadministration of valsartan and gemfibrozil may increase systemic exposure to valsartan. Valsartan is a substrate of the hepatic uptake transporter OATP1B1 and gemfibrozil is an inhibitor of OATP. Patients should be monitored for adverse effects of valsartan.
Selexipag: (Contraindicated) Coadministration of selexipag and gemfibrozil is contraindicated due to doubled exposure to selexipag and approximately 11-fold increased exposure to the selexipag active metabolite, which may cause side effects. Selexipag is a CYP2C8 substrate, and gemfibrozil is a strong CYP2C8 inhibitor.
Semaglutide: (Moderate) Monitor blood glucose during concomitant incretin mimetic and fibric acid derivative use; an incretin mimetic dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
SGLT2 Inhibitors: (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and fibric acid derivative use; a SGLT2 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Simvastatin: (Contraindicated) The use of simvastatin with gemfibrozil is contraindicated due to an increased risk for myopathy and rhabdomyolysis. Gemfibrozil can cause myopathy when used alone, and the risk of myopathy and rhabdomyolysis is increased by concomitant use with simvastatin. In addition, the AUC and Cmax of simvastatin are increased with concomitant gemfibrozil use. This may be due to inhibition of OATP1B1 by gemfibrozil; simvastatin is a substrate of OATP1B1.
Sodium Phenylbutyrate; Taurursodiol: (Major) Avoid coadministration of sodium phenylbutyrate; taurursodiol and gemfibrozil. Concomitant use may increase plasma concentrations of sodium phenylbutyrate; taurursodiol. Sodium phenylbutyrate; taurursodiol is an OATP1B3 substrate and gemfibrozil is an OATP1B3 inhibitor.
Sotagliflozin: (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and fibric acid derivative use; a SGLT2 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Sulfonylureas: (Moderate) There is an increased risk for hypoglycemia when gemfibrozil is used with sulfonylureas. Dose reductions and increased frequency of glucose monitoring may be required. Gemfibrozil is a potent inhibitor of CYP2C9, which metabolizes many of the sulfonylureas. In addition, glyburide is a substrate of the OATP1B1 transporter and gemfibrozil inhibits OATP1B1. Due to the effects of gemfibrozil on sulfonylurea metabolic pathways, an increase in sulfonylurea exposure may occur. Fibric acid derivatives may also enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and increased glucagon secretion.
Sumatriptan; Naproxen: (Moderate) Use naproxen and gemfibrozil together with caution. Naproxen is a substrate of CYP2C8, and gemfibrozil is a strong CYP2C8 inhibitor. Coadministration may result in a significant increase in naproxen exposure. A dose reduction of naproxen may be required if used concomitantly with gemfibrozil.
Terbinafine: (Moderate) Due to the risk for terbinafine related adverse effects, caution is advised when coadministering gemfibrozil. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may increase the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP2C9; gemfibrozil is an inhibitor of this enzyme. Monitor patients for adverse reactions if these drugs are coadministered.
Tirzepatide: (Moderate) Monitor blood glucose during concomitant incretin mimetic and fibric acid derivative use; an incretin mimetic dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Treprostinil: (Moderate) Reduce the starting dose of oral treprostinil to 0.125 mg twice daily when coadministered with gemfibrozil; dose adjustments should be made in 0.125 mg twice daily increments every 3 to 4 days. Human pharmacokinetic studies of oral treprostinil indicate that coadministration of gemfibrozil, a cytochrome CYP2C8 enzyme inhibitor, results in a 2-fold increase in exposure to treprostinil, a CYP2C8 substrate. The clinical significance of this interaction with orally inhaled or parenteral treprostinil or with other CYP2C8 inhibitors is unknown; treprostinil dose adjustments may be necessary.
Tucatinib: (Major) Avoid coadministration of tucatinib and gemfibrozil due to the risk of increased tucatinib exposure which may increase the risk of adverse reactions. If concomitant use is unavoidable, reduce the dose of tucatinib to 100 mg twice daily. If gemfibrozil is discontinued, resume the original tucatinib dose after 3 elimination half-lives of gemfibrozil. Tucatinib is a CYP2C8 substrate and gemfibrozil is a strong CYP2C8 inhibitor. Coadministration with gemfibrozil increased tucatinib exposure by 3-fold.
Ursodeoxycholic Acid, Ursodiol: (Major) Fibric acid derivatives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may counteract the effectiveness of ursodeoxycholic acid, ursodiol.
Valsartan: (Minor) Coadministration of valsartan and gemfibrozil may increase systemic exposure to valsartan. Valsartan is a substrate of the hepatic uptake transporter OATP1B1 an

d gemfibrozil is an inhibitor of OATP. Patients should be monitored for adverse effects of valsartan.
Valsartan; Hydrochlorothiazide, HCTZ: (Minor) Coadministration of valsartan and gemfibrozil may increase systemic exposure to valsartan. Valsartan is a substrate of the hepatic uptake transporter OATP1B1 and gemfibrozil is an inhibitor of OATP. Patients should be monitored for adverse effects of valsartan.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with gemfibrozil is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Gemfibrozil is a weak CYP2C9 inhibitor and the S-enantiomer, the active metabolite of warfarin, is a CYP2C9 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.

Gemfibrozil/Lopid Oral Tab: 600mg

Adults

1200 mg/day PO, up to 1600 mg/day PO has been studied.

Elderly

1200 mg/day PO, up to 1600 mg/day PO has been studied.

Adolescents

Safety and efficacy have not been established.

Children

Safety and efficacy have not been established.

The exact mechanism of action has not been fully defined. Gemfibrozil has been shown to inhibit peripheral lipolysis and to decrease hepatic extraction of free fatty acids, which, in turn, decreases hepatic triglyceride production. Gemfibrozil also inhibits the synthesis and increases the clearance of apolipoprotein B, a carrier molecule for VLDL. Gemfibrozil may also accelerate turnover and removal of cholesterol from the liver and increase excretion of cholesterol into the feces. Gemfibrozil's effects to lower triglyceride concentrations and raise HDL-cholesterol concentrations have been shown to be greater than those of clofibrate, to which it is structurally related.
 
Gemfibrozil has variable effects on LDL cholesterol. Although it causes moderate reductions in patients with type IIa hyperlipoproteinemia, changes in patients with either type IIb or type IV hyperlipoproteinemia are unpredictable. In general, the HMG-CoA reductase inhibitors are more effective than gemfibrozil in reducing LDL cholesterol.

Gemfibrozil is administered orally. Protein binding is approximately 95%. Gemfibrozil mainly undergoes oxidation of a ring methyl group to successively form a hydroxymethyl and a carboxyl metabolite. Approximately seventy percent of the administered human dose is excreted in the urine, mostly as the glucuronide conjugate, with less than 2% excreted as unchanged gemfibrozil. Six-percent of the dose is accounted for in the feces. One of the metabolites possesses pharmacologic activity. The elimination half-life is approximately 1.5 hours.
 
Affected cytochrome P450 isoenzymes and drug transporters: CYP2C9, CYP2C8, OATP1B1, OATP2B1, UGT1A1 and UGT1A3
Gemfibrozil is an inhibitor of CYP2C9 and a strong inhibitor of CYP2C8. Dosing reduction of drugs that are mainly metabolized by CYP2C8 enzyme may be required when gemfibrozil is used concomitantly. Gemfibrozil is also an inhibitor of OATP1B1 and OATP2B1. Dosing reductions of drugs that are substrates of OATP1B1 may be required when gemfibrozil is used concomitantly. Gemfibrozil is also known to inhibit UDP-glucuronosyltransferase (UGT) 1A1 and 1A3.

Oral Route

Gemfibrozil is completely absorbed after oral administration of gemfibrozil tablets, reaching peak plasma concentrations 1 to 2 hours after dosing. Gemfibrozil pharmacokinetics are affected by the timing of meals relative to time of dosing. In one study both the rate and extent of absorption of the drug were significantly increased when administered 0.5 hour before meals. Average AUC was reduced by 14% to 44% when gemfibrozil was administered after meals compared to 0.5 hour before meals. In a subsequent study, rate of absorption of gemfibrozil was maximum when administered 0.5 hour before meals with the Cmax 50% to 60% greater than when given either with meals or fasting. In this study, there were no significant effects on AUC of timing of dose relative to meals.

Pregnancy

There are no adequate and well-controlled studies regarding the use of gemfibrozil in pregnant women. Gemfibrozil has been shown to produce adverse effects in animals at doses between 0.5 and 3 times the human dose. Reactions include decrease in conception rate, increase in stillborns, decrease in litter size, slight reduction in pup weight, dose-related skeletal variations, anophthalmia, and suppression of pup weight during lactation. Gemfibrozil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.[48366]

It is not known if gemfibrozil is excreted into human milk. Due to the potential for adverse effects seen in animal studies, a decision should be made whether to discontinue breast-feeding or to discontinue the drug, taking into account the importance of the drug to the mother. If pharmacotherapy is necessary in the nursing mother, a nonabsorbable resin such as cholestyramine, colesevelam, or colestipol should be considered. These agents do not enter the bloodstream and thus will not be excreted during lactation. However, resins bind fat-soluble vitamins and prolonged use may result in deficiencies of these vitamins in the mother and her nursing infant.