PDR MEMBER LOGIN:
  • PDR Search

    Required field
  • Advertisement
  • CLASSES

    Fibric Acid Derivatives/Fibrates

    DEA CLASS

    Rx

    DESCRIPTION

    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.

    COMMON BRAND NAMES

    Lopid

    HOW SUPPLIED

    Gemfibrozil/Lopid Oral Tab: 600mg

    DOSAGE & INDICATIONS

    For use as an adjunct to diet for the treatment of hyperlipoproteinemia and hypertriglyceridemia.
    For hypertriglyceridemia including Type IV (elevated triglycerides, VLDL) and Type V (elevated triglycerides, chylomicrons, VLDL) in patients who have significant risk of coronary artery disease or pancreatitis, and have not responded to diet.
    NOTE: Gemfibrozil is not indicated for patients with Type I (rare) hyperlipoproteinemia who have elevated chylomicrons, triglycerides, but who have normal VLDL concentrations. Inspection of plasma refrigerated for 14 hours is helpful in distinguishing Types I (rare), IV, and V (rare) hyperlipoproteinemia.
    Oral dosage
    Adults

    600 mg PO twice daily, administered 30 minutes before the morning and evening meals. Serum concentrations of lipoproteins should be monitored regularly and dosage adjusted to individual requirements. In clinical trials, doses have ranged from 900—1600 mg/day PO. Gemfibrozil should be discontinued if serum lipoprotein concentrations do not improve substantially after 3 months of therapy.

    Geriatric

    See adult dosage.

    For second-line therapy for type IIb hypercholesterolemia (elevated cholesterol, triglycerides, LDL, VLDL) in patients with low HDL (< 35 mg/dl) and without evidence of coronary artery disease.
    Oral dosage
    Adults

    600 mg PO twice daily, administered 30 minutes before the morning and evening meals. Serum concentrations of lipoproteins should be monitored regularly and dosage adjusted to individual requirements. In clinical trials, doses have ranged from 900—1600 mg/day PO. Gemfibrozil should be discontinued if serum lipoprotein concentrations do not improve substantially after 3 months of therapy. NOTE: The first-line therapy (e.g., diet, exercise, and other antilipemic drugs which significantly lower LDL and raise HDL levels) for Type IIb hypercholesterolemia should be used prior to initiating gemfibrozil therapy.

    Geriatric

    See adult dosage.

    MAXIMUM DOSAGE

    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.

    DOSING CONSIDERATIONS

    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).

    ADMINISTRATION

    Oral Administration

    Administer 30 minutes before the morning and evening meals.

    STORAGE

    Lopid:
    - Avoid excessive humidity
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Gemfibrozil is contraindicated in patients with a hypersensitivity to gemfibrozil.

    Biliary cirrhosis, cholelithiasis, gallbladder disease, hepatic disease

    Gemfibrozil is contraindicated in patients with hepatic dysfunction or hepatic disease, including primary biliary cirrhosis. Gemfibrozil is primarily eliminated by metabolism and drug clearance may be decreased in patients with hepatic impairment. In patients with biliary cirrhosis, further elevations of serum cholesterol can occur. Gemfibrozil is also contraindicated in patients with pre-existing gallbladder disease. Gemfibrozil is related to clofibrate, which has been associated with gallbladder disease and cholelithiasis. Cases of cholelithiasis have been reported during gemfibrozil therapy.

    Renal disease, renal failure, renal impairment

    Gemfibrozil is contraindicated in patients with renal disease associated with severe renal impairment or renal failure. There have been reports of worsening renal insufficiency with gemfibrozil therapy in patients with baseline serum creatinine > 2 mg/dL. In such patients, the use of alternative therapy should be considered against the risks and benefits of a lower dose.

    Children, infants, neonates

    The safety and efficacy of gemfibrozil in neonates, infants, children and adolescents under 18 years of age have not been established.

    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]

    Breast-feeding

    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.

    ADVERSE REACTIONS

    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

    DRUG INTERACTIONS

    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.
    Albiglutide: (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.
    Aliskiren; 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.
    Alogliptin; Metformin: (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; Pioglitazone: (Major) Do not exceed 15 mg PO per day of pioglitazone if given with gemfibrozil. Gemfibrozil results in increased pioglitazone exposure and increases the risk for hypoglycemia. Monitor for changes in glycemic control. Gemfibrozil is a strong CYP2C8 inhibitor and pioglitazone is a CYP2C8 substrate. 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) In general, avoid use as the risk of myopathy/rhabdomyolysis increases. Consider alternatives to gemfibrozil first. The risk of myopathy/rhabdomyolysis increases when HMG-CoA reductase inhibitors ("statins") 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 creatine kinase will prevent the occurrence of severe myopathy and renal damage. Clinical practice guidelines state the concurrent use of gemfibrozil and atorvastatin is acceptable to use if clinically indicated and fenofibrate or fenofibric acid is not an option.
    Amlodipine; Hydrochlorothiazide, HCTZ; 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; Hydrochlorothiazide, HCTZ; 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; 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.
    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.
    Aspirin, ASA; Pravastatin: (Major) The risk of myopathy during treatment with other HMG-CoA reductase inhibitors is generally increased with concurrent therapy with fibric acid derivatives. The use of fibrates alone may occasionally be associated with myopathy. Combination therapy with pravastatin and gemfibrozil is generally not recommended. The combined use of pravastatin and fibrates should be avoided unless the benefit of further alterations in lipid levels is likely to outweigh the increased risk of this drug combination. Preliminary data suggest that the addition of gemfibrozil to therapy with pravastatin is not associated with greater reduction in LDL-cholesterol than that achieved with pravastatin alone. Pravastatin and gemfibrozil have been administered together in a study of 290 patients, with two patients developing asymptomatic elevations of CPK; severe myopathy was not observed, although muscle biopsies were not performed. In addition, a trial of pravastatin (40 mg/day) coadministration with gemfibrozil (1200 mg/day) has not been shown to be associated with myopathy, although 4 of 75 patients receiving the combination showed marked CPK elevations versus 1 of 73 patients receiving placebo. A trend has been reported toward more frequent CPK elevations and patient withdrawals due to musculoskeletal symptoms in the group receiving combined treatment as compared to the groups receiving placebo, gemfibrozil, or pravastatin monotherapy. In a crossover study in 20 healthy male volunteers given concomitant single doses of pravastatin and gemfibrozil, there was a significant decrease in urinary excretion and protein binding of pravastatin. In addition, there was a significant increase in AUC, Cmax, and Tmax for the pravastatin metabolite SQ 31,906.
    Atorvastatin: (Major) In general, avoid use as the risk of myopathy/rhabdomyolysis increases. Consider alternatives to gemfibrozil first. The risk of myopathy/rhabdomyolysis increases when HMG-CoA reductase inhibitors ("statins") 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 creatine kinase will prevent the occurrence of severe myopathy and renal damage. Clinical practice guidelines state the concurrent use of gemfibrozil and atorvastatin is acceptable to use if clinically indicated and fenofibrate or fenofibric acid is not an option.
    Atorvastatin; Ezetimibe: (Major) In general, avoid use as the risk of myopathy/rhabdomyolysis increases. Consider alternatives to gemfibrozil first. The risk of myopathy/rhabdomyolysis increases when HMG-CoA reductase inhibitors ("statins") 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 creatine kinase will prevent the occurrence of severe myopathy and renal damage. Clinical practice guidelines state the concurrent use of gemfibrozil and atorvastatin is acceptable to use if clinically indicated and fenofibrate or fenofibric acid is not an option. (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.
    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.
    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.
    Canagliflozin: (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.
    Canagliflozin; Metformin: (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.
    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) Concurrent administration of colchicine and fibric acid derivatives may result in the development of myotoxicity (i.e., muscle pain and weakness, rhabdomyolysis). The pharmacokinetic and/or pharmacodynamic mechanism of this interaction is not clear; however, both colchicine and fibric acid derivatives are associated with the development of myotoxicity and concurrent use may increase the risk of myotoxicity. If such agents are co-administered, advise patients to report signs and symptoms of myotoxicity including muscle tenderness, pain, or weakness; monitoring creatine phosphokinase may not predict the development of severe myopathy.
    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) 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.
    Dapagliflozin; Metformin: (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.
    Dapagliflozin; Saxagliptin: (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.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Severe) Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with gemfibrozil is contraindicated due to the potential for dasabuvir-induced QT prolongation. Coadministration increases dasabuvir exposures by 10-fold. Gemfibrozil is an inhibitor of the hepatic isoenzyme CYP2C8; dasabuvir is a substrate of this isoenzyme.
    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) 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.
    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) 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.
    Elagolix: (Severe) 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: (Severe) 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) 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.
    Empagliflozin; Linagliptin: (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.
    Empagliflozin; Metformin: (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.
    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) 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.
    Ertugliflozin; Metformin: (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.
    Ertugliflozin; Sitagliptin: (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.
    Esomeprazole; 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.
    Exenatide: (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.
    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: (Severe) 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.
    Food: (Moderate) Use caution if coadministration of marijuana with gemfibrozil is necessary, and monitor for an increase in marijuana-related adverse reactions (e.g., feeling high, dizziness, confusion, somnolence). Of the over 70 phytocannabinoids in marijuana, delta9-tetrahydrocannabinol (THC), cannabidiol (CBD) and cannibinol are the 3 main constituents. Certain cannabionoids are CYP2C9 and 3A4 substrates; gemfibrozil is a weak inhibitor of CYP2C9. Concomitant use may result in elevated plasma concentrations of certain cannabinoids found in marijuana.
    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.
    Glimepiride; Pioglitazone: (Major) Do not exceed 15 mg PO per day of pioglitazone if given with gemfibrozil. Gemfibrozil results in increased pioglitazone exposure and increases the risk for hypoglycemia. Monitor for changes in glycemic control. Gemfibrozil is a strong CYP2C8 inhibitor and pioglitazone is a CYP2C8 substrate. 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.
    Glimepiride; 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.
    Glipizide; Metformin: (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.
    Glyburide; Metformin: (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.
    Hydrochlorothiazide, HCTZ; 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.
    Hydrochlorothiazide, HCTZ; 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.
    Incretin Mimetics: (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.
    Insulin Degludec; Liraglutide: (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.
    Insulin Glargine; Lixisenatide: (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.
    Insulins: (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.
    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.
    Lansoprazole; 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.
    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) 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.
    Liraglutide: (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.
    Lixisenatide: (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.
    Loperamide: (Moderate) The plasma concentration of loperamide, a CYP2C8 substrate, may be increased when administered concurrently with gemfibrozil, a potent inhibitor of CYP2C8. If these drugs are used together, 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).
    Loperamide; Simethicone: (Moderate) The plasma concentration of loperamide, a CYP2C8 substrate, may be increased when administered concurrently with gemfibrozil, a potent inhibitor of CYP2C8. If these drugs are used together, 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).
    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.
    Lovastatin; Niacin: (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.
    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.
    Metformin: (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.
    Metformin; Pioglitazone: (Major) Do not exceed 15 mg PO per day of pioglitazone if given with gemfibrozil. Gemfibrozil results in increased pioglitazone exposure and increases the risk for hypoglycemia. Monitor for changes in glycemic control. Gemfibrozil is a strong CYP2C8 inhibitor and pioglitazone is a CYP2C8 substrate. 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) 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.
    Metformin; Repaglinide: (Severe) 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) 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.
    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) 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.
    Metformin; Saxagliptin: (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.
    Metformin; Sitagliptin: (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.
    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.
    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; 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.
    Naproxen; Sumatriptan: (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). Some fibric acid derivatives (fenofirbrate) inhibit CYP2C9 and may increase nateglinide exposure. 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: (Severe) 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.
    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.
    Pioglitazone: (Major) Do not exceed 15 mg PO per day of pioglitazone if given with gemfibrozil. Gemfibrozil results in increased pioglitazone exposure and increases the risk for hypoglycemia. Monitor for changes in glycemic control. Gemfibrozil is a strong CYP2C8 inhibitor and pioglitazone is a CYP2C8 substrate. 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.
    Pitavastatin: (Major) The use of fibrates alone, including fenofibrate, may occasionally be associated with myositis, myopathy, or rhabdomyolysis. Concurrent use of fenofibrate and HMG-CoA reductase inhibitors (Statins) has been associated with increases in creatine kinase (CK), an increased risk of rhabdomyolysis, and myoglobinuria leading to acute renal failure. In a single-dose drug interaction study in 23 healthy adults, concomitant administration of fenofibrate (201 mg) with pravastatin (40 mg) resulted in an increase in the mean Cmax and AUC values for pravastatin by 13%. The mean Cmax and AUC for 3-alpha-hydroxy-iso-pravastatin increased by 29% and 26%, respectively. In another drug interaction study, the coadministration of fenofibrate and pravastatin (40 mg) for 10 days resulted in an increase in the mean Cmax and AUC values for pravastatin by 36% and 28%, respectively, and for the metabolite, 3-alpha-hydroxy-iso-pravastatin, by 55% and 39%, respectively. The coadministration of a single dose of fenofibrate and a single dose of fluvastatin resulted in a small increase (approximately 15% to 16%) in exposure to (+)3R,5S-fluvastatin, the active enantiomer of fluvastatin. A single dose of either pravastatin or fluvastatin had no clinically important effect on the pharmacokinetics of fenofibric acid. Concomitant administration of fenofibrate with atorvastatin 20 mg once daily for 10 days resulted in a 17% decrease in atorvastatin AUC values in 22 healthy males. The atorvastatin Cmax values were not significantly affected by fenofibrate. The pharmacokinetics of fenofibric acid were not significantly affected by atorvastatin. Based on studies in other fibrate treated patients, myopathy can occur from 3 weeks to several months after initiating the combined therapy. The combined use of fenofibrate and HMG-CoA reductase inhibitors should be avoided unless the benefit of further alterations in lipid levels is likely to outweigh the increased risk of this drug combination. It is unknown whether any potential benefit in blood lipids derived from concomitant use would outweigh the potential risks. If fenofibrate and HMG-CoA reductase inhibitors are prescribed together, serum CK levels should be monitored closely during the initial weeks of therapy, but there is no assurance that periodic CK levels will prevent the occurrence of myopathy or renal dysfunction. Patients on fenofibrate should be instructed to report any complaints of muscle pain, tenderness, or weakness to their health care professional immediately. Patients complaining of muscle pain, tenderness, or weakness should have prompt medical evaluation for myopathy, including CK level determination. If myopathy or myositis is suspected or diagnosed, fenofibrate should be stopped.
    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) The risk of myopathy during treatment with other HMG-CoA reductase inhibitors is generally increased with concurrent therapy with fibric acid derivatives. The use of fibrates alone may occasionally be associated with myopathy. Combination therapy with pravastatin and gemfibrozil is generally not recommended. The combined use of pravastatin and fibrates should be avoided unless the benefit of further alterations in lipid levels is likely to outweigh the increased risk of this drug combination. Preliminary data suggest that the addition of gemfibrozil to therapy with pravastatin is not associated with greater reduction in LDL-cholesterol than that achieved with pravastatin alone. Pravastatin and gemfibrozil have been administered together in a study of 290 patients, with two patients developing asymptomatic elevations of CPK; severe myopathy was not observed, although muscle biopsies were not performed. In addition, a trial of pravastatin (40 mg/day) coadministration with gemfibrozil (1200 mg/day) has not been shown to be associated with myopathy, although 4 of 75 patients receiving the combination showed marked CPK elevations versus 1 of 73 patients receiving placebo. A trend has been reported toward more frequent CPK elevations and patient withdrawals due to musculoskeletal symptoms in the group receiving combined treatment as compared to the groups receiving placebo, gemfibrozil, or pravastatin monotherapy. In a crossover study in 20 healthy male volunteers given concomitant single doses of pravastatin and gemfibrozil, there was a significant decrease in urinary excretion and protein binding of pravastatin. In addition, there was a significant increase in AUC, Cmax, and Tmax for the pravastatin metabolite SQ 31,906.
    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: (Severe) 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.
    Rifaximin: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, an organic anion-transporting polypeptide (OATP1A1/1B1/1B3) substrate, with gemfibrozil, an OATP inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, OATP inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively.
    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) HMG-CoA reductase inhibitors have been administered safely with fibric acid derivatives in some patients; however the risk of potential myopathy is considerably higher during concurrent therapy. Combination therapy with HMG-CoA reductase inhibitors, such as rosuvastatin and gemfibrozil has been associated with a significantly enhanced risk of myopathy and rhabdomyolysis. When possible, avoid concurrent use of HMG-reductase inhibitors with fibrates. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus 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. Gemfibrozil in particular is a known potent OATP1B1 inhibitor, and rosuvastatin is an OATP1B1 substrate. This is the likely mechanism of the increase in rosuvastatin exposure with gemfibrozil use. If rosuvastatin must be used concurrently with any of these drugs, limit the rosuvastatin dose to 10 mg/day.
    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: (Severe) 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) 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.
    SGLT2 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.
    Simeprevir: (Minor) Use caution with concurrent use of simeprevir and gemfibrozil. Gemfibrozil is an inhibitor of OAT1B1, which may increase the plasma concentrations of simeprevir, a substrate of OATP1B1/3 in vitro, resulting in adverse effects, such as rash.
    Simvastatin: (Severe) 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.
    Simvastatin; Sitagliptin: (Severe) 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.
    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.
    Telbivudine: (Moderate) The risk of myopathy may be increased if a fibric acid derivative is coadministered with telbivudine. Monitor patients for any signs or symptoms of unexplained muscle pain, tenderness, or weakness, particularly during periods of upward dosage titration.
    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.
    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.
    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 and gemfibrozil is an inhibitor of OATP. Patients should be monitored for adverse effects of valsartan.
    Warfarin: (Moderate) Use caution if warfarin is coadministered with gemfibrozil. Reduce the dose of warfarin to maintain the prothrombin time at the desired level to prevent bleeding complications. Frequently monitor prothrombin until it has been definitely determined that the prothrombin level has stabilized.

    PREGNANCY AND LACTATION

    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.

    MECHANISM OF ACTION

    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.

    PHARMACOKINETICS

    Gemfibrozil is administered orally. Protein binding is approximately 95%. It is metabolized by the liver and excreted by the kidneys, mainly as metabolites; fecal elimination is about 6%. One of the metabolites possesses pharmacologic activity. The elimination half-life is approximately 1.5 hours.
     
    Affected cytochrome P450 isoenzymes: CYP2C9, CYP2C8, OATP1B1, OATP2B1.
    Gemfibrozil is an inhibitor of CYP2C9 and a strong inhibitor of CYP2C8. Use caution when administering with drugs that are metabolized by CYP2C9 or CYP2C8. Gemfibrozil is also an inhibitor of OATP1B1 and OATP2B1.

    Oral Route

    Gemfibrozil is rapidly and completely absorbed from the GI tract and undergoes enterohepatic recirculation. Plasma concentrations correlate with dose but not response.