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Gemfibrozil

Pronunciation

Pronunciation

(jem FI broe zil)

Index Terms

  • Cl-719

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Lopid: 600 mg [scored]

Generic: 600 mg

Brand Names: U.S.

  • Lopid

Pharmacologic Category

  • Antilipemic Agent, Fibric Acid

Pharmacology

The exact mechanism of action of gemfibrozil is unknown, however, several theories exist regarding the VLDL effect; it can inhibit lipolysis and decrease subsequent hepatic fatty acid uptake as well as inhibit hepatic secretion of VLDL; together these actions decrease serum VLDL levels; increases HDL-cholesterol; the mechanism behind HDL elevation is currently unknown

Absorption

Well absorbed

Metabolism

Hepatic via oxidation to two inactive metabolites; undergoes enterohepatic recycling

Excretion

Urine (~70% primarily as conjugated drug); feces (6%)

Onset of Action

May require several days

Time to Peak

Serum: 1 to 2 hours

Half-Life Elimination

1.5 hours

Protein Binding

99%

Use: Labeled Indications

Treatment of hypertriglyceridemia in Fredrickson types IV and V hyperlipidemia for patients who are at greater risk for pancreatitis and who have not responded to dietary intervention; to reduce the risk of CHD development in Fredrickson type IIb patients without a history or symptoms of existing CHD who have not responded to dietary and other interventions (including pharmacologic treatment) and who have decreased HDL, increased LDL, and increased triglycerides

Contraindications

Hypersensitivity to gemfibrozil or any component of the formulation; hepatic or severe renal dysfunction; primary biliary cirrhosis; preexisting gallbladder disease; concurrent use with dasabuvir, repaglinide, or simvastatin.

Documentation of allergenic cross-reactivity for fibrates is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Dosing: Adult

Hyperlipidemia/hypertriglyceridemia: Oral: 600 mg twice daily 30 minutes before breakfast and dinner. Note: Discontinue if lipid response is inadequate after 3 months of therapy.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

Manufacturer's labeling:

Mild-to-moderate impairment: There are no dosage adjustments provided in the manufacturer’s labeling; use with caution; deterioration of renal function has been reported in patients with baseline serum creatinine >2 mg/dL

Severe impairment: There are no dosage adjustments provided in the manufacturer’s labeling; use is contraindicated

Alternate recommendations (Aronoff, 2007):

GFR >50 mL/minute: No dosage adjustment necessary.

GFR 10 to 50 mL/minute: Administer 75% of dose.

GFR <10 mL/minute: Administer 50% of dose.

Intermittent hemodialysis: Supplemental dose not necessary.

Peritoneal dialysis: Administer 50% of dose as supplement for dialysis.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling; use is contraindicated.

Administration

Administer 30 minutes prior to breakfast and dinner.

Dietary Considerations

Before initiation of therapy, patients should be placed on a standard cholesterol-lowering diet for 3 to 6 months and the diet should be continued during drug therapy. Administer 30 minutes prior to breakfast and dinner

Storage

Store at 20°C to 25°C (68°F to 77°F). Protect from light and moisture.

Drug Interactions

Acipimox: May enhance the myopathic (rhabdomyolysis) effect of Fibric Acid Derivatives. Monitor therapy

Agomelatine: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Agomelatine. Monitor therapy

Amodiaquine: CYP2C8 Inhibitors may increase the serum concentration of Amodiaquine. Avoid combination

Antidiabetic Agents (Thiazolidinedione): Gemfibrozil may decrease the metabolism of Antidiabetic Agents (Thiazolidinedione). Management: Limit pioglitazone maximum adult dose to 15 mg/day, and consider dose reduction of rosiglitazone, when used in combination with gemfibrozil. Consider therapy modification

Asunaprevir: OATP1B1/SLCO1B1 Inhibitors may increase the serum concentration of Asunaprevir. Avoid combination

AtorvaSTATin: Gemfibrozil may enhance the myopathic (rhabdomyolysis) effect of AtorvaSTATin. Gemfibrozil may increase the serum concentration of AtorvaSTATin. Avoid combination

Bexarotene (Systemic): Gemfibrozil may increase the serum concentration of Bexarotene (Systemic). Avoid combination

Bile Acid Sequestrants: May decrease the absorption of Fibric Acid Derivatives. Management: Separate doses by at least 2 hours to minimize this interaction; fenofibric acid labeling recommends administration one hour prior to or 4-6 hours after a bile acid sequestrant. Exceptions: Colesevelam. Consider therapy modification

Bosentan: CYP2C9 Inhibitors (Strong) may increase the serum concentration of Bosentan. Management: Concomitant use of both a CYP2C9 inhibitor and a CYP3A inhibitor or a single agent that inhibits both enzymes with bosentan is likely to cause a large increase in serum concentrations of bosentan and is not recommended. See monograph for details. Monitor therapy

Cannabis: May increase the serum concentration of CYP2C9 Inhibitors (Strong). More specifically, tetrahydrocannabinol serum concentrations may be increased. Monitor therapy

Carvedilol: CYP2C9 Inhibitors (Strong) may increase the serum concentration of Carvedilol. Specifically, concentrations of the S-carvedilol enantiomer may be increased. Monitor therapy

Chenodiol: Fibric Acid Derivatives may diminish the therapeutic effect of Chenodiol. Management: Monitor clinical response to chenodiol closely when used together with any fibric acid derivative. Monitor therapy

Cilostazol: CYP2C19 Inhibitors may increase the serum concentration of Cilostazol. Management: Consider reducing the cilostazol dose to 50 mg twice daily in patients who are also receiving inhibitors of CYP2C19. Consider therapy modification

Ciprofibrate: May enhance the adverse/toxic effect of Fibric Acid Derivatives. Avoid combination

Citalopram: CYP2C19 Inhibitors (Strong) may increase the serum concentration of Citalopram. Management: Limit citalopram dose to a maximum of 20 mg/day if used with a strong CYP2C19 inhibitor. Patients using this combination should be monitored closely for evidence of citalopram toxicity (e.g., serotonin syndrome, QT prolongation, etc.). Consider therapy modification

Clopidogrel: CYP2C19 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Clopidogrel. Management: Due to a risk for impaired clopidogrel effectiveness with such a combination, carefully consider the need for a strong CYP2C19 inhibitor in patients receiving clopidogrel. Monitor patients closely for evidence of a diminished response to clopidogrel. Consider therapy modification

Colchicine: Fibric Acid Derivatives may enhance the myopathic (rhabdomyolysis) effect of Colchicine. Monitor therapy

CycloSPORINE (Systemic): May enhance the nephrotoxic effect of Fibric Acid Derivatives. Fibric Acid Derivatives may decrease the serum concentration of CycloSPORINE (Systemic). Management: Careful consideration of the risks and benefits should be undertaken prior to use of this combination; extra monitoring of renal function and cyclosporine concentrations will likely be required. Adjustment of cyclosporine dose may be necessary. Consider therapy modification

CYP1A2 Substrates: CYP1A2 Inhibitors (Moderate) may decrease the metabolism of CYP1A2 Substrates. Monitor therapy

CYP2C19 Substrates: CYP2C19 Inhibitors (Strong) may decrease the metabolism of CYP2C19 Substrates. Consider therapy modification

CYP2C8 Substrates: CYP2C8 Inhibitors (Strong) may decrease the metabolism of CYP2C8 Substrates. Consider therapy modification

CYP2C9 Substrates: CYP2C9 Inhibitors (Strong) may decrease the metabolism of CYP2C9 Substrates. Consider therapy modification

Dabrafenib: CYP2C8 Inhibitors (Strong) may increase the serum concentration of Dabrafenib. Avoid combination

Diclofenac (Systemic): CYP2C9 Inhibitors (Strong) may increase the serum concentration of Diclofenac (Systemic). Management: Consider using a lower dose of diclofenac when used together with a strong CYP2C9 inhibitor. Arthrotec (diclofenac and misoprostol) labeling specifically recommends limiting the total daily dose to a maximum of 50 mg twice/day. Consider therapy modification

Dronabinol: CYP2C9 Inhibitors (Strong) may increase the serum concentration of Dronabinol. Monitor therapy

Eluxadoline: Gemfibrozil may increase the serum concentration of Eluxadoline. Management: Decrease the eluxadoline dose to 75 mg twice daily if combined with gemfibrozil and monitor patients for increased eluxadoline effects/toxicities. Consider therapy modification

Enzalutamide: CYP2C8 Inhibitors (Strong) may increase the serum concentration of Enzalutamide. Management: Avoid concurrent use of strong CYP2C8 inhibitors and enzalutamide if possible. If the combination must be used, reduce enzalutamide to 80 mg once daily. Avoid combination

Ezetimibe: Gemfibrozil may enhance the adverse/toxic effect of Ezetimibe. Specifically, the risk of myopathy and cholelithiasis may be increased. Gemfibrozil may increase the serum concentration of Ezetimibe. Avoid combination

Flibanserin: CYP2C19 Inhibitors (Strong) may increase the serum concentration of Flibanserin. Monitor therapy

Fluvastatin: Gemfibrozil may enhance the myopathic (rhabdomyolysis) effect of Fluvastatin. Avoid combination

Grazoprevir: OATP1B1/SLCO1B1 Inhibitors may increase the serum concentration of Grazoprevir. Avoid combination

Imatinib: Gemfibrozil may decrease serum concentrations of the active metabolite(s) of Imatinib. Specifically N-desmethylimatinib concentrations may be decreased. Gemfibrozil may decrease the serum concentration of Imatinib. Monitor therapy

Irinotecan Products: UGT1A1 Inhibitors may increase serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, concentrations of SN-38 may be increased. UGT1A1 Inhibitors may increase the serum concentration of Irinotecan Products. Avoid combination

Lacosamide: CYP2C9 Inhibitors (Strong) may increase the serum concentration of Lacosamide. Monitor therapy

Lovastatin: Gemfibrozil may enhance the myopathic (rhabdomyolysis) effect of Lovastatin. Gemfibrozil may increase the serum concentration of Lovastatin. More specifically, gemfibrozil may increase the serum concentrations of lovastatin acid (active form of parent drug). Avoid combination

Montelukast: Gemfibrozil may increase the serum concentration of Montelukast. Monitor therapy

Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir: CYP2C8 Inhibitors (Strong) may increase the serum concentration of Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir. Specifically, the serum concentrations of dasabuvir may increase significantly. Avoid combination

Ospemifene: CYP2C9 Inhibitors (Strong) may increase the serum concentration of Ospemifene. Monitor therapy

Parecoxib: CYP2C9 Inhibitors (Strong) may increase the serum concentration of Parecoxib. Monitor therapy

Pioglitazone: CYP2C8 Inhibitors (Strong) may increase the serum concentration of Pioglitazone. Management: Limit pioglitazone adult maximum dose to 15 mg/day when used in combination with any strong CYP2C8 inhibitor. Consider therapy modification

Pirfenidone: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Pirfenidone. Management: Use any such combination with caution and close monitoring for pirfenidone toxicity. Avoid the use of pirfenidone with moderate CYP1A2 inhibitors whenever CYP2C9, 2C19, 2C6, or 2E1 is also inhibited (either by the CYP1A2 inhibitor or by a third drug). Consider therapy modification

Pitavastatin: Gemfibrozil may enhance the myopathic (rhabdomyolysis) effect of Pitavastatin. Gemfibrozil may increase the serum concentration of Pitavastatin. Avoid combination

Pravastatin: Gemfibrozil may enhance the myopathic (rhabdomyolysis) effect of Pravastatin. Gemfibrozil may increase the serum concentration of Pravastatin. Avoid combination

Raltegravir: May enhance the myopathic (rhabdomyolysis) effect of Fibric Acid Derivatives. Monitor therapy

Ramelteon: CYP2C9 Inhibitors (Strong) may increase the serum concentration of Ramelteon. Monitor therapy

Repaglinide: Gemfibrozil may increase the serum concentration of Repaglinide. The addition of itraconazole may augment the effect of gemfibrozil on repaglinide. Avoid combination

Rosuvastatin: Gemfibrozil may enhance the myopathic (rhabdomyolysis) effect of Rosuvastatin. Gemfibrozil may increase the serum concentration of Rosuvastatin. Management: If possible, avoid concomitant use of rosuvastatin with gemfibrozil. If concomitant can not be avoided, limit rosuvastatin to 10 mg/day (US recommendation) or 20 mg/day (Canadian recommendation). Monitor for signs/symptoms of rhabdomyolysis. Avoid combination

Selexipag: CYP2C8 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Selexipag. CYP2C8 Inhibitors (Strong) may increase the serum concentration of Selexipag. Avoid combination

Simvastatin: Gemfibrozil may enhance the myopathic (rhabdomyolysis) effect of Simvastatin. Gemfibrozil may increase the serum concentration of Simvastatin. Concentrations of the active simvastatin acid metabolite may also be increased by gemfibrozil. Avoid combination

Sulfonylureas: Fibric Acid Derivatives may enhance the hypoglycemic effect of Sulfonylureas. Monitor therapy

Tetrahydrocannabinol: CYP2C9 Inhibitors (Strong) may increase the serum concentration of Tetrahydrocannabinol. Monitor therapy

TiZANidine: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of TiZANidine. Management: If combined use cannot be avoided, initiate tizanidine in adults at 2 mg and increase in 2-4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Avoid combination

Treprostinil: CYP2C8 Inhibitors (Strong) may increase the serum concentration of Treprostinil. Management: Reduce the initial treprostinil extended release tablet dose to 0.125 mg twice daily, titrating by 0.125 mg twice daily every 3 to 4 days. No preemptive dose adjustment is recommended for other treprostinil products. Consider therapy modification

Ursodiol: Fibric Acid Derivatives may diminish the therapeutic effect of Ursodiol. Monitor therapy

Vitamin K Antagonists (eg, warfarin): Fibric Acid Derivatives may enhance the anticoagulant effect of Vitamin K Antagonists. Consider therapy modification

Adverse Reactions

>10%: Gastrointestinal: Dyspepsia (20%)

1% to 10%:

Cardiovascular: Atrial fibrillation (1%)

Central nervous system: Fatigue (4%), vertigo (2%)

Dermatologic: Eczema (2%), rash (2%)

Gastrointestinal: Abdominal pain (10%), nausea/vomiting (3%)

<1% or case reports with probable causation (limited to important or life-threatening): Alkaline phosphatase increased, anemia, angioedema, arthralgia, bilirubin increased, blurred vision, bone marrow hypoplasia, cholelithiasis, cholecystitis, cholestatic jaundice, creatine phosphokinase increased, depression, dermatitis, dermatomyositis/polymyositis, dizziness, eosinophilia, exfoliative dermatitis, headache, hypoesthesia, hypokalemia, impotence, laryngeal edema, leukopenia, libido decreased, myalgia, myasthenia, myopathy, nephrotoxicity, painful extremities, paresthesia, peripheral neuritis, pruritus, Raynaud's phenomenon, rhabdomyolysis, somnolence, synovitis, taste perversion, transaminases increased, urticaria

Reports where causal relationship has not been established: Alopecia, anaphylaxis, cataracts, colitis, confusion, decreased fertility (male), drug-induced lupus-like syndrome, extrasystoles, hepatoma, intracranial hemorrhage, pancreatitis, peripheral vascular disease, photosensitivity, positive ANA, renal dysfunction, retinal edema, seizure, syncope, thrombocytopenia, vasculitis, weight loss

Warnings/Precautions

Concerns related to adverse effects:

• Cholelithiasis: May increase risk of cholelithiasis; discontinue if gallstones are found upon gallbladder studies.

• Elevated transaminases: Elevations in serum transaminases may be seen with use; periodic monitoring recommended.

• Hematologic effects: May cause mild decreases in hemoglobin, hematocrit, and WBC upon initiation which usually stabilizes with long-term therapy. Anemia, leukopenia, thrombocytopenia, and bone marrow hypoplasia have rarely been reported. Periodic monitoring recommended during the first year of therapy.

• Malignancy: Possible increased risk of malignancy.

• Myopathy/rhabdomyolysis: Has been associated with rare myositis or rhabdomyolysis; patients should be monitored closely. Patients should be instructed to report unexplained muscle pain, tenderness, weakness, or brown urine.

Disease-related concerns:

• Renal impairment: Use with caution in patients with mild-to-moderate renal impairment; contraindicated in patients with severe impairment. Deterioration has been seen when used in patients with a serum creatinine >2 mg/dL.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Appropriate use: Secondary causes of hyperlipidemia should be ruled out prior to therapy. Be careful in patient selection, this is not a first- or second-line choice; other agents may be more suitable. Discontinue if lipid response not seen.

Monitoring Parameters

Serum cholesterol, LFTs periodically, CBC periodically (first year)

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies. The Canadian product labeling specifically contraindicates use during pregnancy and recommends gemfibrozil be discontinued several months prior to conception.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience pyrosis, dyspepsia, or diarrhea. Have patient report immediately to prescriber myalgia, considerable arthralgia, significant joint edema, urinary retention, oliguria, angina, chills, ecchymosis, hemorrhaging, or significant asthenia (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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