Use:

Treatment of hypertriglyceridemia in types IV and V

hyperlipidemia for patients who are at greater risk for
pancreatitis and who have not responded to dietary intervention

Pregnancy Risk Factor:

Lactation:

Excretion in breast milk unknown/contraindicated

Contraindications:

Hypersensitivity to gemfibrozil or any component of the

formulation; significant hepatic or renal dysfunction; primary
biliary cirrhosis; pre-existing gallbladder disease

Warnings/Precautions:

Possible increased risk of malignancy and cholelithiasis. No

evidence of cardiovascular mortality benefit. Anemia and
leukopenia have been reported. Elevations in serum
transaminases can be seen. Discontinue if lipid response not
seen. Be careful in patient selection; this is not a first- or second-
line choice. Other agents may be more suitable. Adjustments in
warfarin therapy may be required with concurrent use. Use
caution when combining gemfibrozil with HMG-CoA reductase
inhibitors (may lead to myopathy, rhabdomyolysis). Renal
function deterioration has been seen when used in patients with
a serum creatinine >2.0 mg/dL. Safety and efficacy in pediatric
patients have not been established.

Adverse Reactions:

>10% Gastrointestinal: Dyspepsia (20%)

1% to 10%:

Central nervous system: Fatigue (4%), vertigo (2%), headache (1%)

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

Gastrointestinal: Abdominal pain (10%), diarrhea (7%),

nausea/vomiting (3%), constipation (1%)

<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, cataracts, cholelithiasis, cholecystitis, cholestatic
jaundice, creatine phosphokinase increased, depression, dermatitis,
dermatomyositis/polymyositis, dizziness, eosinophilia, exfoliative
dermatitis, headache, hypoesthesia, hypokalemia, impotence,
intracranial hemorrhage, laryngeal edema, leukopenia, libido
decreased, myalgia, myasthenia, myopathy, nephrotoxicity,
paresthesia, peripheral neuritis, peripheral vascular disease, pruritus,
rash, Raynaud's phenomenon, rhabdomyolysis, somnolence, synovitis,
taste perversion, transaminases increased, urticaria, vasculitis

Reports where causal relationship has not been established: Weight

loss, extrasystoles, pancreatitis, hepatoma, colitis, confusion, seizure,
syncope, retinal edema, decreased fertility (male), renal dysfunction,
positive ANA, drug-induced lupus-like syndrome, thrombocytopenia,
anaphylaxis, vasculitis, alopecia, photosensitivity
Overdosage/Toxicology:

Symptoms of overdose include abdominal pain, diarrhea, nausea,

and vomiting. Treatment is supportive.

Drug Interactions:

Substrate of CYP3A4 (minor); Inhibits CYP1A2 (moderate),

2C8/9 (strong), 2C19 (strong)
Bexarotene's serum concentration is significantly increased; avoid
concurrent use.
Chlorpropamide: May increase risk of hypoglycemia.
Cyclosporine's blood levels may be reduced; monitor cyclosporine
levels and renal function.
CYP1A2 substrates: Gemfibrozil may increase the levels/effects of
CYP1A2 substrates. Example substrates include aminophylline,
fluvoxamine, mexiletine, mirtazapine, ropinirole, theophylline, and
trifluoperazine.
CYP2C8/9 substrates: Gemfibrozil may increase the levels/effects of
CYP2C8/9 substrates. Example substrates include amiodarone,
fluoxetine, glimepiride, glipizide, nateglinide, phenytoin, pioglitazone,
rosiglitazone, sertraline, and warfarin.
CYP2C19 substrates: Gemfibrozil may increase the levels/effects of
CYP2C19 substrates. Example substrates include citalopram,
diazepam, methsuximide, phenytoin, propranolol, and sertraline.
Furosemide: Increased blood levels of both in hypoalbuminemia.
Glyburide (and possibly other sulfonylureas): The hypoglycemic effects
may be increased.
HMG-CoA reductase inhibitors (atorvastatin, fluvastatin, lovastatin,
pravastatin, simvastatin) may increase the risk of myopathy and
rhabdomyolysis. The manufacturer warns against the concurrent use
of lovastatin (if unavoidable, limit lovastatin to <20 mg/day).
Combination therapy with statins has been used in some patients with
resistant hyperlipidemias (with great caution).
Repaglinide: Gemfibrozil may increase the serum concentration of
repaglinide (prolonged, severe hypoglycemia has been reported). The
addition of itraconazole may augment the effects of gemfibrozil on
repaglinide. Consider alternative therapy.
Rifampin: Decreased gemfibrozil blood levels.
Warfarin: Hypoprothrombinemic response increased; monitor INRs
closely when gemfibrozil is initiated or discontinued.
Ethanol/Nutrition/Herb Interactions:

Ethanol: Avoid ethanol to decrease triglycerides.

Mechanism of Action:

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

Pharmacodynamics/Kinetics:

Onset of action: May require several days

Absorption: Well absorbed

Protein binding: 99%

Metabolism: Hepatic via oxidation to two inactive metabolites;
undergoes enterohepatic recycling

Half-life elimination: 1.4 hours

Time to peak, serum: 1-2 hours

Excretion: Urine (70% primarily as unchanged drug)

Dosage:

Adults: Oral: 1200 mg/day in 2 divided doses, 30 minutes before

breakfast and dinner
Hemodialysis: Not removed by hemodialysis; supplemental dose is not
necessary
Monitoring Parameters:

Serum cholesterol, LFTs

Dietary Considerations:

Before initiation of therapy, patients should be placed on a

standard cholesterol-lowering diet for 3-6 months and the diet
should be continued during drug therapy.

Patient Education:

Inform prescriber of all prescriptions, OTC medications, or herbal

products you are taking, and any allergies you have. Do not take
any new medication during therapy unless approved by
prescriber. Should be taken 30 minutes before meals. Take with
milk or meals if GI upset occurs. Avoid alcohol. Follow dietary
recommendations of prescriber. You will need check-ups and
blood work to assess effectiveness of therapy. You may
experience loss of appetite and flatulence (small, frequent meals
may help); or diarrhea (buttermilk, boiled milk, or yogurt may
help). Report severe stomach pain, nausea, vomiting; headache;
persistent diarrhea; or vision changes. Pregnancy/breast-
feeding precautions: Inform prescriber if you are or intend to
become pregnant. Do not breast-feed.

Anesthesia and Critical Care Concerns/Other Considerations:

Gemfibrozil increases HDL, decreases total cholesterol and

triglycerides. A recent study (HIT), showed that gemfibrozil
therapy resulted in a significant reduction in the risk of major
cardiovascular events in patients with low HDL-cholesterol. These
findings suggest that the rate of coronary events is reduced by
raising HDL-cholesterol levels and lowering triglyceride levels.
The treatment of low HDL in the general population, is not
established.

Cardiovascular Considerations:

Fibric acids decrease triglycerides (TGs) by 20% to 50%, and

increase HDL-cholesterol (HDL-C) by 10% to 35%. They
decrease LDL-cholesterol (LDL-C) by 5% to 20%, however, LDL-
C actually may increase by 10% to 30% when fibrates are
initiated in patients with high TGs (>400 mg/dL).
A recent study (VA-HIT) showed that gemfibrozil therapy resulted in a
significant reduction in the risk of major cardiovascular events in
patients with CHD and isolated low HDL-C 40 mg/dL (average: 32
mg/dL) with LDL-C 140 mg/dL (average: 111 mg/dL) and TGs 300
mg/dL (average: 161 mg/dL) (Rubins, 1999). These findings suggest
that the rate of coronary events is reduced by raising HDL-cholesterol
levels in patients with isolated low HDL-C levels. The treatment of
isolated low HDL-C in the general population is usually reserved for
patients at high risk for developing CAD with therapy focused on
addressing the other risk factors. At present, minimal if any, data are
available on how to use medications in patients with low HDL-C and no
risk factors.
Dental Health: Effects on Dental Treatment:

No significant effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions:

No information available to require special precautions

Mental Health: Effects on Mental Status:

May rarely cause sedation or depression

Mental Health: Effects on Psychiatric Treatment:

None reported
Dosage Forms:

Tablet [film coated]: 600 mg