Contact Us    Contact Us     |     Feedback
MOBILE VIEW  | 

GEMFIBROZIL

Export To Excel

Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Gemfibrozil is an antihyperlipidemic agent similar in structure to clofibrate.

Specific Substances

    1) 2,2-Dimethyl-5-(2,5-xylyloxy)valeric acid
    2) 5-(2,5-Dimethylphenoxy)-2,2-dimethylpentanoic acid
    3) CI-719
    4) Molecular Formula: C15-H22-O3
    5) CAS 25812-30-0

Available Forms Sources

    A) FORMS
    1) Gemfibrozil is available in 600 mg tablets (Prod Info LOPID(R) oral tablets, 2014).
    B) USES
    1) Gemfibrozil is an effective antihyperlipidemic agent in types IV and V hyperlipidemia and in type IIb patients without history or symptoms of existing coronary heart disease (Prod Info LOPID(R) oral tablets, 2014).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Gemfibrozil, a lipid regulating agent, is used as an adjunct therapy to lower severely elevated serum triglycerides (Types IV and V hyperlipidemia) and very low density lipoprotein (VLDL) cholesterol while increasing high density lipoprotein (HDL).
    B) PHARMACOLOGY: The exact mechanism of action is unknown. Gemfibrozil is chemically and pharmacologically similar to clofibrate. It appears to inhibit peripheral lipolysis and to decrease the hepatic extraction of free fatty acids, thereby reducing hepatic triglyceride production. It also inhibits synthesis and increases clearance of VLDL carrier apolipoprotein B that leads to a decrease in VLDL production.
    C) EPIDEMIOLOGY: Overdose is uncommon.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: The adverse therapeutic effects profile would indicate possible gastrointestinal irritation, headache and myopathy as acute adverse effects. Renal failure may occur secondary to rhabdomyolysis.
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: Limited data. It is anticipated that adverse events may be an extension of clinical events reported with therapy. A child developed abdominal cramps, abnormal liver enzymes, diarrhea, increased CPK, joint and muscle pain, nausea and vomiting after ingesting up to 9 g of gemfibrozil.
    2) MILD TO MODERATE TOXICITY: Gastrointestinal irritation (ie, abdominal cramps, nausea, vomiting, diarrhea), joint and muscle pain, increased CPK and abnormal liver enzymes have occurred in a limited number of cases.
    3) SEVERE TOXICITY: Liver injury and rhabdomyolysis may develop. Renal failure may occur secondary to rhabdomyolysis.
    0.2.7) NEUROLOGIC
    A) WITH THERAPEUTIC USE
    1) Headaches have occurred repeatedly in some patients, approximately 30 to 90 minutes following administration of gemfibrozil.
    0.2.8) GASTROINTESTINAL
    A) WITH THERAPEUTIC USE
    1) Gastric pain, dry mouth, constipation, anorexia, diarrhea, and flatulence occurred rarely during therapy. Abdominal pain may develop.
    0.2.9) HEPATIC
    A) WITH THERAPEUTIC USE
    1) Patients may be at higher risk for development of cholelithiasis.
    0.2.10) GENITOURINARY
    A) WITH THERAPEUTIC USE
    1) Renal failure and rhabdomyolysis have been reported in patients taking lovastatin and gemfibrozil.
    0.2.15) MUSCULOSKELETAL
    A) WITH THERAPEUTIC USE
    1) Myopathy, including rhabdomyolysis and myalgia, is associated with the therapeutic use of gemfibrozil-lovastatin combination therapy. Exacerbation of polymyositis has also been noted as well as acute compartment syndrome.
    2) Gout has been associated with therapeutic gemfibrozil administration.
    0.2.20) REPRODUCTIVE
    A) Gemfibrozil is classified as FDA Pregnancy Category C by the manufacturer. There are no data available to evaluate the effects of gemfibrozil during pregnancy in humans.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, no data were available to assess the carcinogenic potential of this agent.

Laboratory Monitoring

    A) Monitor liver enzymes and CK after large overdose or in patients with muscle pain. Monitor electrolytes and renal function in patients with significant rhabdomyolysis.
    B) Elevations of SGOT, SGPT, LDH, CPK, and alkaline phosphatase have been reported following gemfibrozil administration, and may be observed with overdose.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Monitor fluid status in patients with significant gastrointestinal loss; treat significant symptoms with IV fluids and antiemetics.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive; limited overdose data. Monitor liver enzymes.
    C) DECONTAMINATION
    1) PREHOSPITAL: In general, gastrointestinal decontamination is not necessary.
    2) HOSPITAL: In general, gastrointestinal decontamination is not necessary. Consider activated charcoal after a very large overdose or if a more toxic coingestant is involved, and the patient is alert and able to maintain their airway or if the airway is protected.
    D) ANTIDOTE
    1) None.
    E) AIRWAY MANAGEMENT
    1) Airway support or management is unlikely to be necessary following a gemfibrozil exposure.
    F) ENHANCED ELIMINATION
    1) Hemodialysis is unlikely to be beneficial because gemfibrozil is highly bound to plasma proteins (99%).
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: An asymptomatic child with an inadvertent exposure (a single dose) can be managed at home with adult supervision. An adult with an inadvertent exposure of an extra dose can be managed at home.
    2) OBSERVATION CRITERIA: All patients with deliberate self-harm ingestions should be evaluated in a healthcare facility and monitored until symptoms resolve.
    3) ADMISSION CRITERIA: Patients who remain symptomatic despite adequate treatment should be admitted.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    H) PHARMACOKINETICS
    1) Gemfibrozil is well absorbed orally with peak serum levels occurring 1 to 2 hours after dosing. Gemfibrozil is highly bound to plasma proteins. Following multiple doses, gemfibrozil has a half-life of 1.5 hours.
    I) DIFFERENTIAL DIAGNOSIS
    1) Preexisting hepatic insufficiency.

Range Of Toxicity

    A) TOXICITY: A minimum toxic dose has not been established. In one study, children up to age 5 years of age tolerated doses up to 1800 mg of gemfibrozil. An overdose of up to 9 g of gemfibrozil in a young child produced no permanent sequelae. Overdoses of up to 18 g of gemfibrozil have been reported in adults with full recovery in all cases.
    B) THERAPEUTIC DOSE: ADULT: 600 mg orally twice daily 30 minutes before the morning and evening meal. PEDIATRIC: The safety and efficacy of gemfibrozil in pediatric patients have not been established.

Clinical Effects

Summary Of Exposure

    A) USES: Gemfibrozil, a lipid regulating agent, is used as an adjunct therapy to lower severely elevated serum triglycerides (Types IV and V hyperlipidemia) and very low density lipoprotein (VLDL) cholesterol while increasing high density lipoprotein (HDL).
    B) PHARMACOLOGY: The exact mechanism of action is unknown. Gemfibrozil is chemically and pharmacologically similar to clofibrate. It appears to inhibit peripheral lipolysis and to decrease the hepatic extraction of free fatty acids, thereby reducing hepatic triglyceride production. It also inhibits synthesis and increases clearance of VLDL carrier apolipoprotein B that leads to a decrease in VLDL production.
    C) EPIDEMIOLOGY: Overdose is uncommon.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: The adverse therapeutic effects profile would indicate possible gastrointestinal irritation, headache and myopathy as acute adverse effects. Renal failure may occur secondary to rhabdomyolysis.
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: Limited data. It is anticipated that adverse events may be an extension of clinical events reported with therapy. A child developed abdominal cramps, abnormal liver enzymes, diarrhea, increased CPK, joint and muscle pain, nausea and vomiting after ingesting up to 9 g of gemfibrozil.
    2) MILD TO MODERATE TOXICITY: Gastrointestinal irritation (ie, abdominal cramps, nausea, vomiting, diarrhea), joint and muscle pain, increased CPK and abnormal liver enzymes have occurred in a limited number of cases.
    3) SEVERE TOXICITY: Liver injury and rhabdomyolysis may develop. Renal failure may occur secondary to rhabdomyolysis.

Neurologic

    3.7.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Headaches have occurred repeatedly in some patients, approximately 30 to 90 minutes following administration of gemfibrozil.
    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A frontotemporal headache occurred repeatedly, approximately 30 to 90 minutes following administration of gemfibrozil in a 46-year-old woman (Arellano et al, 1988).
    b) CASE REPORT: A 49-year-old man developed a pulsatile headache, dry mouth, and blurred vision after 600 mg orally twice daily for 4 weeks. Headache symptoms were observed to occur within 1 hour of ingestion, abated upon withdrawal, and recurred when reinstituted (Alvarez-Sabin et al, 1988).
    2) WITH POISONING/EXPOSURE
    a) CASE SERIES: Between 2000-2005, there were 118 reported cases of gemfibrozil ingestions to the Texas Poison Control Centers. The mean dose ingested was 2407 mg (range: 300 to 18,000 mg). A specific adverse effect was recorded in a total of 9% of cases. Neurologic effects, mainly consisting of headache, accounted for 3% of adverse effects, and were observed most frequently with low dose ingestions. All patients made a full recovery; most being managed at home (Forrester, 2007).

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Gastric pain, dry mouth, constipation, anorexia, diarrhea, and flatulence occurred rarely during therapy. Abdominal pain may develop.
    3.8.2) CLINICAL EFFECTS
    A) DRUG-INDUCED GASTROINTESTINAL DISTURBANCE
    1) WITH THERAPEUTIC USE
    a) Gastric pain, dry mouth, constipation, anorexia, diarrhea, and flatulence occurred rarely during therapy (Kaukola et al, 1981; Konttinen et al, 1979). Abdominal pain occurs in approximately 6% of patients (Prod Info Lopid(R), gemfibrozil, 2001).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 7-year-old child developed abdominal cramps, abnormal liver function tests, diarrhea, increased CPK, joint and muscle pain, nausea and vomiting after ingesting up to 9 g of gemfibrozil (Prod Info LOPID(R) oral tablets, 2009).
    b) CASE SERIES: Between 2000 to 2005, there were 118 reported cases of gemfibrozil ingestions to the Texas Poison Control Centers. The mean dose ingested was 2407 mg (range: 300 to 18,000 mg). A specific adverse effect was recorded in a total of 9% of cases. Gastrointestinal effects (abdominal pain, nausea, vomiting) accounted for 5% of adverse effects, and were observed with high dose ingestions. Most patients were managed at home; all made a full recovery (Forrester, 2007).

Hepatic

    3.9.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Patients may be at higher risk for development of cholelithiasis.
    3.9.2) CLINICAL EFFECTS
    A) BILIARY CALCULUS
    1) WITH THERAPEUTIC USE
    a) Patients may be at higher risk for development of cholelithiasis. If gallstones are found, discontinue gemfibrozil (Prod Info LOPID(R) oral tablets, 2009). There are no case reports in the literature.
    B) LIVER ENZYMES ABNORMAL
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 7-year-old child developed abdominal cramps, abnormal liver enzymes, diarrhea, increased CPK, joint and muscle pain and nausea and vomiting after ingesting up to 9 g of gemfibrozil (Prod Info LOPID(R) oral tablets, 2009).

Genitourinary

    3.10.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Renal failure and rhabdomyolysis have been reported in patients taking lovastatin and gemfibrozil.
    3.10.2) CLINICAL EFFECTS
    A) IMPOTENCE
    1) WITH THERAPEUTIC USE
    a) Cases of impotence have been reported while taking therapeutic amounts. The impotence appears to be reversible upon discontinuation of the drug (Bain et al, 1990; Bharani, 1992; Figueras & Castel, 1993).
    B) ACUTE RENAL FAILURE SYNDROME
    1) WITH THERAPEUTIC USE
    a) Acute renal failure resulting from gemfibrozil and lovastatin induced rhabdomyolysis has been reported in patients following therapeutic dosages (Marais & Larson, 1990; De Alava et al, 1994).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) GENERALIZED PUSTULAR PSORIASIS
    1) WITH THERAPEUTIC USE
    a) Psoriasis may be exacerbated by gemfibrozil (Fisher et al, 1988).

Musculoskeletal

    3.15.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Myopathy, including rhabdomyolysis and myalgia, is associated with the therapeutic use of gemfibrozil-lovastatin combination therapy. Exacerbation of polymyositis has also been noted as well as acute compartment syndrome.
    2) Gout has been associated with therapeutic gemfibrozil administration.
    3.15.2) CLINICAL EFFECTS
    A) TOXIC MYOPATHY
    1) WITH THERAPEUTIC USE
    a) Myopathy, some with rhabdomyolysis, has been associated with the therapeutic use of gemfibrozil (Magarian et al, 1991; London et al, 1991; Jensen, 1991). Exacerbation of polymyositis has also been noted (Fusella & Strosberg, 1990).
    b) Rhabdomyolysis, associated with acute renal failure, has been reported in patients taking gemfibrozil and lovastatin as combination therapy (Marais & Larson, 1990; De Alava et al, 1994).
    c) Rosenson observed that patients receiving combined gemfibrozil-lovastatin therapy developed myalgia (Rosenson, 1993).
    d) CASE REPORT: Myositis occurred in a patient following 6 weeks of gemfibrozil therapy, 600 mg twice daily. As a result of the myositis, an acute compartment syndrome developed (Chow & Chow, 1993).
    B) GOUT
    1) WITH THERAPEUTIC USE
    a) Gout of the acromioclavicular joint was associated with, but not shown to be caused by gemfibrozil administration (Miller-Blair et al, 1992).
    C) PAIN
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 7-year-old child developed abdominal cramps, abnormal liver function tests, diarrhea, increased CPK, joint and muscle pain, and nausea and vomiting after ingesting up to 9 g of gemfibrozil (Prod Info LOPID(R) oral tablets, 2009).
    D) TOXIC MYOPATHY
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 7-year-old child developed abdominal cramps, abnormal liver function tests, diarrhea, increased CPK, joint and muscle pain, and nausea and vomiting after ingesting up to 9 g of gemfibrozil (Prod Info LOPID(R) oral tablets, 2009).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ACUTE ALLERGIC REACTION
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 56-year-old woman developed eosinophilic gastroenteritis (eosinophil count was 1820/mm(3), later increasing to 4850/mm(3); normal, 0 to 440/mm(3)) following the use of gemfibrozil (dose unspecified) for 2 weeks for hyperlipidemia. She experienced watery diarrhea and mild abdominal cramping, which was progressively worsening. Endoscopy showed prominent antral folds, a gastric polyp, and duodenal and jejunal mucosal granularity. Multiple biopsies of the upper and lower GI tract revealed eosinophilic aggregation and infiltration most prominently in the mucosal layers of the stomach antrum, duodenum, ascending colon, transverse colon, and rectum. Gemfibrozil was withdrawn; methylprednisolone (125 mg twice a day) followed by prednisone (40 mg/day) brought gradual resolution of symptoms. The patient was rechallenged twice with gemfibrozil and each time diarrhea and peripheral eosinophilia returned (Lee et al, 2000).

Reproductive

    3.20.1) SUMMARY
    A) Gemfibrozil is classified as FDA Pregnancy Category C by the manufacturer. There are no data available to evaluate the effects of gemfibrozil during pregnancy in humans.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) SKELETAL AND OCULAR ABNORMALITIES
    a) RATS, RABBITS: In rat offspring, increases in skeletal variations were noted with exposures before and during gestation to twice the human dose. Anophthalmia rarely occurred. Rabbits exposed to 3 times the human dose during organogenesis showed more parietal bone variations (Prod Info LOPID(R) oral tablets, 2014).
    b) MICE: No increase in the frequency or mean latency time of tumors was noted (Fitzgerald et al, 1981).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Gemfibrozil is classified as FDA Pregnancy Category C (Prod Info LOPID(R) oral tablets, 2014).
    2) No human studies of pregnancy outcomes after exposure to gemfibrozil have been published, and there have been no reports of outcomes after inadvertent exposure during pregnancy. In animal studies, teratogenicity has occurred following exposures to 2 to 3 times the human dose during gestation. Due to the lack of human safety information, gemfibrozil should be used in pregnant women only if the potential benefit outweighs the potential risk to the fetus (Prod Info LOPID(R) oral tablets, 2014).
    B) ANIMAL STUDIES
    1) RATS, RABBITS: In rat offspring, exposures to twice the human dose before and during gestation were associated with reduced conception and an increase in stillborns, while reduced birth weights were seen with exposures of 0.6 to twice the human dose from gestation day 15 through weaning. In rabbits, decreased litter sizes were noted with exposures to 1 and 3 times the human dose during organogenesis (Prod Info LOPID(R) oral tablets, 2014).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST FEEDING
    1) It is not know whether gemfibrozil is excreted in human breast milk, and the potential for adverse effects in the nursing infant from exposure to the drug are unknown. Animal data have shown adverse effects in nursing offspring with doses 0.6 to 2 times the human exposure during gestation and lactation. Until additional data are available, nursing or gemfibrozil should be discontinued after considering the importance of the drug to the mother (Prod Info LOPID(R) oral tablets, 2014).
    B) ANIMAL STUDIES
    1) RATS: In rat offspring, exposures to twice the human dose before and during gestation were associated with slightly reduced pup weights during lactation. Pup growth was reduced during lactation following exposures of 0.6 and 2 times the human dose from gestation day 15 through weaning (Prod Info LOPID(R) oral tablets, 2014).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) RATS: Doses of approximately 2 times the human dose over 10 weeks led to reduced fertility in male rats. This effect was reversed after about 8 weeks of no exposure, and the fertility of offspring was not reduced (Prod Info LOPID(R) oral tablets, 2014).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, no data were available to assess the carcinogenic potential of this agent.
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the carcinogenic potential of this agent.

Genotoxicity

    A) Mutagenic response was negative in bacterial assays (Fitzgerald et al, 1981).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor liver enzymes and CK after large overdose or in patients with muscle pain. Monitor electrolytes and renal function in patients with significant rhabdomyolysis.
    B) Elevations of SGOT, SGPT, LDH, CPK, and alkaline phosphatase have been reported following gemfibrozil administration, and may be observed with overdose.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Elevations of SGOT, SGPT, LDH, CPK, and alkaline phosphatase have been reported following gemfibrozil administration, and might be seen with overdose. The levels generally return to normal when gemfibrozil is discontinued (Prod Info LOPID(R) oral tablets, 2009).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients who remain symptomatic despite adequate treatment should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) An asymptomatic child with an inadvertent exposure (a single dose) can be managed at home with adult supervision. An adult with an inadvertent exposure of an extra dose can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) All patients with deliberate self-harm ingestions should be evaluated in a healthcare facility and monitored until symptoms resolve.

Monitoring

    A) Monitor liver enzymes and CK after large overdose or in patients with muscle pain. Monitor electrolytes and renal function in patients with significant rhabdomyolysis.
    B) Elevations of SGOT, SGPT, LDH, CPK, and alkaline phosphatase have been reported following gemfibrozil administration, and may be observed with overdose.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital GI decontamination is generally not necessary.
    6.5.2) PREVENTION OF ABSORPTION
    A) GI decontamination is generally not necessary. It should be considered after a very large ingestion or if a more toxic coingestant is involved.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment is symptomatic and supportive. There is no antidote.
    B) MONITORING OF PATIENT
    1) Monitor liver enzymes and renal function tests in cases of myopathy. Monitor electrolytes and renal function in patients with myopathy.
    C) RHABDOMYOLYSIS
    1) SUMMARY: Early aggressive fluid replacement is the mainstay of therapy and may help prevent renal insufficiency. Diuretics such as mannitol or furosemide may be added if necessary to maintain urine output but only after volume status has been restored as hypovolemia will increase renal tubular damage. Urinary alkalinization is NOT routinely recommended.
    2) Initial treatment should be directed towards controlling acute metabolic disturbances such as hyperkalemia, hyperthermia, and hypovolemia. Control seizures, agitation, and muscle contractions (Erdman & Dart, 2004).
    3) FLUID REPLACEMENT: Early and aggressive fluid replacement is the mainstay of therapy to prevent renal failure. Vigorous fluid replacement with 0.9% saline (10 to 15 mL/kg/hour) is necessary even if there is no evidence of dehydration. Several liters of fluid may be needed within the first 24 hours (Walter & Catenacci, 2008; Camp, 2009; Huerta-Alardin et al, 2005; Criddle, 2003; Polderman, 2004). Hypovolemia, increased insensible losses, and third spacing of fluid commonly increase fluid requirements. Strive to maintain a urine output of at least 1 to 2 mL/kg/hour (or greater than 150 to 300 mL/hour) (Walter & Catenacci, 2008; Camp, 2009; Erdman & Dart, 2004; Criddle, 2003). To maintain a urine output this high, 500 to 1000 mL of fluid per hour may be required (Criddle, 2003). Monitor fluid input and urine output, plus insensible losses. Monitor for evidence of fluid overload and compartment syndrome; monitor serum electrolytes, CK, and renal function tests.
    4) DIURETICS: Diuretics (eg, mannitol or furosemide) may be needed to ensure adequate urine output and to prevent acute renal failure when used in combination with aggressive fluid therapy. Loop diuretics increase tubular flow and decrease deposition of myoglobin. These agents should be used only after volume status has been restored, as hypovolemia will increase renal tubular damage. If the patient is maintaining adequate urine output, loop diuretics are not necessary (Vanholder et al, 2000).
    5) URINARY ALKALINIZATION: Alkalinization of the urine is not routinely recommended, as it has never been documented to reduce nephrotoxicity, and may cause complications such as hypocalcemia and hypokalemia (Walter & Catenacci, 2008; Huerta-Alardin et al, 2005; Brown et al, 2004; Polderman, 2004). Retrospective studies have failed to demonstrate any clinical benefit from the use of urinary alkalinization (Brown et al, 2004; Polderman, 2004; Homsi et al, 1997).
    6) MANNITOL/INDICATIONS
    a) Osmotic diuretic used in the management of rhabdomyolysis and myoglobinuria (Zimmerman & Shen, 2013).
    7) RHABDOMYOLYSIS/MYOGLOBINURIA
    a) ADULT: TEST DOSE: (for patients with marked oliguria or those with inadequate renal function) 0.2 g/kg IV as a 15% to 25% solution infused over 3 to 5 minutes to produce a urine flow of at least 30 to 50 mL/hr; a second test dose may be given if urine flow does not increase within 2 to 3 hours. The patient should be reevaluated if there is inadequate response following the second test dose (Prod Info MANNITOL intravenous injection, 2009). TREATMENT DOSE: 50 to 100 g IV as a 15% to 25% solution may be used. The rate should be adjusted to maintain urinary output at 30 to 50 mL/hour (Prod Info mannitol IV injection, urologic irrigation, 2006) OR 300 to 400 mg/kg or up to 100 g IV administered as a single dose (Prod Info MANNITOL intravenous injection, 2009).
    b) PEDIATRIC: Dosing has not been established in patients less than 12 years of age(Prod Info Mannitol intravenous injection, 2009). TEST DOSE (for patients with marked oliguria or those with inadequate renal function): 0.2 g/kg or 6 g/m(2) body surface area IV as a 15% to 25% solution infused over 3 to 5 minutes to produce a urine flow of at least 30 to 50 mL/hr; a second test dose may be given if urine flow does not increase; TREATMENT DOSE: 0.25 to 2 g/kg or 60 g/m(2) body surface area IV as a 15% to 20% solution over 2 to 6 hours; do not repeat dose for persistent oliguria (Prod Info MANNITOL intravenous injection, 2009).
    8) ADVERSE EFFECTS
    a) Fluid and electrolyte imbalance, in particular sodium and potassium; expansion of the extracellular fluid volume leading to pulmonary edema or CHF exacerbations(Prod Info MANNITOL intravenous injection, 2009).
    9) PRECAUTION
    a) Contraindicated in well-established anuria or impaired renal function not responding to a test dose, pulmonary edema, CHF, severe dehydration; caution in progressive oliguria and azotemia; do not add to whole blood for transfusions(Prod Info Mannitol intravenous injection, 2009); enhanced neuromuscular blockade observed with tubocurarine(Miller et al, 1976).
    10) MONITORING PARAMETERS
    a) Renal function, urine output, fluid balance, serum potassium, serum sodium, and serum osmolality (Prod Info Mannitol intravenous injection, 2009).
    D) FLUID/ELECTROLYTE BALANCE REGULATION
    1) Provide suitable replacement should gastrointestinal irritation result in excessive fluid and electrolyte loss due to vomiting and diarrhea.

Enhanced Elimination

    A) SUMMARY
    1) Hemodialysis is unlikely to be beneficial because gemfibrozil is highly bound to plasma proteins (99%) (Prod Info LOPID(R) oral tablets, 2009).

Range Of Toxicity

Summary

    A) TOXICITY: A minimum toxic dose has not been established. In one study, children up to age 5 years of age tolerated doses up to 1800 mg of gemfibrozil. An overdose of up to 9 g of gemfibrozil in a young child produced no permanent sequelae. Overdoses of up to 18 g of gemfibrozil have been reported in adults with full recovery in all cases.
    B) THERAPEUTIC DOSE: ADULT: 600 mg orally twice daily 30 minutes before the morning and evening meal. PEDIATRIC: The safety and efficacy of gemfibrozil in pediatric patients have not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) RECOMMENDED DOSE: 1200 mg daily administered in 2 divided doses 30 minutes before morning and evening meals (Prod Info LOPID(R) oral tablets, 2014).
    7.2.2) PEDIATRIC
    A) The safety and efficacy of gemfibrozil in pediatric patients have not been established (Prod Info LOPID(R) oral tablets, 2014).

Minimum Lethal Exposure

    A) SUMMARY
    1) The minimum lethal human dose for gemfibrozil has not been established.

Maximum Tolerated Exposure

    A) CASE SERIES
    1) Between 2000 to 2005, there were 118 reported cases of gemfibrozil ingestions to the Texas Poison Control Centers. The mean dose ingested was 2407 mg (range: 300 to 18,000 mg). A specific adverse effect was recorded in a total of 9% of cases. All patients made a full recovery; most being managed at home. Doses up to 1800 mg were well tolerated in children up to age 5 years, while doses of up to 18,000 mg (or 30 tablets/capsules) in adults were not associated with serious toxicity (Forrester, 2007).
    B) CASE REPORT
    1) An overdose of up to 9 g of gemfibrozil in a 7-year-old child was reported, with recovery following treatment (Prod Info gemfibrozil oral tablets, 2006).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (ORAL)MOUSE:
    a) 2218 mg/kg (RTECS, 2001)
    2) LD50- (INTRAPERITONEAL)RAT:
    a) 445 mg/kg (RTECS, 2001)
    3) LD50- (ORAL)RAT:
    a) 1414 mg/kg (RTECS, 2001)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Gemfibrozil is postulated to reduce hepatic triglyceride production by inhibiting peripheral lipolysis and decreasing the hepatic extraction of plasma free fatty acids.
    1) The drug may also inhibit synthesis of VLDL carrier apoproteins. The production of LDL from VLDL is thus prevented by the drug (Kaukola et al, 1981).
    2) In animal studies, gemfibrozil has been shown to decrease the incorporation of radiolabeled palmitic acid into triglycerides secreted as VLDL, and to decrease lipolysis in adipose tissue (Rodney et al, 1976).
    3) Sirtori et al (1987), based upon patient studies, suggest that the mode of action is the reduction of secretion of atherogenic lipoproteins, primarily VLDL, as well as stimulating the production of small HDL particles.

References

General Bibliography

    1) Ahmad S: Gemfibrozil interaction with warfarin sodium (Coumadin) (letter). Chest 1990; 98:1041-1042.
    2) Alvarez-Sabin J, Codina A, & Rodriguez C: Gemfibrozil-induced headache. Lancet 1988; 2:1246.
    3) Arellano F, de Cos MA, & Valiente R: Gemfibrozil-induced headache. Lancet 1988; 1:705.
    4) Bain SC, Lemon M, & Jones AF: Gemfibrozil-induced impotence (letter). Lancet 1990; 1389.
    5) Bharani A: Sexual dysfunction after gemfibrozil (letter). Br Med J 1992; 305:693.
    6) Brown CV, Rhee P, Chan L, et al: Preventing renal failure in patients with rhabdomyolysis: do bicarbonate and mannitol make a difference?. J Trauma 2004; 56(6):1191-1196.
    7) Camp NE: Drug- and toxin-induced Rhabdomyolysis. J Emerg Nurs 2009; 35(5):481-482.
    8) Chow LTC & Chow WH: Acute compartment syndrome: an unusual presentation of gemfibrozil induced myositis. Med J Aust 1993; 158:48-49.
    9) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    10) Criddle LM: Rhabdomyolysis. Pathophysiology, recognition, and management. Crit Care Nurse 2003; 23(6):14-22, 24-26, 28.
    11) De Alava E, Sola JJ, & Lozano MD: Rhabdomyolysis and acute renal failure in a heart transplant recipient treated with hypolipemiants (letter). Nephron 1994; 66:242-243.
    12) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    13) Erdman AR & Dart RC: Rhabdomyolysis. In: Dart RC, Caravati EM, McGuigan MA, et al, eds. Medical Toxicology, 3rd ed. Lippincott Williams & Wilkins, Philadelphia, PA, 2004, pp 123-127.
    14) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    15) Figueras A & Castel JM: Gemfibrozil-induced impotence (letter). Ann Pharmacother 1993; 27:982.
    16) Fisher DA, Elias PM, & LeBoit PL: Exacerbation of psoriasis by the hypolipidemic agent, gemfibrozil. Arch Dermatol 1988; 124:854-855.
    17) Fitzgerald JE, Sanyer JL, & Schardein JL: Carcinogenic bioassay and mutagenicity studies with the hypolipidemic agent gemfibrozil. J Nat Canc Instit 1981; 67:1105-1116.
    18) Forland SC, Feng Y, & Cutler RE: Apparent reduced absorption of gemfibrozil when given with colestipol. J Clin Pharmacol 1990; 30:29-32.
    19) Forrester MB: Gemfibrozil ingestions reported to Texas poison control centers, 2000-2005. J Toxicol Environ Health A 2007; 70(24):2027-2032.
    20) Fusella J & Strosberg JM: Polymyositis exacerbated by gemfibrozil (letter). J Rheumatol 1990; 17:572-573.
    21) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    22) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    23) Hamberger C, Barre J, & Zini R: In vitro binding study of gemfibrozil to human serum proteins and erythrocytes: interactions with other drugs. Int J Clin Pharmacol Res 1986; 6:441-449.
    24) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    25) Homsi E, Barreiro MF, Orlando JM, et al: Prophylaxis of acute renal failure in patients with rhabdomyolysis. Ren Fail 1997; 19(2):283-288.
    26) Huerta-Alardin AL, Varon J, & Marik PE: Bench-to-bedside review: Rhabdomyolysis -- an overview for clinicians. Crit Care 2005; 9(2):158-169.
    27) Jensen K: Myopathy during treatment with fibrates and lovastatin. Ugeskrift For Laeger 1991; 153:862.
    28) Kaukola S, Manninen V, & Malkonen M: Gemfibrozil in the treatment of dyslipidaemias in middle-aged male survivors of myocardial infarction. Acta Med Scand 1981; 209:69-73.
    29) Konttinen A, Kuisma I, & Ralli R: The effect of gemfibrozil on serum lipids in diabetic patients. Ann Clin Res 1979; 11:240-245.
    30) Lee JY, Medellin MV, & Tumpkin C: Allergic reaction to gemfibrozil manifesting as eosinophilic gastroenteritis. South Med J 2000; 93(8):807-808.
    31) London SF, Gross KF, & Ringel SP: Cholesterol-lowering agent myopathy (CLAM). Neurology 1991; 41:1159-1160.
    32) Magarian GJ, Lucas LM, & Colley C: Gemfibrozil-induced myopathy. Arch Intern Med 1991; 151(9):1873-1874.
    33) Marais G & Larson K: Rhabdomyolysis and acute renal failure induced by combination lovastatin and gemfibrozil.. Ann Intern Med 1990; 112(3):228-30.
    34) Miller RD, Sohn YJ, & Matteo RS: Enhancement of d-tubocurarine neuromuscular blockade by diuretics in man. Anesthesiology 1976; 45:442-445.
    35) Miller-Blair D, White R, & Greenspan A: Acute gout involving the acromioclavicular joint following treatment with gemfibrozil. J Rheumatol 1992; 19:166-168.
    36) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    37) Okerholm RA, Keeley FJ, & Peterson FE: The metabolism of gemfibrozil. Proc R Soc Med 1976; 69(Suppl 2):11-14.
    38) Pierce LR, Wysowski DK, & Gross TP: Myopathy and rhabdomyolysis associated with lovastatin-gemfibrozil combination therapy. JAMA 1990; 264:71-75.
    39) Pogson GW, Kindred LH, & Carper BG: Rhabdomyolysis and renal failure associated with cerivastatin-gemfibrozil combination therapy. Am J Cardiol 1999; 83:1146.
    40) Polderman KH: Acute renal failure and rhabdomyolysis. Int J Artif Organs 2004; 27(12):1030-1033.
    41) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    42) Product Information: LOPID(R) oral tablets, gemfibrozil oral tablets. Parke-Davis (per FDA), New York, NY, 2014.
    43) Product Information: LOPID(R) oral tablets, gemfibrozil oral tablets. Parke-Davis, New York, NY, 2009.
    44) Product Information: Lopid(R), gemfibrozil. Parke-Davis Co, Morris Plains, NJ, 2001.
    45) Product Information: MANNITOL intravenous injection, mannitol intravenous injection. Hospira, Inc. (per DailyMed), Lake Forest, IL, 2009.
    46) Product Information: MEVACOR(R) tablets, lovastatin tablets. Merck, Whitehouse Station, NJ, 2005.
    47) Product Information: Mannitol intravenous injection, mannitol intravenous injection. American Regent, Inc. (per DailyMed), Shirley, NY, 2009.
    48) Product Information: gemfibrozil oral tablets, gemfibrozil oral tablets. Zydus Pharmaceuticals USA,Inc, Princeton, NJ, 2006.
    49) Product Information: mannitol IV injection, urologic irrigation, mannitol IV injection, urologic irrigation. Abraxis Pharmaceutical Products, Schaumburg, IL, 2006.
    50) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    51) Rodney G, Uhlendorf P, & Maxwell RE: The hypolipidemic effect of gemfibrozil (CI-719) in laboratory animals. Proc R Soc Med 1976; 69(Suppl 2):6-10.
    52) Rosenson RS: Gemfibrozil-lovastatin-associated myalgia (letter). Am J Cardiol 1993; 71:497.
    53) Tal A, Rajeshawari M, & Isley W: Rhabdomyolysis associated with simvastatin-gemfibrozil therapy. South Med J 1997; 90:546-547.
    54) Vanholder R, Sever MS, Erek E, et al: Rhabdomyolysis. J Am Soc Nephrol 2000; 11(8):1553-1561.
    55) Walter LA & Catenacci MH: Rhabdomyolysis. Hosp Physician 2008; 44(1):25-31.
    56) Zimmerman JL & Shen MC: Rhabdomyolysis. Chest 2013; 144(3):1058-1065.