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FENOFIBRATE AND RELATED AGENTS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Fibric acid derivatives, including clofibrate, fenofibrate, bezafibrate, and simfibrate, are antilipidemic agents which decrease serum lipids by reducing the very-low-density lipoprotein fraction (Sf 20 to 400) rich in triglycerides.

Specific Substances

    A) BEZAFIBRATE
    1) BM-15075
    2) LO-44
    3) 2-[4-(2-p-Chlorobenzamidoethyl)phenoxy]-2-
    4) methylpropionic acid
    5) CAS 41859-67-0
    CLOFIBRATE
    1) AY-61123
    2) Clofibratum
    3) Ethyl p-Chlorophenoxyisobutyrate
    4) Ethyl Clofibrate
    5) ICI-28257
    6) NSC-79389
    7) Ethyl 2-(4-chlorophenoxy)-2-methylpropionate
    8) CAS 637-07-0 (clofibrate)
    9) CAS 882-09-7 (clofibric acid)
    CIPROFIBRATE
    1) Ciprofibrato
    2) Ciprofibratum
    3) Win-35833
    4) Molecular Formula: C(13)H(14)Cl(2)O(3)
    5) CAS 52214-84-3
    FENOFIBRATE
    1) LF-178
    2) Procetofene
    3) Isopropyl 2-[4-(4-chlorobenzoyl)phenoxy]-2-
    4) methylpropionate
    5) CAS 49562-28-9
    SIMFIBRATE
    1) CLY-503
    2) Diclofibrate
    3) Trimethylene bis[2-(4-chlorophenoxy)-2-
    4) methylpropionate]
    5) CAS 14929-11-4

Available Forms Sources

    A) FORMS
    1) FENOFIBRATE
    a) Fenofibrate is available as 40 mg, 48 mg, 54 mg, 120 mg, 145 mg, and 160 mg oral tablets, and 50 mg and 150 mg oral capsules (Prod Info TRIGLIDE oral tablets, 2015; Prod Info TRICOR(R) oral tablets, 2014; Prod Info LIPOFEN(R) oral capsules, 2013; Prod Info TRICOR(R) oral tablets, 2013; Prod Info Fenoglide(R) oral tablets, 2012).
    2) FENOFIBRIC ACID
    a) Fenofibric acid is available as 35 mg and 105 mg oral tablets, and 45 mg and 135 mg delayed-release oral capsules (Prod Info TRILIPIX oral delayed-release capsules, 2015; Prod Info FIBRICOR(R) oral tablets, 2014).
    3) MICRONIZED FENOFIBRATE
    a) Micronized fenofibrate is available as 30 mg, 43 mg, 67 mg, 90 mg, 130 mg, 134 mg, and 200 mg oral capsules (Prod Info ANTARA(R) oral capsules, 2013; Prod Info ANTARA(R) oral capsules, 2012; Prod Info fenofibrate oral capsules, micronized, 2005).
    B) USES
    1) Fenofibrate is indicated in conjunction with diet for patients with primary hypercholesterolemia, mixed dyslipidemia, or severe hypertriglyceridemia (Fredrickson types IV and V) (Prod Info TRIGLIDE oral tablets, 2015; Prod Info LIPOFEN(R) oral capsules, 2013; Prod Info ANTARA(R) oral capsules, 2013).
    2) Fenofibric acid is used in the treatment of severe hypertriglyceridemia and for the reduction of elevated LDL-C, total cholesterol, triglycerides, and increases HDL-C in patients with primary hypercholesterolemia or mixed dyslipidemia (Prod Info TRILIPIX oral delayed-release capsules, 2015; Prod Info FIBRICOR(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: Fibrates are indicated to reduce elevated levels of LDL-C, Total-C, TG, and Apo B, and to increase HDL-C in patients with primary or mixed dyslipidemia.
    B) PHARMACOLOGY: Fibrates activate peroxisome proliferator activated receptor alfa (PPARa), leading to elimination of triglyceride-rich particles, transformation and increased elimination of small, dense LDL particles, and synthesis of apolipoproteins AI, AII, and HDL-C.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: COMMON: Headache, back pain, nasopharyngitis, nausea, myalgia, diarrhea, and upper respiratory tract infection. Increases of serum transaminase levels greater than 3 times the upper limit of normal were reported following fenofibrate therapy.
    2) LESS COMMON: Fatigue, increased ALT, and muscle spasms.
    E) WITH POISONING/EXPOSURE
    1) TOXICITY: The extent of symptoms in human overdose is unknown.
    0.2.4) HEENT
    A) WITH THERAPEUTIC USE
    1) Photophobia is possible.
    0.2.5) CARDIOVASCULAR
    A) WITH THERAPEUTIC USE
    1) Peripheral vascular disease, pulmonary embolism, thrombophlebitis, angina pectoris, cardiac dysrhythmias, cardiomegaly, and intermittent claudication.
    0.2.7) NEUROLOGIC
    A) WITH THERAPEUTIC USE
    1) Fatigue, weakness, drowsiness, dizziness, and headache have been reported during fibrate therapy.
    0.2.8) GASTROINTESTINAL
    A) WITH THERAPEUTIC USE
    1) Nausea, vomiting, constipation, dyspepsia, diarrhea, and flatulence occur transiently in approximately 10% of patients. Epigastric pain has been reported as a frequent side effect and cholelithiasis is increased.
    0.2.9) HEPATIC
    A) WITH THERAPEUTIC USE
    1) Hepatomegaly, jaundice, hepatitis, and transient increases in serum transaminase levels have been reported.
    0.2.10) GENITOURINARY
    A) WITH THERAPEUTIC USE
    1) Impotence and decreased libido have been reported.
    2) Renal effects of clofibrate have included dysuria, hematuria, proteinuria, and oliguria.
    0.2.14) DERMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Various rashes and alopecia have been reported.
    0.2.15) MUSCULOSKELETAL
    A) WITH THERAPEUTIC USE
    1) Muscular syndrome may be dose-dependent; the most frequent effect is myalgia, with the most commonly affected muscles being those of the lower extremities. Arthralgia and flulike symptoms have also been reported.
    0.2.20) REPRODUCTIVE
    A) Clofibrate, fenofibrate, and fenofibric acid are classified as FDA Pregnancy Category C. It is not known whether fenofibrate is excreted in human breast milk; however, the potential for tumorigenicity has been demonstrated in animal studies. The use of fenofibric acid in nursing mothers is contraindicated. Fertility studies in rats did not show adverse effects in males or females.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, no human data were available to assess the potential carcinogenic activity of choline fenofibrate, fenofibrate, or fenofibric acid.

Laboratory Monitoring

    A) Patients should be observed for CNS depression. Monitor liver enzyme concentrations, urinalysis, and renal function tests in patients with significant overdose. Monitor CK in patients with muscle pain or tenderness.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Observe clinical status and vital signs in substantial ingestions.
    C) DECONTAMINATION
    1) PREHOSPITAL: Serious toxicity is not expected after ingestion of roflumilast alone, and prehospital gastrointestinal decontamination is not routinely required.
    2) HOSPITAL: Significant toxicity is not expected after overdose; gastrointestinal decontamination is generally not necessary. Activated charcoal should be considered after extremely large ingestions or if more toxic coingestants are involved.
    3) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    D) ANTIDOTE
    1) None.
    E) ENHANCED ELIMINATION PROCEDURE
    1) Hemodialysis is UNLIKELY to be of value because of the high degree of protein binding and large volume of distribution.
    F) PATIENT DISPOSITION
    1) HOME CRITERIA: Patients with a minor unintentional exposure who are asymptomatic or have mild symptoms can likely be managed at home.
    2) OBSERVATION CRITERIA: Patients with an inadvertent overdose who have more than mild symptoms and patients with deliberate self-harm ingestions should be sent to a health care facility for evaluation and treated until symptoms resolve.
    3) ADMISSION CRITERIA: Patients who remain symptomatic despite adequate treatment should be admitted.
    4) CONSULT CRITERIA: Consult a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    G) PITFALLS
    1) Failure to recognize the possible involvement of coingestants.
    H) PHARMACOKINETICS
    1) FENOFIBRATE: Well absorbed from the gastrointestinal tract with peak plasma levels occurring 6 to 8 hours after administration. Absorption is increased by approximately 35% after meals as compared to fasting conditions; Protein binding is approximately 99%; Rapidly hydrolyzed by esterases to the active metabolite, fenofibric acid. Mainly excreted in the urine as metabolites, fenofibric acid and fenofibric acid glucuronide. The elimination half-life of fenofibrate is 20 hours.
    2) FENOFIBRIC ACID: Well absorbed from the gastrointestinal tract with peak plasma levels occur approximately 4 to 5 hours after administration in the fasted state; Steady state is reached within 8 days; concentrations at steady state are approximately double those following a single dose.
    I) DIFFERENTIAL DIAGNOSIS
    1) Includes other medications or conditions that can cause elevated liver enzymes (ie, statins).

Range Of Toxicity

    A) TOXICITY: A specific toxic dose has not been established.
    B) THERAPEUTIC DOSE: FENOFIBRATE: The recommended dose of fenofibrate is 48 to 145 mg orally once daily; MAX dose 145 mg. FENOFIBRIC ACID: The recommended dose of fenofibric acid is 45 to 135 mg orally once daily; MAX dose 135 mg. CLOFIBRATE: 2 grams daily in divided doses.

Clinical Effects

Summary Of Exposure

    A) USES: Fibrates are indicated to reduce elevated levels of LDL-C, Total-C, TG, and Apo B, and to increase HDL-C in patients with primary or mixed dyslipidemia.
    B) PHARMACOLOGY: Fibrates activate peroxisome proliferator activated receptor alfa (PPARa), leading to elimination of triglyceride-rich particles, transformation and increased elimination of small, dense LDL particles, and synthesis of apolipoproteins AI, AII, and HDL-C.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: COMMON: Headache, back pain, nasopharyngitis, nausea, myalgia, diarrhea, and upper respiratory tract infection. Increases of serum transaminase levels greater than 3 times the upper limit of normal were reported following fenofibrate therapy.
    2) LESS COMMON: Fatigue, increased ALT, and muscle spasms.
    E) WITH POISONING/EXPOSURE
    1) TOXICITY: The extent of symptoms in human overdose is unknown.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) CASE REPORT: Howard & Brown (1973) reported a patient who received 2 g/day clofibrate for 2 years and developed daily fevers to 38.3 degrees C. The clofibrate was discontinued and within 2 weeks the fever subsided (Howard & Brown, 1973).

Heent

    3.4.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Photophobia is possible.
    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) PHOTOPHOBIA was reported following clofibrate 2 g/day for 2 years (Howard & Brown, 1973).

Cardiovascular

    3.5.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Peripheral vascular disease, pulmonary embolism, thrombophlebitis, angina pectoris, cardiac dysrhythmias, cardiomegaly, and intermittent claudication.
    3.5.2) CLINICAL EFFECTS
    A) CARDIOVASCULAR FINDING
    1) WITH THERAPEUTIC USE
    a) If clofibrate is given to patients who have had a myocardial infarction, a significant increase in cardiovascular toxicity may occur.
    b) Clofibrate therapy was associated with peripheral vascular disease, pulmonary embolism, thrombophlebitis, angina pectoris, cardiac dysrhythmias, cardiomegaly, and intermittent claudication in a large series of patients (Coronary Drug Project Research Group, 1975). These complications were not observed in a large WHO study (WHO Cooperative Trial Report, 1978).
    B) CONDUCTION DISORDER OF THE HEART
    1) WITH THERAPEUTIC USE
    a) Cardiac dysrhythmias have been reported during clofibrate therapy (Coronary Drug Project Research Group, 1975).
    b) CASE REPORT: Larosa et al (1972) reported a patient on clofibrate who developed increased ventricular irritability and sensitivity to antiarrhythmic drugs (LaRosa, 1972).
    c) CASE REPORT: Chung (1975) described a 63-year-old man treated with clofibrate who previously had asymptomatic cardiac rhythm problems, who demonstrated sinus rhythm with frequent atrial and premature ventricular contractions and paroxysmal atrial tachycardia. Clofibrate was discontinued and the condition disappeared (Chung, 1975).
    C) THROMBOPHLEBITIS
    1) WITH THERAPEUTIC USE
    a) An increase in thrombophlebitis and pulmonary emboli have been reported with clofibrate therapy (Prod Info Atromid-S(R), clofibrate, 2000). Swelling and phlebitis at the site of xanthomas may occur (Prod Info Atromid-S(R), clofibrate, 2000).
    D) CARDIOMYOPATHY
    1) WITH THERAPEUTIC USE
    a) Myocardial damage and disseminated intravascular coagulation were reported in one patient with renal failure taking therapeutic amounts (Scionti et al, 1984).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) ALLERGIC PNEUMONIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: An isolated case of eosinophilic pneumonia has been reported in a 73-year-old man treated therapeutically with clofibrate for 18 months (Hendrickson & Simpson, 1982).
    B) UPPER RESPIRATORY INFECTION
    1) WITH THERAPEUTIC USE
    a) Upper respiratory infections, including sinusitis and nasopharyngitis, were rare adverse effects (incidence less than 3%) with fibric acid therapy (Prod Info Trilipix delayed release oral capsules, 2011).

Neurologic

    3.7.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Fatigue, weakness, drowsiness, dizziness, and headache have been reported during fibrate therapy.
    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) Fatigue, weakness, drowsiness, dizziness and headache have been reported during therapy with clofibrate, fenofibrate, and fibric acid (Prod Info Trilipix delayed release oral capsules, 2011; Prod Info Atromid-S(R), clofibrate, 2000; Krasno & Kidera, 1972; Greenhouse, 1968) .

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Nausea, vomiting, constipation, dyspepsia, diarrhea, and flatulence occur transiently in approximately 10% of patients. Epigastric pain has been reported as a frequent side effect and cholelithiasis is increased.
    3.8.2) CLINICAL EFFECTS
    A) GASTROENTERITIS
    1) WITH THERAPEUTIC USE
    a) Nausea, vomiting, constipation, dyspepsia, diarrhea, and flatulence are common adverse effects (Prod Info Trilipix delayed release oral capsules, 2011) that occur transiently in approximately 10% of patients (von Lowis & Klemens, 1973) Dewar, 1971c.
    B) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) Epigastric pain has been reported as a frequent side effect (Summerfield et al, 1975) Dewar, 1971;(Gietz, 1967).
    C) BILIARY CALCULUS
    1) WITH THERAPEUTIC USE
    a) Cholelithiasis is increased approximately 2-fold compared with nonusers (Bateson et al, 1978; WHO Cooperative Trial Report, 1978; Cooper et al, 1975).

Hepatic

    3.9.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Hepatomegaly, jaundice, hepatitis, and transient increases in serum transaminase levels have been reported.
    3.9.2) CLINICAL EFFECTS
    A) ABNORMAL LIVER FUNCTION
    1) WITH THERAPEUTIC USE
    a) CLOFIBRATE: Hepatomegaly, jaundice, and transient increases in serum transaminase levels have been reported (Prod Info Atromid-S(R), clofibrate, 2000; Keller et al, 1990). Hepatitis has also been reported (Migneco et al, 1986).
    b) FENOFIBRATE: The incidence of ALT or AST elevations greater than or equal to 3 times the upper limit of normal were reported in approximately 13% of patients receiving doses equivalent to 90 mg and 135 mg(Prod Info Trilipix delayed release oral capsules, 2011).

Genitourinary

    3.10.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Impotence and decreased libido have been reported.
    2) Renal effects of clofibrate have included dysuria, hematuria, proteinuria, and oliguria.
    3.10.2) CLINICAL EFFECTS
    A) IMPOTENCE
    1) WITH THERAPEUTIC USE
    a) Three cases of impotence were reported. They were treated with 1.5 g/day for 3 to 12 months (Schneider & Kaffarnik, 1975).
    b) DECREASED LIBIDO has been reported to occur during therapy (Krasno & Kidera, 1972) (Coronary Drug Project Research Group, 1975).
    B) TOXIC NEPHROPATHY
    1) WITH THERAPEUTIC USE
    a) Renal effects of clofibrate have included dysuria, hematuria, proteinuria, and oliguria (Prod Info Atromid-S(R), clofibrate, 2000).
    b) Pokroy (1977) reported increased renal impairment in a patient receiving 500 mg/day for 2 months. Renal function continued to deteriorate after clofibrate was discontinued (Pokroy et al, 1977).
    c) Bridgman et al (1972) reported increased diuresis (Bridgman et al, 1972).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) Leukopenia has occurred rarely (Prod Info Atromid-S(R), clofibrate, 2000) . Only 1 of 354 patients receiving clofibrate chronically experienced leukopenia (Hood, 1968).
    B) EOSINOPHIL COUNT RAISED
    1) WITH THERAPEUTIC USE
    a) Eosinophilia was found in only 1 of 63 patients (1.6 g/day clofibrate for 1 year) (Harrold et al, 1969).

Dermatologic

    3.14.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Various rashes and alopecia have been reported.
    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Arif & Vahrman (1975) report a case of a 54-year-old man treated with 1 g twice daily who after 8 days developed a total body rash, periorbital and facial edema, and erythema. The rash gradually disappeared over 6 days (Arif & Vahrman, 1975).
    B) ALOPECIA
    1) WITH THERAPEUTIC USE
    a) Alopecia has been reported as an adverse effect (Dewar, 1971b).
    C) ERYTHEMA MULTIFORME
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Rare erythema multiforme described in a 72-year-old woman following approximately 1 year of therapy (750 mg daily) for hyperlipidemia (Murata et al, 1988).

Musculoskeletal

    3.15.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Muscular syndrome may be dose-dependent; the most frequent effect is myalgia, with the most commonly affected muscles being those of the lower extremities. Arthralgia and flulike symptoms have also been reported.
    3.15.2) CLINICAL EFFECTS
    A) DRUG-INDUCED MYOPATHY
    1) WITH THERAPEUTIC USE
    a) Arthralgia, back pain, muscle spams, myalgia, and pain in extremities were reported in less than 10% of patients taking fibric acid (Prod Info Trilipix delayed release oral capsules, 2011).
    1) It is postulated that the toxic effect of clofibrate on muscle tissue is dose-dependent and not an idiosyncratic or hypersensitivity reaction.
    2) In most patients, the onset of the muscular syndrome occurs within the first 3 weeks of therapy with renal failure patients demonstrating an earlier onset.
    3) The most frequent symptom is myalgia, with the most commonly affected muscles being those of the lower extremities. Increases in CPK activity occur in 94% of patients, with increases in ALT occurring in 77%; EMG abnormalities were observed in 3 of 8 reported cases.
    b) CASE REPORT: Rimon et al (1984) described a clofibrate-induced muscular syndrome in a 70-year-old taking 2 g orally daily for 6 days. Degenerative changes consisted of irregularities and disruption of the Z-band material and numerous dilated vacuoles of various sizes. Activities of AST, CPK, LDH, and aldolase decreased gradually, normalizing 3 weeks after withdrawal of the drug (Rimon et al, 1984).
    B) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) Arthralgias have occurred rarely during treatment. Flulike symptoms have been described (muscular aching, soreness, cramping) (Prod Info Atromid-S(R), clofibrate, 2000; Prod Info Trilipix delayed release oral capsules, 2011).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) ADRENAL CORTICAL HYPOFUNCTION
    1) WITH THERAPEUTIC USE
    a) Heshmati et al (1989) reported clofibrate had little effect on adrenal steroid secretion in 6 hyperlipidemic males receiving chronic therapy with 2 g/day orally (Heshmati et al, 1989).
    b) Mastroberardino et al (1989) reported a reduced response of plasma cortisol to ACTH stimulation in 16 patients with familial heterozygous hypercholesterolemia receiving clofibrate 1500 mg/day during a 30-day period (Mastroberardino et al, 1989).

Reproductive

    3.20.1) SUMMARY
    A) Clofibrate, fenofibrate, and fenofibric acid are classified as FDA Pregnancy Category C. It is not known whether fenofibrate is excreted in human breast milk; however, the potential for tumorigenicity has been demonstrated in animal studies. The use of fenofibric acid in nursing mothers is contraindicated. Fertility studies in rats did not show adverse effects in males or females.
    3.20.2) TERATOGENICITY
    A) LACK OF EFFECT
    1) FENOFIBRATE
    a) A 30-year-old woman with hypertriglyceridemia who was treated with fenofibrate 267 mg/day (3.6 mg/kg/day) for 1 year, including the first 8 weeks of pregnancy, delivered a healthy baby with no complications. Fetal development was normal throughout the pregnancy. Because there was evidence of fetal distress at 36 weeks, the baby was delivered via cesarean section and was healthy with no signs of congenital abnormalities. A 1-year exam showed the infant was still healthy with normal development (Sunman et al, 2012).
    B) ANIMAL STUDIES
    1) CLOFIBRATE
    a) In a rat study, clofibrate reduced the viability and the birth weight of fetuses which showed weight loss. Survival of newborn rabbits tested also was reduced (Sanfeliu et al, 1981).
    2) FENOFIBRATE
    a) An increase in gross, visceral, and skeletal findings (dome head, hunched shoulders, rounded body, abnormal chest, kyphosis, stunted fetuses, elongated sternal ribs, malformed sternebrae, extra foramen in platine, misshapen vertebrae and supernumerary ribs) were noted in female rats treated with fenofibrate approximately 10 times the maximum recommended human dose (MRHD) on days 6 through 15 of gestation (Prod Info LIPOFEN(R) oral capsules, 2010; Prod Info TRIGLIDE(R) oral tablets, 2007).
    b) LACK OF EFFECT - Adverse findings were not demonstrated in pregnant rats treated with 14 mg/kg/day (less than 1 times the MRHD) from gestation day 6 through 15 during organogenesis. No developmental findings were reported when pregnant rabbits were treated with oral gavage doses of 15 mg/kg/day (less than 1 times the MRHD) from gestation day 6 through 18 during the period of organogenesis (Prod Info TRILIPIX(R) delayed release oral capsules, 2008; Prod Info TRICOR(R) oral tablets, 2007). Teratogenicity and mutagenicity tests in animals have been negative with regard to non-micronized fenofibrate (Roberts, 1989).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) CLOFIBRATE
    a) Clofibrate is classified as FDA pregnancy category C (Briggs et al, 1998)
    2) FENOFIBRATE
    a) The manufacturer has classified fenofibrate as FDA pregnancy category C (Prod Info TRICOR oral tablets, 2011; Prod Info Fenoglide(R) oral tablets, 2011; Prod Info LIPOFEN(R) oral capsules, 2010)
    3) FENOFIBRIC ACID
    a) The manufacturer has classified fenofibric acid as FDA pregnancy category C (Prod Info FIBRICOR(R) oral tablets, 2012; Prod Info TRILIPIX(R) delayed release oral capsules, 2008)
    B) LACK OF EFFECT
    1) FENOFIBRATE
    a) A 30-year-old woman with hypertriglyceridemia who was treated with fenofibrate 267 mg/day (3.6 mg/kg/day) for 1 year, including the first 8 weeks of pregnancy, delivered a healthy baby with no complications. Fetal development was normal throughout the pregnancy. Because there was evidence of fetal distress at 36 weeks, the baby was delivered via cesarean section and was healthy with no signs of congenital abnormalities. A 1-year exam showed the infant was still healthy with normal development (Sunman et al, 2012).
    C) ANIMAL STUDIES
    1) FENOFIBRATE
    a) In animal studies, delayed deliveries (100%), increase in post-implantation loss (60%), decreased litter size, reduced birth weight, decreased offspring survival rate at birth (40%), decreased neonate survival rate (4%), and an increase in spina bifida were reported in female rats treated with fenofibrate 9 times the MRHD before and during gestation. Delayed delivery, decrease in live births (40%), decrease in neonatal survival (75%) and reduced pup birth weight where reported in female rats treated with fenofibrate approximately 7 times the MRHD from day 15 of gestation through weaning, as well as days 4 and 21 postpartum. Pregnant rabbits treated with fenofibrate at 9 to 18 times the MRHD resulted in abortion in 10% to 25% of rabbits and death in 7% of fetuses at 18 times MRHD (Prod Info LIPOFEN(R) oral capsules, 2010; Prod Info TRIGLIDE(R) oral tablets, 2007).
    b) MATERNAL TOXICITY: In animal studies, maternal toxicity was observed at 0.3 times and less than 1 times the maximum recommended human dose (MRHD) in female rats treated with fenofibrate from 15 days prior to mating through weaning and from gestation day 15 through lactation day 21, respectively (Prod Info TRICOR oral tablets, 2011).
    2) FENOFIBRIC ACID
    a) There are no adequate and well-controlled studies of fenofibric acid use in pregnant women. In animals, maternal toxicity was observed at less than 1 times the maximum recommended human dose (MRHD) in female rats treated with oral fenofibrate 15, 75, and 300 mg/kg/day from gestation day 15 through lactation day 21. Adverse findings were not demonstrated in pregnant rats treated with 14 mg/kg/day (less than 1 times the MRHD) from gestation day 6 through 15 during organogenesis; maternal toxicity was noted at higher multiples of human doses. Aborted litters were reported when pregnant rabbits were treated with oral gavage doses of 150 mg/kg/day (10 times the MRHD) from gestation day 6 through 18 during the period of organogenesis; no developmental findings were observed at 15 mg/kg/day (less than 1 times the MRHD) (Prod Info FIBRICOR(R) oral tablets, 2012; Prod Info TRILIPIX(R) delayed release oral capsules, 2008).
    3) ABORTIONS: Aborted litters were reported when pregnant rabbits were treated with oral gavage doses of 150 mg/kg/day (10 times the MRHD) from gestation day 6 through 18 during the period of organogenesis (Prod Info TRILIPIX(R) delayed release oral capsules, 2008; Prod Info TRICOR oral tablets, 2011).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) FENOFIBRATE
    1) Fenofibrate is contraindicated in nursing women and use should be avoided in nursing mothers. A decision should be made whether to discontinue nursing or discontinue fenofibrate taking into account the importance of the drug to the mother (Prod Info TRICOR oral tablets, 2011; Prod Info LIPOFEN(R) oral capsules, 2010).
    B) FENOFIBRIC ACID
    1) Lactation studies with fenofibric acid have not been conducted in humans. Nursing mothers should not use fenofibric acid. A decision should be made to either discontinue nursing or discontinue fenofibric acid (Prod Info TRILIPIX(R) delayed release oral capsules, 2008), taking into account the importance of the drug to the mother (Prod Info FIBRICOR(R) oral tablets, 2012).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) FENOFIBRATE
    a) In fertility studies of male and female rats in which oral doses were given to males 61 days prior to mating and females 15 days prior to mating through weaning, no adverse effect on fertility was noted at doses up to 300 mg/kg/day (approximately 10 times the maximum recommended human dose, based on surface area) (Prod Info TRICOR oral tablets, 2011).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, no human data were available to assess the potential carcinogenic activity of choline fenofibrate, fenofibrate, or fenofibric acid.
    3.21.3) HUMAN STUDIES
    A) NEOPLASM
    1) In vitro testing with cell test systems did not show carcinogenicity for clofibrate, but it was a tumor promoter in micromolar concentrations (Lillehaug et al, 1986).
    3.21.4) ANIMAL STUDIES
    A) CLOFIBRATE
    1) RATS: A carcinogenicity study of 117-week duration resulted in increased interstitial cell tumors, pancreatic acinar adenomas, hepatocellular carcinomas, and hepatic neoplastic nodules in rats administered clofibrate 400 mg/kg/day (approximately 2 times the maximum recommended human dose) (Prod Info TRILIPIX oral delayed release capsules, 2012).
    B) FENOFIBRATE
    1) RATS: During 2 dietary carcinogenicity studies in rats administered fenofibrate 10, 45, or 200 mg/kg/day (approximately 0.3, 1 and 6 times the maximum recommended human dose (MRHD), respectively), the incidence of liver carcinomas increased in both sexes after the 200 mg/kg/day dose. An increase in the rates of pancreatic carcinomas was observed male rats at fenofibrate doses approximately 1 and 6 times the MRHD. Pancreatic adenomas and benign testicular interstitial cell tumors were observed at 6 times the MRHD in male rats (Prod Info TRILIPIX oral delayed release capsules, 2012).
    2) RATS: A 24-month carcinogenicity study in rats revealed an increased incidence of pancreatic acinar adenomas and increased interstitial cell tumors of the testes following administration of fenofibrate 10 or 60 mg/kg/day (approximately 0.3 and 2 times the maximum recommended human dose, respectively) (Prod Info TRILIPIX oral delayed release capsules, 2012).
    3) RATS: A carcinogenicity study of 117-week duration resulted in increased pancreatic acinar adenomas and increased testicular interstitial cell tumors in rats administered fenofibrate 10 or 60 mg/kg/day (approximately 0.3 and 2 times the maximum recommended human dose, respectively) (Prod Info TRILIPIX oral delayed release capsules, 2012).
    4) MICE: During a 21-month study in CF-1 mice, administration of fenofibrate 10, 45, and 200 mg/kg/day (approximately 0.2, 1, and 3 times the maximum recommended human dose (MRHD), respectively) resulted in increased liver carcinomas at 3 times the MRHD. Similarly, in an 18-month study of rats administered fenofibrate 10, 60, and 200 mg/kg/day, increased liver carcinomas were reported at 3 times the MRHD (Prod Info TRILIPIX oral delayed release capsules, 2012).

Genotoxicity

    A) There was no evidence of genotoxicity or mutagenicity in the following tests: Ames, micronucleus in vivo/rat, mouse lymphoma, chromosomal aberration, sister chromatid exchange in human lymphocytes, and unscheduled DNA synthesis in primary rat hepatocytes (Prod Info TRILIPIX oral delayed release capsules, 2012).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Patients should be observed for CNS depression. Monitor liver enzyme concentrations, urinalysis, and renal function tests in patients with significant overdose. Monitor CK in patients with muscle pain or tenderness.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Determinations of CPK and AST should be performed during therapy (Rimon et al, 1984).
    2) ALDOLASE, SERUM - Bridgman et al (1972) reported that 6 of 6 patients with nephrotic syndrome, hypolipoproteinemia, and clofibrate, had increased levels of serum aldolase. Five of the six patients also had experienced pain and muscle stiffness.
    3) BROMSULPHALEIN - Clofibrate may increase BSP retention (Prod Info Atromid-S(R), clofibrate, 2000).
    4) CHOLESTEROL, SERUM - Clofibrate interferes with cholesterol synthesis and lowers serum levels. Schaffer (1969) reported that a paradoxical increase in cholesterol levels is seen in patients with biliary cirrhosis who are treated with clofibrate.
    5) CREATINE PHOSPHOKINASE, SERUM - Clofibrate has been associated with elevated levels of serum creatine phosphokinase (Langer & Levy, 1968).
    6) GAMMA-GLUTAMYL TRANSPEPTIDASE, SERUM (GGT) - Ferrari et al (1976) reported that in 8 patients treated with 2 g/day of clofibrate there was a reduction in GGPT levels. The effect in overdose is unknown.
    7) GLUTAMIC-OXALOACETIC TRANSAMINASE, SERUM (AST) Belaiche et al (1977) reported increased SGOT (20.5 mU/mL) in a patient who had been treated with clofibrate 1.5 g/day for 3 weeks. Overdose effects are unknown.
    8) FENOFIBRATE - Regular monitoring of liver function tests should be conducted during fenofibrate therapy, according to the manufacturer. Fenofibrate therapy should be discontinued if enzyme levels persist above three times the normal limit (Prod Info Tricor(R), fenofibrate, 1998).
    9) Serum creatinine and elevated BUN have occurred more frequently compared to placebo during clinical trials. Decreases in hemoglobin and uric acid have also been observed.
    B) ENDOCRINE
    1) THYROID FUNCTION TESTS - Hansten (1979) reported that clofibrate may have some effect on PSI and other thyroid function tests. Muca et al (1968) reported 7 patients with a decrease in plasma thyroxine levels.
    C) COAGULATION STUDIES
    1) FIBRINOGEN - Clofibrate may decrease plasma fibrinogen levels (Prod Info Atromid-S(R), clofibrate, 2000).
    D) LABORATORY INTERFERENCE
    1) ALKALINE PHOSPHATASE, SERUM - Hansten (1979) reported that clofibrate decreases serum alkaline phosphatase levels. The hepatic fraction of the alkaline phosphatase is reduced rather than the bone fraction.
    2) THYMOL TURBIDITY - Clofibrate may increase thymol turbidity (Prod Info Atromid-S(R), clofibrate, 2000).
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) MYOPATHY - Periodic examinations for muscle tenderness and dysfunction are mandatory to detect the muscular syndrome

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) Patients with a minor unintentional exposure who are asymptomatic or have mild symptoms can likely be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with an inadvertent overdose who have more than mild symptoms and patients with deliberate self-harm ingestions should be sent to a health care facility for evaluation and treated until symptoms resolve.

Monitoring

    A) Patients should be observed for CNS depression. Monitor liver enzyme concentrations, urinalysis, and renal function tests in patients with significant overdose. Monitor CK in patients with muscle pain or tenderness.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) Prehospital GI decontamination is generally not necessary as severe toxicity is not expected.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) A toxic amount in overdose is unknown, so it is unknown when gastric decontamination is required. Gastric decontamination is probably usually not necessary and should only be considered after large, recent ingestions.
    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) MONITORING OF PATIENT
    1) Patients should be observed for CNS depression. Monitor liver enzyme concentrations, urinalysis, and renal function tests in patients with significant overdose. Monitor CK in patients with muscle pain or tenderness.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Minimal removal by dialysis should occur based on the high protein binding of clofibrate (Anderson et al, 1976; Goldberg et al, 1977).
    a) Goldberg et al (1977) reported that clofibrate clearance was 1.5 to 2.0 mL/min with a blood flow of 150 mL/min.

Range Of Toxicity

Summary

    A) TOXICITY: A specific toxic dose has not been established.
    B) THERAPEUTIC DOSE: FENOFIBRATE: The recommended dose of fenofibrate is 48 to 145 mg orally once daily; MAX dose 145 mg. FENOFIBRIC ACID: The recommended dose of fenofibric acid is 45 to 135 mg orally once daily; MAX dose 135 mg. CLOFIBRATE: 2 grams daily in divided doses.

Therapeutic Dose

    7.2.1) ADULT
    A) SPECIFIC SUBSTANCE
    1) FENOFIBRATE
    a) The recommended dose of fenofibrate is 54 to 160 mg orally once daily; MAXIMUM daily dose is 160 mg (Prod Info TRICOR(R) oral tablets, 2014).
    2) FENOFIBRATE, MICRONIZED
    a) Primary Hypercholesterolemia and Mixed Dyslipidemia: The initial dose is 90 mg per day (Prod Info ANTARA(R) oral capsules, 2013).
    b) Severe Hypertriglyceridemia: The initial dose is 30 to 90 mg per day. Dosage should be adjusted according to patient response at 4 to 8 week intervals. MAXIMUM dose is 90 mg per day (Prod Info ANTARA(R) oral capsules, 2013).
    3) FENOFIBRIC ACID
    a) The recommended dose of fenofibric acid is 45 to 135 mg orally once daily; MAXIMUM dose 135 mg (Prod Info Trilipix delayed release oral capsules, 2011).
    4) CLOFIBRATE
    a) NORMAL ORAL DOSE
    1) Ranges from 1 to 2 g/day in 2 to 4 divided doses (Perlemuter, 1975) Zakharov, 1977; (Dewar, 1972). The manufacturer recommends 2 g daily in divided doses in hyperlipidemia (Prod Info Atromid-S(R), clofibrate, 2000).
    2) An initial dose of 0.5 to 1 g twice daily with a maintenance dose of 1 gram twice daily is recommended (Levy, 1969).
    7.2.2) PEDIATRIC
    A) The safety and efficacy for the use of fenofibric acid, fenofibrate, or fenofibrate, micronized in the pediatric population has not been established (Prod Info TRICOR(R) oral tablets, 2014; Prod Info ANTARA(R) oral capsules, 2013; Prod Info Trilipix delayed release oral capsules, 2011).

Minimum Lethal Exposure

    A) A specific toxic dose has not been established for fibrate therapy.

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) CLOFIBRATE
    a) Therapeutic plasma levels of p-chlorophenoxyisobutyric acid (CPIB) have been reported to be 80 to 150 mcg/mL (Harvengt & Desager, 1977; Rimon et al, 1984).
    b) Following a single 500 mg oral dose maximum plasma levels of 53.3 +/- 14.3 mcg/mL were seen in 4 to 6 hours (Gugler & Hartlapp, 1978).
    c) Haselbarth (1976) found the average maximum plasma levels to be 44 mcg/mL which were observed in 5 hours after a single oral dose of 500 mg (Haselbarth, 1976).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) CLOFIBRATE
    1) LD50- (ORAL)MOUSE:
    a) 1.28 g/kg (Budavari, 1996)
    2) LD50- (ORAL)RAT:
    a) 1.65 g/kg (Budavari, 1996)
    B) FENOFIBRATE
    1) LD50- (ORAL)MOUSE:
    a) 1600 mg/kg (Budavari, 1996)
    C) SIMFIBRATE
    1) LD50- (ORAL)MOUSE:
    a) 3.3 to 3.5 g/kg (Budavari, 1996)
    2) LD50- (ORAL)RAT:
    a) 7.3 to 8.0 g/kg (Budavari, 1996)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) The lipid-modifying effects are a result from the activation of peroxisome proliferator activated receptor alfa (PPARa), which increases lipolysis and elimination of triglyceride-rich particles from plasma by activation of lipoprotein lipase and reducing the production of Apo CIII (an inhibitor of lipoprotein lipase). The decrease in triglycerides also produces an alteration in the size and composition of LDL from small, dense particles to a large buoyant particles, which have a greater affinity for cholesterol receptors and are catabolized rapidly. Activation of PPARa also induces and increase in the synthesis of apolipoproteins AI, AII and HDL-C (Prod Info Atromid-S(R), clofibrate, 2000; Prod Info Trilipix delayed release oral capsules, 2011; Prod Info TRICOR oral tablets, 2011).

Physicochemical

Physical Characteristics

    A) Clofibrate is an oil that is insoluble in water but miscible with ethanol, acetone, chloroform, and ether (Budavari, 1996).

Molecular Weight

    A) Clofibrate: 242.70 (Budavari, 1996)

References

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    56) Product Information: ANTARA(R) oral capsules, fenofibrate oral capsules. Lupin Pharma (per FDA), Baltimore, MD, 2012.
    57) Product Information: ANTARA(R) oral capsules, fenofibrate oral capsules. Lupin Pharma (per FDA), Baltimore, MD, 2013.
    58) Product Information: Atromid-S(R), clofibrate. Ayerst Laboratories, Philadelphia, PA, 2000.
    59) Product Information: Atromid-S(R), clofibrate. Wyeth-Ayerst Laboratories, Philadelphia, PA, 1995.
    60) Product Information: FIBRICOR(R) oral tablets, fenofibric acid oral tablets. AR Scientific, Inc. (per FDA), Philadelphia, PA, 2012.
    61) Product Information: FIBRICOR(R) oral tablets, fenofibric acid oral tablets. Caraco Pharmaceutical Laboratories, Ltd. (per FDA), Detroit, MI, 2014.
    62) Product Information: Fenoglide(R) oral tablets, fenofibrate oral tablets. Santarus, Inc. (per FDA), San Diego, CA, 2012.
    63) Product Information: Fenoglide(R) oral tablets, fenofibrate oral tablets. Shore Therapeutics, Inc. (per Dailymed), Stamford, CT, 2011.
    64) Product Information: LIPOFEN(R) oral capsules, fenofibrate oral capsules. Kowa Pharmaceuticals America, Inc. (per DailyMed), Montgomery, AL, 2010.
    65) Product Information: LIPOFEN(R) oral capsules, fenofibrate oral capsules. Kowa Pharmaceuticals America, Inc. (per FDA), Montgomery, AL, 2013.
    66) Product Information: TRICOR oral tablets, fenofibrate oral tablets. Abbott Laboratories (per FDA), North Chicago, IL, 2011.
    67) Product Information: TRICOR(R) oral tablets, fenofibrate oral tablets. Abbott Laboratories, North Chicago, IL, 2007.
    68) Product Information: TRICOR(R) oral tablets, fenofibrate oral tablets. AbbVie Inc. (per FDA), North Chicago, IL, 2014.
    69) Product Information: TRICOR(R) oral tablets, fenofibrate oral tablets. Abbott Laboratories (per FDA), North Chicago, IL, 2013.
    70) Product Information: TRIGLIDE oral tablets, fenofibrate oral tablets. Shionogi Inc (per FDA), Florham Park, NJ, 2015.
    71) Product Information: TRIGLIDE(R) oral tablets, fenofibrate oral tablets. Sciele Pharma Inc, Atlanta, GA, 2007.
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    76) Product Information: Trilipix delayed release oral capsules, fenofibric acid delayed release oral capsules. Abbott Laboratories, North Chicago, IL, 2011.
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