LIPIDIL EZ (fenofibrate) lowers elevated serum lipids by decreasing the low-density lipoprotein (LDL) fraction rich in cholesterol and the very low-density lipoprotein (VLDL) fraction rich in triglycerides. In addition, fenofibrate increases the high-density lipoprotein (HDL) cholesterol fraction.

Fenofibrate appears to have a greater depressant effect on the very low-density lipoproteins (VLDL) than on the low-density lipoproteins (LDL). Therapeutic doses of fenofibrate produce elevations of HDL cholesterol, a reduction in the content of the low-density lipoprotein cholesterol, and a substantial reduction in the triglyceride content of very low-density lipoproteins.

Recent findings suggest that the lipid modulating effects of fenofibrate are mediated by the activation of a specific nuclear receptor called peroxisome proliferator activated receptor alpha (PPARα), which produces:

• a reduction in apo C-III, and therefore a reduction in the level of dense atherogenic LDL particles;

  
  

• a stimulation of mitochondrial beta-oxidation, and therefore a reduction in triglyceride secretion;

  
  

• a rise in lipoprotein lipase production, and therefore an acceleration of triglyceride rich lipoprotein breakdown;

  
  

• a rise in apo A-I and apo A-II production, and a corresponding rise in HDL.

  
  

 

After oral administration, fenofibrate is rapidly hydrolysed to fenofibric acid, the active metabolite. In man, fenofibric acid is eliminated as the glucuronic acid conjugate and is mainly excreted through the kidney.

In man, the elimination half-life of fenofibric acid is about 20-24 hours, a value that is not modified after multiple dosing.

In healthy elderly patients (77 to 87 years of age), the terminal half-life is prolonged, but no dose adjustment is required due to unchanged clearance.

Safety and effectiveness have not been established in pediatric patients.

In patients with severe renal impairment (creatinine clearance <50 mL per min), the rate of clearance of fenofibric acid is greatly reduced, and the compound accumulates during chronic dosage. In patients having moderate renal impairment (creatinine clearance of 50 to 90 mL per min), the oral clearance and oral volume of distribution of fenofibric acid are increased compared to healthy adults (2.1 L/h and 95 L versus 1.1 L/h and 30 L, respectively). Therefore, the dosage of LIPIDIL EZ should be minimized in patients who have severe renal impairment, while no modification of dosage is required in patients having moderate renal impairment.

No pharmacokinetic studies have been conducted in patients having hepatic insufficiency.

No gender-related differences in pharmacokinetics and metabolism have been observed.

Fenofibric acid is extensively bound (>99%) to plasma albumin. This binding is not saturable.

Absorption of a micronized fenofibrate formulation (LIPIDIL Micro 200 mg capsules) is low and variable when administered under fasting conditions and increases when given with food. Fenofibrate, given in a micro-coated formulation (LIPIDIL Supra 160 mg tablets), requires lower doses (160 mg) to achieve equivalent plasma levels to the micronized (200 mg) formulation. Nanocrystallization of fenofibrate allows for further reduction in the dose (LIPIDIL EZ 145 mg tablets), and LIPIDIL EZ may be taken without regard to meals, because of optimized product absorption.

In a single-dose three-way randomized crossover bioavailability study in 72 healthy male and female volunteers, under low fat fed conditions, one 145 mg LIPIDIL EZ or three 48 mg LIPIDIL EZ tablets were compared to one 200 mg micronized capsule (LIPIDIL Micro 200 mg). Each subject received a single oral dose of each formulation with a low fat breakfast (30% fat, approx. 400 Kcal), with a two-week interval between doses. See Table 1 and Table 2.

Table 1: LIPIDIL EZ

Summary Table of the Comparative Bioavailability Data: A Single Dose Study (LIPIDIL EZ 145 mg tablet vs LIPIDIL Micro 200 mg capsule)

Analyte: Fenofibric Acid From measured and log transformed data Geometric Mean Arithmetic Mean (CV %)
Parameter	Test: LIPIDIL EZ 145 mg	Reference: LIPIDIL Micro 200 mg	% Ratio of Geometric Means	90% Confidence Interval
AUCT (μg·h/mL)	148.47 153.5 (27%)	170.49 174.2 (25%)	87.1%	85.2–89.0%
AUCI (μg·h/mL)	151.69 157.4 (28%)	176.03 180.4 (27%)	86.2%	84.3–88.1%
CMAX (μg/mL)	8.646 8.80 (19%)	8.582 8.87 (26%)	100.8%	96.8–104.9%
TMAX a (h)	3.5 (35%)	4.4 (38%)
T½ a (h)	20.7 (24%)	22.0 (34%)

^a. Expressed as arithmetic mean (CV%) only.



Table 2: LIPIDIL EZ

Summary Table of the Comparative Bioavailability Data: A Single Dose Study (LIPIDIL EZ 3×48 mg tablet vs LIPIDIL Micro 200 mg capsule)

Analyte: Fenofibric Acid From measured and log transformed data Geometric Mean Arithmetic Mean (CV %)
Parameter	Test: LIPIDIL EZ 3×48 mg	Reference: LIPIDIL Micro 200 mg	% Ratio of Geometric Means	90% Confidence Interval
AUCT (μg·h/mL)	148.29 153.3 (27%)	170.49 174.2 (25%)	87.0%	85.1–88.9%
AUCI (μg·h/mL)	151.34 157.0 (29%)	176.03 180.4 (27%)	86.0%	84.3–88.1%
CMAX (μg/mL)	8.399 8.54 (19%)	8.582 8.87 (26%)	97.9%	94.0–101.9%
TMAX a (h)	3.6 (35%)	4.4 (38%)
T½ a (h)	20.1 (23%)	22.0 (34%)

^a. Expressed as arithmetic mean (CV%) only.

These data demonstrate that comparable bioavailability was achieved between LIPIDIL EZ, 145 mg or 3×48 mg tablets, and LIPIDIL Micro 200 mg capsules.

In a single-dose two-way randomized crossover bioavailability study in 40 healthy male volunteers, under low fat fed conditions, one 145 mg LIPIDIL EZ tablet was compared to one 160 mg LIPIDIL Supra tablet. Each subject received a single oral dose of each formulation with a low fat breakfast (30% fat, approx. 400 Kcal), with a two-week interval between doses. See Table 3.

Table 3: LIPIDIL EZ

Summary Table of the Comparative Bioavailability Data: A Single Dose Study (LIPIDIL EZ 145 mg tablet vs Lipidil Supra 160 mg tablet)

Analyte: Fenofibric Acid From measured and log transformed data Geometric Mean Arithmetic Mean (CV %)
Parameter	Test LIPIDIL EZ 145 mg tablet	Reference LIPIDIL Supra 160 mg tablet	% Ratio of Geometric Means	90% Confidence Interval
AUCT (μg·h/mL)	103.52 107.99 (29%)	103.93 108.96 (29%)	99.6%	96.2–103.1%
AUCI (μg·h/mL)	105.00 109.53 (29%)	105.80 110.86 (29%)	99.2%	96.0–102.6%
CMAX (μg/mL)	8.02 8.14 (17%)	6.73 6.91 (23%)	119.2%	111.5–127.4%
TMAX a (h)	2.88 (42%)	3.72 (31%)
T½ a (h)	17.15 (20%)	18.74 (20%)

^a. Expressed as arithmetic mean (CV %) only.

These data demonstrate that comparable bioavailability was achieved between, 145 mg LIPIDIL EZ tablets and LIPIDIL Supra 160 mg tablets.

A study to examine the effect of food on the absorption of nanocrystallized fenofibrate was performed as a single-dose three-way randomized cross-over bioavailability study in 45 healthy male and female volunteers. Each subject received a single dose of 145 mg LIPIDIL EZ with either a high fat breakfast [50% fat, approx. 1000 Kcal, High Fat Fed (HFF)], a low fat breakfast [30% fat, approx. 400 Kcal; Low Fat Fed (LFF)] or no breakfast (fasted state), with a two-week interval between study arms. See Table 4 and Table 5.

Table 4: LIPIDIL EZ

Summary Table of the Comparative Bioavailability Data: A Single Dose Study (LIPIDIL EZ 145 mg tablets (High Fat Fed vs Fasted Conditions)

Analyte: Fenofibric Acid From measured and log transformed data Geometric Mean Arithmetic Mean (CV %)
Parameter	Test: 145 mg high fat fed	Reference: 145 mg fasted	% Ratio of Geometric Means	90% Confidence Interval
AUCT (μg·h/mL)	123.0 127.9 (27.7%)	116.5 121.6 (28.1%)	105.4%	102.0–109.0%
AUCI (μg·h/mL)	124.8 129.9 (28.0%)	118.5 123.8 (28.8%)	105.2%	101.8–108.8%
CMAX (μg/mL)	7.82 7.96 (18.5)	7.77 7.94 (20.1%)	100.7%	96.3–105.4%
TMAX a (h)	4.27 (45.5%)	2.33 (31.4%)
T½ a (h)	17.8 (23.3%)	18.9 (24.9%)

^a. Expressed as arithmetic mean (CV %) only.



Table 5: LIPIDIL EZ

Summary Table of the Comparative Bioavailability Data: A Single Dose Study (LIPIDIL EZ 145 mg tablets (Low Fat Fed vs Fasted Conditions)

Analyte: Fenofibric Acid From measured and log transformed data Geometric Mean Arithmetic Mean (CV %)
Parameter	Test: 145 mg low fat fed	Reference: 145 mg fasted	% Ratio of Geometric Means	90% Confidence Interval
AUCT (μg·h/mL)	118.1 123.2 (28.4%)	116.5 121.6 (28.1%)	101.3%	98.1–104.7%
AUCI (μg·h/mL)	119.8 125.1 (28.7%)	118.5 123.8 (28.8%)	101.2%	97.8–104.6%
CMAX (μg/mL)	7.84 7.96 (17.9%)	7.77 7.94 (20.1%)	100.9%	96.4–105.5%
TMAX a (h)	3.56 (33.1%)	2.33 (31.4%)
T½ a (h)	18.7 (19.5%)	18.9 (24.9%)

^a. Expressed as arithmetic mean (CV %) only.

These data demonstrate that LIPIDIL EZ can be administered with or without food, as there was no effect of food on the bioavailability of the nanocrystallized fenofibrate tablets when compared to the bioavailability under the fasted state.

LIPIDIL EZ is indicated as an adjunct to diet, at least equivalent to the Adults Treatment Panel III (ATP III) and Therapeutic Lifestyle Changes (TLC diet), and other therapeutic measures when the response to diet and other measures has been inadequate for:

 

LIPIDIL EZ alone may not be adequate therapy in some patients with familial combined hyperlipidemia with Type IIb and Type IV hyperlipoproteinemia.

LIPIDIL EZ (fenofibrate) is not indicated for the treatment of Type I hyperlipoproteinemia.

Fenofibrate and HMG-CoA Reductase Inhibitors (Statins): The concomitant administration of fenofibrate and statins should be avoided unless the benefit for further alteration in lipid levels is likely to outweigh the increased risk of this combination.

The concomitant administration of fenofibrate (equivalent to 145 mg LIPIDIL EZ) with Pravastatin (40 mg) once daily for 10 days, in healthy adults, increased the mean C_max and AUC values for pravastatin by 36% (range: from a 69% decrease to a 321% increase) and 28% (range: from a 54% decrease to a 128% increase), respectively. Co-administration of fenofibrate with Pravastatin also increased the mean C_max and AUC of the major metabolites, 3-alpha-hydroxy-isopravastatin by 55% (range: from a 32% decrease to a 314% increase) and 39% (range: from a 24% decrease to a 261% increase), respectively.

The combined use of fibric acid derivatives and HMG-CoA reductase inhibitors has been associated, in the absence of a marked pharmacokinetic action, in numerous case reports, with rhabdomyolysis, markedly elevated creatine kinase (CK) levels and myoglobinuria, leading to a high proportion of cases to acute renal failure.

The use of fibrates alone, including LIPIDIL EZ, may occasionally be associated with myositis, myopathy or rhabdomyolysis. Patients receiving LIPIDIL EZ and complaining of muscle pain, tenderness, or weakness should have prompt medical evaluation for myopathy, including serum creatine kinase level determination. If myopathy and or myositis is suspected or diagnosed, LIPIDIL EZ therapy should be stopped.

This combination therapy must not be used in patients with predisposing factors for myopathy (pre-existing myopathy, age >70 years, renal impairment, hepatic impairment, severe infection, surgery and trauma, frailty, hypothyroidism or electrolyte imbalance, personal or family history of hereditary muscular disorders, previous history of muscle toxicity with another HMG-CoA reductase inhibitor, concomitant use of a fibrate, niacin or ezetimibe, alcohol abuse, excessive physical exercise, diabetes with hepatic fatty change situations where an increase in plasma levels of active ingredient may occur).

For information on a specific HMG-CoA reductase inhibitor, consult a respective Product Monograph.

Abnormal liver function tests have occasionally been observed during fenofibrate administration, including elevations of transaminases, and decreases or, rarely, increases in alkaline phosphatase. From 5 placebo-controlled trials of 2 to 6 months' duration, increases up to >3 times the upper limit of normal occurred in 2.9% (14/477) of patients taking fenofibrate versus 0.5% (2/386) of those treated with placebo. In the DAIS study (3 years duration), increases up to 3 times the upper limit of normal occurred in 1.9% (4/207) of patients taking fenofibrate versus 0% of those treated with placebo (0/211). Follow-up measurements, performed either at the end of treatment or during continued treatment, showed that transaminase values generally returned to normal limits. Therefore, regular periodic liver function tests (AST, ALT and GGT) in addition to other baseline tests are recommended after 3 to 6 months and at least yearly thereafter. LIPIDIL EZ (fenofibrate) should be discontinued if abnormalities persist.

Fenofibrate may increase cholesterol excretion into the bile, and may lead to cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated. LIPIDIL EZ therapy should be discontinued if gallstones are found.

Mild hemoglobin, haematocrit and white blood cell decreases have been observed occasionally in patients following initiation of fenofibrate therapy. However, these levels stabilize during long-term administration. Periodic blood counts are recommended during the first 12 months of fenofibrate administration.

Before instituting fenofibrate therapy, laboratory tests should be conducted to ensure that lipid levels are consistently abnormal. Attempts should be made to control serum lipids with appropriate diet, exercise and weight loss in obese patients. Other medical problems, such as diabetes mellitus and hypothyroidism, should also be controlled. In patients at high risk, consideration should be given to the control of other risk factors such as smoking, excessive alcohol intake, hormonal contraceptive use and inadequately controlled hypertension.

Because long-term administration of fenofibrate is recommended, the potential risks and benefits should be carefully weighed. Adequate pretreatment laboratory studies should be performed to ensure that patients have elevated serum cholesterol and/or triglycerides or low HDL-cholesterol levels.

Treatment with drugs of the fibrate class has been associated on rare occasions with myositis or rhabdomyolysis, usually in patients with impaired renal function. Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of creatine phosphokinase levels.

Patients should be advised to promptly report unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. CK levels should be assessed in patients reporting these symptoms, and fenofibrate therapy should be discontinued if markedly elevated CK levels (5 times the upper limit of normal) occur or myopathy is diagnosed.

Standard tests for teratology, fertility and peri- and post-natal effects in animals have shown a relative absence of risk; however, embryo-toxicity has occurred in animals at maternally toxic doses.

Safety in pregnant women has not been established. Fenofibrate has been shown to be embryocidal in rats when given in doses 7 to 10 times the maximum recommended human dose (MRHD) and in rabbits when given in doses 9 times the MRHD (on the basis of mg/m² surface area). There are no adequate and well-controlled studies in pregnant women. Fenofibrate should not be used during pregnancy. (See Contraindications.)

In the absence of information concerning the presence of fenofibrate in human breast milk, LIPIDIL EZ should not be used by nursing mothers.

In long-term animal toxicity and carcinogenicity studies, fenofibrate has been shown to be tumorigenic for the liver in male rats at 12 times the human dose. At this dose level in male rats there was also an increase in benign Leydig cell tumors. Pancreatic acinar cell tumors were increased in male rats at 9 and 40 times the human dose. However, mice and female rats were unaffected at similar doses. Florid hepato-cellular peroxisome proliferation has been observed following fenofibrate administration to rats. Such changes have not been found in the human liver after up to 3.5 years of fenofibrate administration.

In patients with a past history of jaundice or hepatic disorder, fenofibrate should be used with caution.

Fenofibrate may increase cholesterol excretion into the bile, and may lead to cholelithiasis.

In patients with hypoalbuminemia, e.g., nephrotic syndrome, and in patients with renal insufficiency, the dosage of fenofibrate must be reduced and renal function should be monitored regularly (See Precautions, Skeletal Muscle and Dosage). Fenofibrate should not be used in dialysis patients.

In common with some other fibrates, pancreatitis has been reported in patients taking fenofibrate. This occurrence may represent a failure of efficacy in patients with severe hypertriglyceridemia, a direct drug effect, or a secondary phenomenon mediated through biliary tract stone or sludge formation with obstruction of the common bile duct.

Fenofibrate is excreted by the kidney. Therefore, the risk of adverse reactions to LIPIDIL EZ may be greater in the elderly patients with impaired renal function. Since elderly patients are more likely to have a decreased renal function, dose should be carefully selected (See Dosage).

No drug-drug interaction studies with fenofibrate and statins have been conducted in patients.

Pharmacokinetic interaction studies conducted with drugs in healthy subjects may not detect the possibility of a potential drug interaction in some patients due to differences in underlying disease and use of concomitant medications (see Warnings.)

Concomitant administration in 23 healthy adults of fenofibrate (equivalent to 145 mg LIPIDIL EZ)) with pravastatin, 40 mg once daily for 10 days, has been shown to increase the mean C_max and AUC values for pravastatin by 36% (range: from a 69% decrease to a 321% increase) and 28% (range: from a 54% decrease to a 128% increase), respectively. Co-administration of fenofibrate with pravastatin also increased the mean C_max and AUC of the major metabolite, 3-alpha-hydroxy-iso-pravastatin by 55% (range: from a 32% decrease to a 314% increase) and 39% (range: from a 24% decrease to a 261% increase), respectively.

Concomitant administration of fenofibrate (equivalent to 145 mg LIPIDIL EZ) with atorvastatin (20 mg) once daily for 10 days resulted in a 14% decrease in the mean atorvastatin AUC value (range: from a 67% decrease to a 44% increase) in 22 healthy males. There was a 0% change in the atorvastatin mean C_max value (range: from a 60% decrease to a 136% increase). No significant pharmacokinetic interaction was observed in the mean fenofibric acid AUC (2.3% decrease, range: from a 39% decrease to a 40 % increase) or in the mean C_max (3.8% decrease, range: from a 29% decrease to a 42% increase) when fenofibrate was co-administered with multiple doses of atorvastatin.

In a 10-day trial, fenofibrate (equivalent to 145 mg LIPIDIL EZ) was taken once daily. On day 10, simvastatin 40 mg was added to the fenofibrate regimen. The mean AUC of simvastatin acid, the main active metabolite, decreased by 42% (range: from a 77% decrease to a 50% increase) in the presence of fenofibrate. Fenofibrate had no impact (0%) on the mean simvastatin acid C_max (range: from a 67% decrease to a 92% increase). The mean fenofibric acid C_min plasma levels increased by 14% (range: from a 7% decrease to a 48% increase) following the co-administration of simvastatin, indicating that fenofibric acid concentrations are not significantly affected by the addition of a 40 mg dose of simvastatin.

Co-administration of fenofibrate (67 mg three times daily) and rosuvastatin (10 mg once daily) for seven days did not lead to a clinically significant change in the plasma concentrations of either drug.

The safety and effectiveness of ezetimibe and fibrate combination therapy have not been established, therefore co-administration is not recommended until use in patients has been studied.

Caution should be exercised when oral anticoagulants are given in conjunction with LIPIDIL EZ (fenofibrate). The dosage of oral anticoagulant should be reduced to maintain the prothrombin time at the desired level to prevent bleeding complications. Careful monitoring of prothrombin time is therefore recommended until it has been definitely determined that the prothrombin level has been stabilized.

Severe myositis and rhabdomyolysis have occurred when a statin or cyclosporine was administered in combination therapy with a fibrate. Therefore, the benefits and risks of using fenofibrate concomitantly with these drugs should be carefully considered.

When a fibrate is used concurrently with cholestyramine or any other resin, an interval of at least 2 hours should be maintained between the administration of the two drugs, since the absorption of fibrates is impaired by cholestyramine.

Estrogens may lead to a rise in lipid levels. Prescribing fibrates in patients taking estrogens or estrogen-containing contraceptives must be considered clinically on an individual basis.

In five placebo-controlled clinical trials, conducted in the U.S. and Europe, a total of 477 patients on fenofibrate and 386 patients on placebo were evaluated for adverse effects during 2 to 6 months of treatment.

Adverse events led to the withdrawal of treatment in 5.5% of patients (26/477) treated with fenofibrate, the most common symptoms being abnormal elevation in transaminases, skin reactions and digestive disorders. Of the placebo-treated patients, 2.6% (10/386) were discontinued due to adverse effects. Adverse events, regardless of their causality, reported in more than 1% of patients are shown in Table 6.

Table 6: LIPIDIL EZ

Number (%) Of Patients Reporting Adverse Events

Safety was monitored for 3 years during the placebo-controlled DAIS study for both adverse events and laboratory anomalies. Fenofibrate was used safely in type 2 diabetic patients, as the overall incidence and severity of adverse events were comparable in fenofibrate and placebo groups. Table 7 summarizes the incidence of adverse events, by body system, observed in both treatment groups.

Table 7: LIPIDIL EZ

DAIS Study: Incidence of Adverse Events (AEs) by system, Experienced by Type 2 Diabetic Patients During Treatment with Fenofibrate or Placebo (ITT Population)

Body System	Fenofibrate (N=207)		Placebo (N=211)
	AEs	Patients	AEs	Patients
Total # pts. with at least 1 AE	Total AEs: 1710	201 (97.1%)	Total AEs: 1759	202 (95.7%)
Body as a Whole	371 (21.7%)	136 (65.7%)	362 (20.6%)	146 (69.2%)
Cardiovascular	183 (10.7%)	84 (40.6%)	220 (12.5%)	96 (45.5%)
Digestive	196 (11.5%)	86 (41.6%)	194 (11.0%)	87 (41.2%)
Endocrine	11 (0.6%)	10 (4.8%)	19 (1.1%)	11 (5.2%)
Haemic/Lymphatic	31 (1.8%)	19 (9.2%)	23 (1.3%)	15 (7.1%)
Metabolic/ Nutritional	50 (2.9%)	32 (15.5%)	70 (4.9%)	41 (19.4%)
Musculoskeletal	155 (9, 1%)	84 (40.6%)	180 (10.2%)	84 (39.8%)
CNS	103 (6.0%)	59 (28.5%)	98 (5.6%)	58 (27.5%)
Respiratory	301 (17.6%)	108 (52.2%)	279 (15.9%)	105 (49.8%)
Skin/appendage	107 (6.3%)	58 (28.0%)	107 (6.1%)	48 (22.8%)
Special senses	73 (4.3%)	44 (21.3%)	90 (5.1%)	50 (23.7%)
Urogenital	118 (6.9%)	55 (26.6%)	103 (5.9%)	46 (21.8%)
Other	11 (0.6%)	9 (4.4%)	14 (0.8%)	11 (5.2%)

In two open, non-controlled clinical studies conducted in Canada and Germany, a total of 375 patients on fenofibrate, microcoated formulation, were evaluated for adverse events. Listed in Table 8 are the adverse events possibly or probably related to fenofibrate, microcoated formulation and reported by more than 0.5% of the patients.

Table 8: LIPIDIL EZ

Number (%) of Patients Reporting Adverse Events Possibly or Probably Related to Fenofibrate

In most trials, sporadic and transient increases in aminotransferase levels have been associated with the use of fenofibrate. The reported frequency of AST and ALT elevations was variable; in the clinical studies conducted in Canada and Germany elevations above three times the upper limit of normal were observed in 2.0% of the patients (7/375) treated with fenofibrate, microcoated formulation. In two dose-ranging studies, the incidence of increases in transaminases (>3×ULN) due to fenofibrate therapy appears to be dose related; 0.6% (1/157) (80 mg tablet), 1.9% (3/158) (160 mg tablet) and 4.0% (6/149) (240 mg tablet). Values usually return to normal without interruption of treatment (see Precautions). Reductions in alkaline phosphatase levels have also been observed.

Mild decreases in hemoglobin, haematocrit, and white blood cell counts have been observed occasionally in patients following initiation of fenofibrate therapy but these observations were without clinical significance. However, these levels stabilize during long-term administration. In addition, a decrease in heptoglobin concentration has been observed in some patients with Type IV hyperlipidemia during long-term use of fenofibrate. However, this decrease in heptoglobin was not associated with any other sign of blood dyscrasia and/or haemolysis.

The mean plasma levels of urea and creatinine showed increases, particularly during long-term fenofibrate treatment, most of them remaining within the limits of normal values.

Fenofibrate also has the potential to provoke CK elevations and changes in haematologic parameters, which generally subside when the drug is discontinued (see Precautions). In the clinical studies conducted in Canada and Germany, the reported frequency of CK elevations above five times the upper limit of normal was approximately 0.3% (2/375) of the patients treated with fenofibrate, microcoated formulation (LIPIDIL Supra).

While there has been no reported case of overdosage, symptomatic and supportive measures should be taken. Fenofibrate is not dialysable because the main metabolite (fenofibric acid) is highly bound to plasma proteins.