Lipidil Supra: Indications, Dosage, Precautions, Adverse Effects
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Lipidil Supra - Product Information

Manufacture: Abbott
Country: Canada
Condition: Hypertriglyceridemia, Hyperlipoproteinemia Type V, Elevated Chylomicrons VLDL, Hyperlipoproteinemia Type IV, Elevated VLDL, Hyperlipoproteinemia Type IIb, Elevated LDL VLDL, Hyperlipoproteinemia Type IIa, Elevated LDL, Hyperlipoproteinemia
Class: Fibric acid derivatives
Form: Tablets
Ingredients: Fenofibrate, colloidal silicon dioxide, crospovidone, lactose monohydrate, microcrystalline cellulose, polyvinyl alcohol, povidone, sodium stearyl fumerate and sodium lauryl sulfate, soybean lecithin, talc, titanium dioxide and xantham gum.

Action and Clinical Pharmacology

LIPIDIL SUPRA (fenofibrate, microcoated formulation) 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 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 lipoproteins cholesterol, and a substantial reduction in the triglyceride content of VLDL.

Fenofibrate is a fibric acid derivative whose lipid modifying effects reported in humans are mediated by the activation of a specific nuclear receptor called peroxisome proliferator activated receptor alpha (PPARa), 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.

Metabolism and Excretion

After oral administration, fenofibrate is rapidly hydrolysed to fenofibric acid. In man it is mainly excreted through the kidney. Half-life is about 20 hours.

Absorption

Fenofibrate’s absorption is low and variable when the product is administered under fasting conditions. Fenofibrate’s absorption is increased when the compound is given with food.

Renal Insufficiency

In patients with severe renal failure, significant accumulation was observed with a large increase in half-life. Therefore, the dose of fenofibrate may need to be reduced, depending on the rate of creatinine clearance.

Pediatrics

Limited experience is available in children and adolescents, at the dose of 5 mg/kg/day fenofibrate non-micronized formulation. However, safety and effectiveness have not been established in this sub-population (see selected bibliography).

Distribution

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

Indications and Clinical Use

LIPIDIL SUPRA (fenofibrate, microcoated formulation) is indicated as an adjunct to diet, at least equivalent to the Adult 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:

  1. Treatment of patients, including patients with type 2 diabetes (non-insulin dependent), with dyslipoproteinemia (hypercholesterolemia, Fredrickson classification Types IIa and IIb mixed hyperlipidemia), to regulate lipid levels by reducing serum triglycerides and LDL cholesterol levels and increasing HDL cholesterol.
  1. Treatment of adult patients with very high serum triglyceride levels, Fredrickson classification Type IV and Type V hyperlipidemia, who are at a high risk of sequelae and complications (i.e., pancreatitis) from their hyperlipidemia.

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

LIPIDIL SUPRA is not indicated for the treatment of Type I hyperlipoproteinemia.

Contraindications

  • Hepatic insufficiency (including primary biliary cirrhosis and unexplained persistent liver function abnormality).
  • Pre-existing gallbladder disease (see WARNINGS).
  • Severe renal dysfunction.
  • Chronic or acute pancreatitis.
  • Hypersensitivity to fenofibrate, any component of this medication or other drugs of the fibrate class.
  • Should not be taken in patients allergic to peanut or arachis oil or soya lecithin or related products due to the risk of hypersensitivity reactions.
  • The drug should not be used during pregnancy and breast-feeding.
  • Known photoallergy or phototoxic reaction during treatment with fibrates or ketoprofen.
  • Should not be co-administered with HMG-CoA reductase inhibitors (statins) in patients with pre-disposing factors for myopathy.
  • Under 18 years of age.

Warnings

Fenofibrate and HMG-CoA Reductase Inhibitors (Statins)

The concomitant administration of LIPIDIL SUPRA (fenofibrate, microcoated formulation) 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 LIPIDIL SUPRA with Pravastatin (40 mg) once daily for 10 days, in healthy adults, increased the mean Cmax 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 Cmax 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.

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.

The use of fibrates alone, including LIPIDIL SUPRA, may occasionally be associated with myositis, myopathy or rhabdomyolysis. Patients receiving LIPIDIL SUPRA 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 SUPRA therapy should be stopped.

Liver Function

Abnormal liver function tests have been observed occasionally 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 every 3 months for the first 12 months and at least yearly thereafter. LIPIDIL SUPRA should be terminated if abnormalities persist and/ or AST and ALT levels increase to more than 3 times the upper limit of normal.

Cholelithiasis

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

Haematologic Changes

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.

Precautions

Initial Therapy

Before instituting LIPIDIL SUPRA (fenofibrate, microcoated formulation) 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. Secondary causes of hypercholesterolemia, such as uncontrolled type 2 diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemia, obstructive liver disease, pharmacological treatment and excessive alcohol intake should be adequately treated before fenofibrate therapy is initiated. In patients at high risk, consideration should be given to the control of other risk factors such as smoking, use of preparations containing estrogen and inadequately controlled hypertension.

Long-Term Therapy

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. Response to therapy should be monitored by determination of serum lipid values (e.g. total cholesterol, LDL-C, triglycerides). If a significant serum lipidil response is not obtained in 3 months, LIPIDIL SUPRA should be discontinued.

Skeletal Muscle

Treatment with drugs of the fibrate class has been associated on rare occasions with myositis or rhabdomyolysis, usually in patients with impaired renal function and in cases of hypoalbuminaemia. Myopathy should be considered in any patient with diffuse myalgias, myositis, muscle cramps, 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.

Patients with pre-disposing factors for myopathy may be at an increased risk of developing rhabdomyolysis (see WARNINGS). For these patients, the putative benefits and risks of fenofibrate therapy should be carefully weighed.

The risk of muscle toxicity may be increased if the drug is administered with another fibrate or an HMG-CoA reductase inhibitor, especially in case of pre-existing muscular disease (see WARNINGS). Consequently, the co-administration of fenofibrate with a HMG-CoA reductase inhibitor or another fibrate should be reserved to patients with severe combined dyslipidaemia and high cardiovascular risk without any history of muscular disease or other pre-disposing factors for myopathy (see WARNINGS) and with a close monitoring of potential muscle toxicity.

Reproductive Studies

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.

Use in Pregnancy

Safety in pregnant women has not bee 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).

Nursing Mothers

It is unknown whether fenofibrate and/or its metabolites are excreted in human milk. A risk to the suckling child cannot be excluded. Therefore LIPIDIL SUPRA should not be used during breast-feeding.

Carcinogenicity

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.

Hepatobiliary Disease

LIPIDIL SUPRA is not recommended for use in patients with hepatic impairment due to the lack of data.

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

Renal Function

LIPIDIL SUPRA should not be used in patients with severe renal dysfunction including patients on dialysis. In patients with hypoalbuminemia, e.g., nephrotic syndrome, and in patients with renal insufficiency, the dosage of fibrates must be reduced and renal function should be monitored regularly (see PRECAUTIONS, Skeletal muscle and DOSAGE AND ADMINISTRATION).

Treatment should be interrupted in case of an increase in creatinine levels > 50% upper limit of normal. It is recommended that creatinine measurement may be considered during the first three months after initiation of treatment.

Pancreatitis

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. In patients with severe hypertriglyceridemia, cases of acute pancreatitis have been reported.

Geriatric Population

Fenofibrate is excreted by the kidney. Therefore, the risk of adverse reactions to LIPIDIL SUPRA 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 AND ADMINISTRATION).

Pediatric Population

The safety and efficacy of fenofibrate in children have not yet been established. Only limited paediatric data are available. Therefore the use of LIPIDIL SUPRA is not recommended in paediatric subjects under 18 years.

Drug Interactions

General

Fenofibrate is highly protein bound (>99%), mainly to albumin. Consideration should be given to the potential for displacement drug interactions with other highly protein-bound drugs.

Statins

No drug-drug interaction studies with LIPIDIL SUPRA 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).

Pravastatin

Concomitant administration in 23 healthy adults of fenofibrate with pravastatin, 40 mg once daily for 10 days, has been shown to increase the mean Cmax 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 Cmax 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.

Atorvastatin

Concomitant administration of fenofibrate 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 Cmax 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 Cmax (3.8% decrease, range: from a 29% decrease to a 42% increase) when fenofibrate was co-administered with multiple doses of atorvastatin.

Simvastatin

In a 10-day trial, fenofibrate 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 Cmax (range: from a 67% decrease to a 92% increase). The mean fenofibric acid Cmin 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.

Rosuvastatin

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.

Ezetimibe

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.

Oral Anticoagulants

Caution should be exercised when oral anticoagulants are given in conjunction with LIPIDIL SUPRA. 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.

Statins and Cyclosporine

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 LIPIDIL SUPRA concomitantly with these drugs should be carefully considered.

Some severe cases of reversible renal function impairment have been reported during concomitant administration of fenofibrate and cyclosporine. The renal function of these patients must therefore be closely monitored and treatment with LIPIDIL SUPRA stopped in the case of severe alteration of laboratory parameters.

Bile Acid Sequestrants

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

Estrogens

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

Rosiglitazone

Some epidemiologic studies and case reports suggest that markedly decreased HDL-C in some patients involve the interaction of rosiglitazone with fenofibrate or bezafibrate. Laboratory findings in some published case reports demonstrated that, in some cases, it is the combination of rosiglitazone and fenofibrate, and neither agent alone, that lowers HDL-C.

Adverse Reactions

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.

The most frequently reported adverse events include: gastrointestinal (epigastric distress, flatulence, abdominal pain, nausea, diarrhea, constipation), dermatologic (erythema, pruritus, urticaria), musculoskeletal (muscle pain and weakness, arthralgia), central nervous system (headache, dizziness, insomnia), miscellaneous (decreased libido, hair loss, weight loss).

Adverse events, regardless of their causality, reported in more than 1% of patients are shown in Table 1.

Table 1: Number (%) of Patients Reporting Adverse Events
 Fenofibrate
N= 477
Placebo
N= 386
Body as a whole68 (14.3%)51 (13.2%)
 Abdominal pain12 (2.5%)8 (2.1%)
 Asthenia14 (2.9%)7 (1.8%)
 Headache15 (3.1%)11 (2.8%)
Cardiovascular system15 (3.1%)13 (3.4%)
Digestive system63 (13.2%)47 (12.2%)
 Diarrhea10 (2.1%)13 (3.4%)
 Nausea12 (2.5%)7 (1.8%)
 Constipation6 (1.3%)3 (0.8%)
 Dyspepsia5 (1.0%)6 (1.6%)
 Flatulence10 (2.1%)10 (2.6%)
Endocrine system1 (0.2%)1 (0.3%)
Haemic & lymphatic system3 (0.6%)1 (0.3%)
Metabolic & nutritional disorders18 (3.8%)14 (3.6%)
 ALT increase12 (2.5%)4 (1.0%)
 AST increase8 (1.7%)1 (0.3%)
 ALT/AST increase9 (4.9%)0
 CPK increase1 (0.2%)5 (1.3%)
 Creatinine increase8 (1.7%)1 (0.3%)
Musculo-skeletal system31 (6.5%)21 (5.4%)
 Arthralgia11 (2.3%)11 (2.8%)
 Myalgia3 (0.6%)4 (1.0%)
Nervous system31 (6.5%)11 (2.8%)
 Dizziness5 (1.0%)4 (1.0%)
Respiratory system34 (7.1%)25 (6.5%)
 Rhinitis10 (2.1%)4 (1.0%)
Skin and appendages24 (5.0%)12 (3.1%)
 Rash11 (2.3%)3 (0.8%)
 Pruritus10 (2.1%)3 (0.8%)
Special senses14 (2.9%)10 (2.6%)
Urogenital system14 (2.9%)9 (2.3%)

Safety was monitored for 3 years during the placebo-controlled DAIS study (See Clinical Studies) 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 2 below summarizes the incidence of adverse events, by body system, observed in both treatment groups.

Table 2: DAIS study: Incidence of adverse events (AEs) by system, experienced by type 2 diabetic patients during treatment with fenofibrate or placebo (ITT population)
Body SystemFenofibrate
(N=207)
Placebo
(N=211)

Total # pts. with at
least 1 AE
AEsPatientAEsPatient
Total AEs:
1710
201 (97.1%)Total AEs:
1759
202 (95.7%)
Body as a whole371 (21.7%)136 (65.7%)362 (20.6%)146 (69.2%)
Cardiovascular183 (10.7%)84 (40.6%)220 (12.5%)96 (45.5%)
Digestive196 (11.5%)86 (41.6%)194 (11.0%)87 (41.2%)
Endocrine11 (0.6%)10 (4.8%)19 (1.1%)11 (5.2%)
Haemic/lymphatic31 (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%)
Musculo-skeletal155 (9, 1%)84 (40.6%)180 (10.2%)84 (39.8%)
CNS103 (6.0%)59 (28.5%)98 (5.6%)58 (27.5%)
Respiratory301 (17.6%)108 (52.2%)279 (15.9%)105 (49.8%)
Skin/appendage107 (6.3%)58 (28.0%)107 (6.1%)48 (22.8%)
Special senses73 (4.3%)44 (21.3%)90 (5.1%)50 (23.7%)
Urogenital118 (6.9%)55 (26.6%)103 (5.9%)46 (21.8%)
Other11 (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 3 are the adverse events possibly or probably related to fenofibrate, microcoated formulation and reported by more than 0.5% of the patients.

Table 3: Number (%) of patients reporting adverse events possibly or probably related to fenofibrate
Canadian and German multicenter studies (12-week treatment)
Adverse Eventsmicrocoated fenofibrate
(n = 375)
Digestive system 
 Gastrointestinal disorder4 (1.1%)
 Nausea3 (0.8%)
 Flatulence2 (0.5%)
 Diarrhea2 (0.5%)
 Liver function tests abnormal2 (0.5%)
 Dyspepsia2 (0.5%)
 Gastritis2 (0.5%)
 Constipation2 (0.5%)
Body as a whole 
 Abdominal pain4 (1.1%)
 Headache2 (0.5%)
 Asthenia2 (0.5%)
 Lab test abnormal2 (0.5%)
Metabolic and Nutritional Disorders 
 ALT increased  (> 3 x UNL)3 (0.8%)
 AST increased  (> 3 x UNL)4 (1.1%)
 Creatine kinase increased  (> 5 x UNL)1 (0.3%)
Nervous system 
 Dizziness2 (0.5%)
 Libido decreased2 (0.5%)

Some epidemiological studies and case reports support paradoxical HDL-C lowering with fenofibrate.

Other adverse events include commonly reported cases of vomiting. Uncommonly reported cases of pancreatitis and venous thromboembolism (pulmonary embolism and deep vein thrombosis). Rarely reported cases of alopecia, sexual asthenia, myositis and muscular cramps. Very rarely reported cases of rhabdomyolysis and interstitial pneumopathies. Episodes of hepatitis have been reported. When symptoms indicative of hepatitis occur (e.g. jaundice, pruritus), and diagnosis is confirmed by laboratory testing, fenofibrate therapy should be discontinued (see WARNINGS).

Photosensitivity reactions, development of gallstones and cutaneous hypersensitivity with erythema and vesiculation or nodulation on parts of the skin exposed to sunlight or artificial UV light in individual cases (even after many months of uncomplicated use) have also been reported.

Post-Marketing

In addition to those events reported during clinical trials, the following side effects have been reported spontaneously during post-marketing use:

Hepatobiliary Disorders: jaundice, complications of cholelithiasis (e.g., cholecystitis, cholangitis, biliary colic, etc.)

Skin and Subcutaneous Tissue Disorders: severe cutaneous reactions (e.g erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis)

Laboratory Tests

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 x UNL) due to fenofibrate therapy appears to be dose related; 0.6% (1/157) (80mg tablet), 1.9% (3/158) (160mg tablet) and 4.0% (6/149) (240mg 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 haptoglobin concentration has been observed in some patients with Type IV hyperlipidemia during long-term use of fenofibrate. However, this decrease in haptoglobin 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.

Symptoms and Treatment of Overdosage

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.

Dosage and Administration

Patients should be placed on a standard cholesterol-lowering diet (at least equivalent to the Adult Treatment Panel III (ATP III TLC diet)) before receiving LIPIDIL SUPRA (fenofibrate, microcoated formulation), and should continue on this diet during treatment with LIPIDIL SUPRA. If appropriate, a program of weight control and physical exercise should be implemented.

Prior to initiating therapy with LIPIDIL SUPRA, secondary causes for elevations in plasma lipid levels should be excluded. A lipid profile should also be performed.

If a significant serum lipid response is not obtained in three months, LIPIDIL SUPRA should be discontinued.

The usual recommended dose for LIPIDIL SUPRA in adults is one 160 mg tablet daily taken with the main meal. Tablets should be swallowed whole with a glass of water.

The maximum recommended total daily dose of LIPIDIL SUPRA is 200 mg (2 tablets of 100 mg).

In patients with renal insufficiency (creatinine clearance between 20 and 100 ml/min), LIPIDIL SUPRA treatment should be initiated at the dose of 100 mg/day and increased only after evaluation of the tolerance and effects on the lipid parameters. LIPIDIL SUPRA should not be used when the creatinine clearance is lower than 20 ml/min.