PMS-Fenofibrate Micro Product Monograph

INDICATIONS AND CLINICAL USE

pms-FENOFIBRATE MICRO (fenofibrate) is indicated as an adjunct to diet and other therapeutic measures for:

$ Treatment of patients with hypercholesterolemia, Fredrickson classification Type IIa and IIb mixed hyperlipidemias, to regulate lipid levels (reduce serum triglycerides and LDL cholesterol levels and increase HDL cholesterol).

$ Treatment of adult patients with very high serum triglyceride levels, Fredrickson classification Type IV and Type V hyperlipidemias, who are at a high risk of sequelae and complications (i.e., pancreatitis) from their hyperlipidemia.

pms-FENOFIBRATE MICRO alone may not be adequate therapy in some patients with familial combined hyperlipidemia with Type IIb and Type IV hyperlipoproteinemia.

Initial therapy for hyperlipidemia should include a specific diet, weight reduction, and an exercise program; and for patients with diabetes mellitus, a good diabetic control.

CONTRAINDICATIONS

1. 1. Hepatic or renal dysfunction (creatinine clearance < 20 mL/min), including primary biliary cirrhosis.
2. 2. Pre-existing gallbladder disease (see WARNINGS).
3. 3. Hypersensitivity to fenofibrate, or other drugs of the fibrate class.
4. 4. The drug should not be used in pregnant or lactating patients.
5. 5. pms-FENOFIBRATE MICRO (fenofibrate) are not indicated for the treatment of Type I hyperlipoproteinemia.

WARNINGS

1. 1.

   Drug Interactions:

   Concomitant Oral Anticoagulants: Caution should be exercised when anticoagulants are given in conjunction with fenofibrate. The dosage of anticoagulants 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 combined therapy with a fibrate. Therefore, the benefits and risks of using fenofibrate concomitantly with these drugs should be carefully considered.

   MAO Inhibitors: MAO inhibitors with hepatotoxic potential must not be administered together with fibrates such as fenofibrate as they may increase the risk of hepatotoxicity.

   Sulfonylureas and Insulin: It has been previously reported that the fibrates may potentiate the effects of these classes of drug. This effect has not yet been documented in the case of fenofibrate. No case of hypoglycemia or hypoglycemic reaction has been reported to date.

2. 2. Pediatric Use: Limited experience is available in children and adolescents, at the dose of 5 mg/kg/day nonmicronized formulation. However, safety and effectiveness has not been established in this sub-population.
3. 3. Use in Pregnancy: Strict birth control procedures must be exercised by women of childbearing potential. If pregnancy occurs despite birth control procedures, fenofibrate should be discontinued. Women who are planning pregnancy should discontinue fenofibrate several months prior to conception.
4. 4. Nursing Mothers: In the absence of information concerning the presence of fenofibrate in human breast milk, fenofibrate should not be used by nursing mothers.
5. 5. Cholelithiasis: Fenofibrate may increase cholesterol excretion into the bile and may lead to cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated. Fenofibrate therapy should be discontinued if gallstones are found.
6. 6. Fenofibrate clinically and pharmacologically shows similarities with clofibrate. Physicians prescribing fenofibrate should also be familiar with the risks and benefits of clofibrate.
7. 7. 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 hepatocellular 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.
8. 8. Since a relationship between reduction of mortality from coronary artery disease and total mortality has not been established, fenofibrate should be administered only to those patients described in Indications. If a significant serum lipid response is not obtained in 3 months, fenofibrate should be discontinued. If fenofibrate is chosen for treatment, the prescribing physician should discuss the proposed therapy and inform the patient of the expected benefits and potential risks which may be associated with long-term administration (see Precautions).

PRECAUTIONS

Initial Therapy:

Before instituting fenofibrate therapy, 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.

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. Periodic determination of serum lipids, fasting glucose, creatinine and ALT should be considered during fenofibrate treatment, particularly during the first months of therapy.

Reproduction Studies:

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

Hematologic Changes:

Mild hemoglobin, hematocrit 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.

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.

However, these abnormalities disappear when therapy with fenofibrate is discontinued. Therefore, periodic liver function tests (AST, ALT and GGT [if originally elevated]) in addition to other baseline tests are recommended after 3 to 6 months and at least yearly thereafter. Fenofibrate

therapy should be terminated if abnormalities persist. Fenofibrate may increase cholesterol excretion into the bile and may lead to cholelithiasis.

Hepatobiliary Disease:

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

Skeletal Muscle:

Treatment with drugs of the fibrate class has been associated on rare occasions with rhabdomyolysis, or myositis, 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 creatinine phosphokinase levels.

Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. CPK levels should be assessed in patients reporting these symptoms, and fenofibrate therapy should be discontinued if markedly elevated CPK levels

(10 times the upper limit of normal) occur or myopathy is diagnosed.

Drug Interactions (see also Warnings):

Resins: 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 are impaired by cholestyramine.

Estrogens: Since estrogens may lead to a rise in lipid levels, the prescribing of fibrates in patients taking estrogens or estrogen-containing contraceptives must be critically considered on an individual basis.

Renal Function:

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). Fenofibrate is not removed by hemodialysis and should not be used in dialysis patients.

ADVERSE REACTIONS

Clinical adverse effects of fenofibrate therapy have been reported at an incidence between 2 and

15% with a mean of 6.3% in European trials of less than 12 months duration. In longer term studies, the incidence was between 7 and 14% with a mean of 11.3%. The most frequently reported adverse effects 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).

In 2 separate controlled clinical studies conducted in the U.S., a total of 191 patients on fenofibrate

(116 Type II and 75 Type IV/V patients) were evaluated for adverse effects versus 183 patients on placebo (111 Type II and 72 Type IV/V patients). Listed in Table I are the adverse reactions considered by the investigators to be possibly or probably related to treatment, and reported by more than 1% of the patients receiving fenofibrate in these trials.

Table 1: Numbers (%) of Patients Reporting Adverse Reactions

* One patient reported multiple adverse effects

In these studies, the difference between the numbers of nonmicronized fenofibrate and placebo patients reporting these adverse reactions was not statistically significant (p>0.05). While the nature

of the adverse reactions reported was similar in both studies, these reactions were observed in most cases at a higher frequency in the longer term, 6-month trial in Type II patients.

Adverse reactions for micronized fenofibrate at recommended therapeutic doses in clinical trials have shown a comparable profile with those described for the nonmicronized fenofibrate formulation.

Surveillance in countries in which fenofibrate has been marketed for up to 20 years, such as France,

Germany and the United Kingdom, indicates that clinical adverse effects reported include gastrointestinal complaints, painful muscles, skin disorders typically classified as pruritus, urticaria or erythema, loss of weight, impotence, diverse nervous complaints, hair loss, gallstones, pancreatitis and hepatitis.

Laboratory Parameters:

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 U.S.

clinical trials, elevations above twice the upper limit of normal were observed in 6.8% of the patients treated with fenofibrate, versus 1.6% of the patients on placebo. Values usually return to normal without interruption of treatment. On some occasions, more severe elevations of transaminases (above twice the upper limit of normal values) were noted; such rises subside when fenofibrate therapy is discontinued (see Precautions). Reductions in alkaline phosphatase levels have also been observed.

Mild decreases in hemoglobin, hematocrit and white blood cell counts have been observed occasionally in patients following initiation of fenofibrate therapy. 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 hemolysis.

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 CPK elevations and changes in hematologic parameters which generally subside when the drug is discontinued (see Precautions).

SYMPTOMS AND TREATMENT OF OVERDOSAGE

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

DOSAGE AND ADMINISTRATION

The recommended dose for pms-FENOFIBRATE MICRO (fenofibrate) in adults is 200mg daily administered as one 200 mg capsule taken with the main meal. The maximum recommended total daily dose is 267 mg.

In patients with renal insufficiency (creatinine clearance between 20 and 100 ml/min), pms-

FENOFIBRATE MICRO treatment should be initiated at the dose of 67 mg/day and increased progressively after evaluation of the tolerance and effects on the lipid parameters.

Fenofibrate is not removed by hemodialysis and should not be used when the creatinine clearance is lower than 20 ml/min.

INFORMATION FOR THE CONSUMER

Full prescribing information is available to doctors and pharmacists on request.

pms-FENOFIBRATE MICRO reduce blood cholesterol, in particular cholesterol associated with low and very low density lipoproteins (LDL and VLDL-cholesterol). pms-FENOFIBRATE MICRO also reduce high triglyceride levels associated with a primary hypercholesterolemia. Blood uric acid levels are also reduced by pms-FENOFIBRATE MICRO treatment. The mechanism of action of pms-FENOFIBRATE MICRO is not fully established.

pms-FENOFIBRATE MICRO are only available by prescription. This medicine should only be used to supplement an appropriate diet recommended and followed up by your doctor for the long term treatment of raised lipid levels: prescribing of this medicine in no way replaces dietary treatment. In addition, depending on the situation, your doctor may have recommended further physical exercise, weight loss or other measures.

Take this medicine exactly as prescribed. It is most effective if taken with the main meal each day.

If you forget to take your medicine, take it as soon as you remember, but do not take a dose if it=s almost time for your next dose. Taking double doses is not recommended. Do not change the dose without your doctor's advice. Consult your doctor before stopping treatment since doing so may result in an increase in your blood lipid levels.

BEFORE STARTING TREATMENT WITH THIS MEDICINE, your doctor must know:

• if you have taken pms-FENOFIBRATE MICRO (fenofibrate micronized) before and if it caused an allergy or was otherwise poorly tolerated,
• if you suffer from liver or kidney problems,
• if you have gallbladder or gallstone problems,
• if you are pregnant, or intend to become pregnant, or are breast-feeding, or intend to breastfeed,

• if you are taking other medicines, in particular, an oral anticoagulant such as warfarin.

  PROPER USE OF THE MEDICINE

pms-FENOFIBRATE MICRO should be taken as a once-a-day dose with the main meals of the day.

It is particularly important to follow this advice because pms-FENOFIBRATE MICRO is better absorbed and hence more effective when taken with food.

• Your doctor will ask you to have regular medical check-ups and laboratory tests. We strongly recommend that you faithfully keep these appointments.

• Inform your doctor of any health problem that occurs while you are taking pms-

  FENOFIBRATE MICRO. Also, keep your doctor informed of any prescription or non-prescription medicines you may be taking. If you need other medical treatment let the doctor know that you are taking pms-FENOFIBRATE MICRO.

• Tell your doctor if you feel in any way unwell taking pms-FENOFIBRATE MICRO (see

  UNWANTED EFFECTS).

• Safe use of fenofibrate in children and young adolescents has not been established with fenofibrate.
• The effect pms-FENOFIBRATE MICRO in preventing heart attacks, atherosclerosis or heart disease is not known.
• pms-FENOFIBRATE MICRO should not be used during pregnancy. In the event of pregnancy during treatment, pms-FENOFIBRATE MICRO should be discontinued and the physician should be informed.

• It is not recommended to take pms-FENOFIBRATE MICRO while breast-feeding.

  UNWANTED EFFECTS

In addition to its intended action any medicine may cause unwanted effects.

Unwanted effects may occur in certain patients. They may appear and disappear without involving any particular risk but if any unwanted effects persist or become bothersome you must let your doctor know without delay. Such unwanted effects may consist of abdominal pain, constipation, diarrhea, nausea, headache, dizziness, skin reactions, muscular pain or cramps, fatigue.

THIS MEDICINE IS PRESCRIBED FOR A PARTICULAR HEALTH PROBLEM AND

FOR YOUR PERSONAL USE. DO NOT GIVE IT TO ANY OTHER PERSON.

KEEP ALL MEDICINES OUT OF THE REACH OF CHILDREN.

IF YOU REQUIRE FURTHER INFORMATION, ASK YOUR DOCTOR OR

PHARMACIST.

Pharmascience Inc. Montreal, Canada

PHARMACEUTICAL INFORMATION

DRUG SUBSTANCE:

Proper Name: Fenofibrate

Chemical Name: Isopropyl 2-[p-(p-chlorobenzoyl)phenoxy]-2-methylpropionate.

Structural Formula:

Molecular Formula: C₂₀H₂₁ClO₄

Molecular Weight: 360.84

Description: Fenofibrate is a crystalline, cream-coloured, odourless and tasteless powder. It has a melting point of 79 to 82EC. Fenofibrate is practically insoluble in water, soluble in ethanol, freely soluble in acetone and chloroform.

Stability and Storage Recommendations:

Store bottles between 15E-30EC.

Store blister packs between 15E-25EC. Protect from high humidity.

Non-medicinal ingredients:

Cl C

O

O C

CH₃

CH₃

COO

CH₃

CH₃ CH

pms-FENOFIBRATE MICRO capsule contains: lactose, pregelatinized starch, croscarmellose sodium, sodium lauryl sulfate, crospovidone and magnesium stearate. Each capsule shell contains:

titanium dioxide, gelatin, silicon dioxide, and black ink.

Utilizing a specific process of manufacturing, the size of the particles of fenofibrate contained in pms-FENOFIBRATE MICRO are reduced, thus providing an increase in the effective surface area of particles to facilitate the dissolution rate and absorption.

AVAILABILITY OF DOSAGE FORMS

pms-FENOFIBRATE MICRO 200 mg Capsules: Each opaque orange cap and body capsule contains

200 mg of fenofibrate, printed in black ink ‘N’ on one end and ‘200’ on the other.

pms-FENOFIBRATE MICRO is supplied in bottles of 100, 500 and 1000 and in blister packs of 30 and 60.

PHARMACOLOGY

Animal

The antilipemic activity of fenofibrate was studied in normal and hyperlipidemic rats. Fenofibrate significantly lowers total lipids, LDL and VLDL-cholesterol, and triglyceride levels. At the same time it has been found to variably increase HDL-cholesterol concentrations. Its effect is more pronounced in hyperlipidemic rats and those fed high fat diets than in normal rats and those fed standard diets. Studies comparing fenofibrate with clofibrate have found that fenofibrate is a potent cholesterol-lowering drug.

The pronounced hypolipidemic effect in hyperlipidemic animals suggest that fenofibrate reduces cholesterol by enhancing the rate of cholesterol elimination. In normocholesterolemic rats, the main effect of fenofibrate is an inhibition of cholesterol biosynthesis.

Fenofibrate has no anti-inflammatory, cardiovascular, respiratory, CNS, autonomic nervous system, or other basal metabolism activities.

Pharmacokinetics:

In rats, dogs and man, fenofibrate is poorly absorbed from the gastrointestinal tract. The absorption is increased when the compound is administered in oil with food.

In man, a dose of 300 mg per day of non-micronized fenofibrate produced mean steady-state plasma drug concentrations ranging between 10 and 15 :g/mL after 5 days of administration.

Fenofibrate is metabolized by hydrolysis to its active form, fenofibric acid. In man, fenofibric acid is eliminated as conjugated glucuronic acid. In rats this glucuroconjugation is very low and in dogs, practically non-existent. In these two species the main metabolic pathway is carbonyl reduction.

The excretion in rat is principally a biliary excretion. In man within 7 days after oral administration of fenofibrate with food, about 60% is excreted in urine and 25% in feces.

The elimination half-life is about 7-8 hours in rats and 24 hours in dogs. In man elimination half-life of fenofibric acid is about 20-24 hours. This value is not modified after multiple dosing. Very minor changes of pharmacokinetic parameters were observed elderly subjects, but in patients with severe renal failure, significant accumulation was observed with large increase of the half-life.

No sex related differences in pharmacokinetics and metabolism were observed in any species.

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

Pharmacokinetic studies were performed on a fenofibrate micronized capsule 67 mg and 200 mg formulations.

A single dose study in 18 healthy volunteers (9M, 9F) demonstrated that one capsule of 200mg micronized fenofibrate was bioequivalent to one capsule containing 300 mg of non-micronized fenofibrate. In this balanced crossover study, the two formulations were administered immediately after a high-fat meal. The mean results are presented in the following table:

A second single dose study in 18 healthy male volunteers demonstrated that one capsule of micronized fenofibrate 200 mg is equivalent to three 100 mg capsules of non-micronized fenofibrate taken simultaneously.

The two formulation were administered immediately after a high-fat meal according to a balanced crossover design. The mean results are presented in the following table:

In a third cross-over study, 18 healthy volunteers (8F,10M) received either one 200 mg capsule of fenofibrate micronized or three 100 mg capsules of non-micronized fenofibrate once daily, during a low fat, low calorie meal, for 10 days.

The comparison of the pharmacokinetic parameters obtained at steady-state (Day 10) with the two formulations shows that the amount of fenofibrate absorbed is slightly higher with one capsule of micronized fenofibrate that with three capsules of non-micronized fenofibrate but also that the better absorption of the micronized fenofibrate leads to a better homogeneity of the fenofibric acid plasma concentrations. This lower inter-subject variability with the micronized fenofibrate formulation is shown by the decrease of the coefficients of variation of AUC0-24, Cmax as well as Cmin obtained on day 10. The mean values obtained on day 10 and their coefficients of variation (CV%) are presented in the following table:

In a fourth cross-over study, 5 healthy adult volunteers (male) received either one 200 mg capsule of micronized fenofibrate or three 100 mg capsules on non-micronized fenofibrate once daily, during a standard supper containing 40% lipids, for 10 days.

The comparison of the pharmacokinetic parameters obtained at steady-state (day 10) with the two formulations shows that the amount of fenofibrate absorbed is slightly higher with three capsules of non-micronized fenofibrate than with one 200 mg capsules of micronized fenofibrate. The mean

values of the pharmacokinetic parameters measured at Day 10 (CV%) are presented in the following table:

The apparent discrepancy of the results of the two multiple-dose studies can be explained by the difference in fat content of the meals used in these studies and by the difference of particle size of fenofibrate in the two formulations.

The larger size particles of fenofibrate contained in the non-micronized formulation are indeed poorly absorbed in the presence of a low-fat meal whereas the smaller particles of the micronized formulation are already well absorbed.

Fenofibrate dissolves more easily in the presence of a larger amount of fat and food, this seems to affect the absorption of non-micronized fenofibrate.

One specific pharmacokinetic study was performed with a 67 mg micronized fenofibrate capsule formulation. Twenty-four healthy male volunteers took part and completed this two-way, open

randomized, cross-over study. Each volunteer received a single oral dose of each formulation with a standard breakfast and with a one week interval between doses.

Values obtained for the two formulations were as follows:

Clinical Pharmacology

Action on Lipid Parameters

The oral administration of 300 mg/day of fenofibrate for one week significantly reduced the plasma cholesterol and triglyceride levels in normolipidemic men. However, no change in HDL cholesterol levels was observed.

The effects of fenofibrate 300 mg/day, clofibrate 1500 mg/day and placebo on plasma lipoprotein and biliary lipid composition were compared in a double-blind study involving 12 normolipidemic subjects. Each treatment lasted two weeks. Fenofibrate lowered plasma cholesterol by 17%, triglycerides by 9% and LDL cholesterol by 16%.

Fenofibrate 400 mg/day was administered for one month to 18 patients with hyperlipoproteinemia who failed to achieve normal lipid levels with a lipid-lowering diet. Fenofibrate treatment significantly reduced the total plasma cholesterol concentrations by 14%, plasma triglycerides by

49% and VLDL triglycerides by 62%. No significant change was observed in HDL cholesterol concentration. LDL-cholesterol was reduced in patients with Type IIa and IIb hyperlipoprotein and increased in Types IV and V. Lipoprotein-lipase activity was significantly increased.

In a double-blind study, two parallel groups of hyperlipidemic patients were treated with either 400 mg/day of fenofibrate (15 patients) or placebo (8 patients) for one month. Significant decreases in total cholesterol, triglycerides and Apo-B were observed in the fenofibrate treated group, along with a significant increase in HDL-cholesterol.

Uricosuric Action

Fenofibrate decreased the plasma uric acid levels in normal as well as hyperuricemic subjects. In a study involving 10 normal male volunteers, single doses of 300 mg of fenofibrate were compared to benzbromarone. A uricosuric action was observed with both drugs. During a 14 day study in hyperlipidemic patients, a 28% decrease in plasma uric acid concentration was observed less than four days after the onset of treatment with 300 mg/day of fenofibrate. This effect was consistent until the end of the study. An additional study conducted in healthy volunteers confirmed the rapid onset of the fenofibrate induced hypouricemic effect and demonstrated the increased capability of the kidneys under these conditions to eliminate uric acid without damage to the proximal tubules.

Effect on Lithogenic Index

By virtue of structural similarity to other fibrates, fenofibrate might be suspected to increase the risk of gallstones as a result of increased cholesterol excretion via the bile.

Thus, five investigators have studied the biliary lithogenic index in fenofibrate-treated patients. In the majority of studies, the lithogenic index was shown to be increased but the effect of fenofibrate was not marked and the degree of significance varied from one study to another. The relative proportions of bile lipids were also affected by fenofibrate treatment.

It is not known if fenofibrate treatment modifies the lipid composition of the bile.

Human Liver Biopsies

Two specific studies have been conducted in hyperlipidemic patients to evaluate the potential hepatocellular toxicity of fenofibrate. Examination of biopsies from liver samples of 38 patients including 28 receiving fenofibrate over a mean period of approximately 2 years did not show any difference between the treated and untreated patients. Peroxisomes were relatively rare, and macroscopic light and electron-microscopic observations revealed no signs of treatment-associated cellular abnormality. A similar study, taking biopsies from 10 patients who had, on average, received fenofibrate for 9 months, and comparing these with tissue from 13 hyperlipidemic patients who had only received dietary treatment did not show any morphological difference between the two groups or any significant difference in the number or in the size of peroxisomes.

Clinical Experience

The activity of fenofibrate has been evaluated in more than 150 clinical trials performed in the U.S.,

Canada and Europe. The majority of these were conducted with non-micronized fenofibrate at a daily dose of 300 mg.

US Studies

Two multicenter, double-blind, placebo-controlled studies were conducted in the US, one in patients with Type II hyperlipoproteinemia, the other in Type IV/V patients.

Type II Study:

Two hundred twenty seven (227) hypercholesterolemic patients (181 Type IIa and 46 IIb) were enrolled during 6 months. After the double-blind phase, the study became open and all patients were given fenofibrate for the ensuing six months period.

One hundred and sixteen (116) patients received fenofibrate (100 mg tid) and one hundred and eleven (111) received placebo. At the end of this first period, ninety-eight (98) of the one hundred and sixteen (116) who were given fenofibrate and ninety-four (94) of the one hundred and eleven

(111) patients who were given placebo, entered the second 6 month open phase of fenofibrate treatment.

Fenofibrate reduced the mean plasma concentrations of total cholesterol and VLDL-cholesterol in both Type IIa and IIb patients. LDL-cholesterol concentration was substantially decreased in all

Type IIa patients, whereas there was little change in the Type IIb patients in whom the pre-treatment

LDL-cholesterol levels were relatively normal. The mean concentrations of HDL-cholesterol levels were increased in both types of patients. Plasma triglyceride levels were decreased in the hypertriglyceridemic Type IIb patients. These effects were observed in the double-blind and open phases of the study (table 2).

Table 2: Effect of fenofibrate on percent change of lipoprotein lipids from baseline

N.B. p-values <0.01 for differences between fenofibrate and placebo groups for all parameters except LDL-cholesterol in type IIb. Inversely, placebo treatment induced no statistical significant changes in the lipid parameters.

Type IV/V Study:

One hundred forty seven (147) patients entered the study and all were stabilized on a low-fat diet.

Following a placebo baseline period, patients were stratified according to plasma triglyceride (TG)

levels (group A, 350-499 mg/dL, group B, 500-1500 mg/dL) and randomly assigned to treatment with either 100 mg fenofibrate or one placebo capsule three times a day with meals.

Demographically the treatment groups were similar. A dramatic reduction in total TG levels

occurred in the fenofibrate-treated patients but not in the placebo-treated patients. This effect, occurred in both group A (46%) and group B (55%) patients, reached near maximum reduction in only 2 weeks of treatment, and continued throughout the 8 week treatment period. In both groups fenofibrate treatment also decreased very low-density lipoprotein (VLDL) TG, total cholesterol and

VLDL cholesterol, and increased high-density lipoprotein (HDL) levels (table 3).

LDL cholesterol levels increased 45% from baseline in group B but not in group A. It should be noted that baseline LDL cholesterol levels were considerably depressed in group B as compared with group A patients.

Table 3: Percent change in lipid/lipoprotein values (mg/dL)

from baseline to end-point

Mean values rounded to nearest whole number.

*Not significantly different from placebo at p<0.05. All other changes with fenofibrate were significantly different from placebo at p ranging from 0.05 to <0.001.

Canadian study

Seventeen (17) patients with hypercholesterolemia were included in this six month open study. The dosage of fenofibrate was 100 mg t.i.d. Twelve (12) patients had familial hypercholesterolemia with tendon xanthomas (FHX) and five (5) patients were suffering from various types of hyperlipidemia including two cases of mixed familial hyperlipidemia, one case of Type IV-hyperlipidemia and two cases of familial dysbetalipoproteinemia (Type Ill). Ten (10) patients showed serum cholesterol levels greater than 400 mg/dL; severe atherosclerosis was present in four other patients.

Plasma cholesterol and triglyceride concentrations were measured monthly and VLDL-C, LDL-C and HDL-C concentrations were measured every three months. These results were compared to the values obtained during a period of diet control. In the 12 patients suffering from familial hypercholesterolemia with tendon xanthomas, fenofibrate was very effective in lowering both cholesterol (mean decrease 19.8 percent) and LDL-C (mean decrease of 20.4 percent) (p < 0.0001 in both cases). However, the drug had no effect on HDL-C. Ten of the 12 patients showed a response characterized by a significant decrease in serum cholesterol of 15 percent or more. A marked and significant effect was observed in three of the other five patients. This effect, apparent on both cholesterol (decreases ranging from 33.6 to 38.2 percent) and triglycerides (decreases ranging from

36.3 to 77.8 percent), was accompanied by a corresponding effect on VLDL-C and a significant increase in HDL-C. One case of mixed familial hyperlipidemia proved resistant to treatment and the treatment in one Type III patient had to be interrupted after 3 months because of deterioration of lipoprotein profile and digestive problems.

In nine hundred and seventy one (971) patients with hyper-cholesterolemia (Type IIa), fenofibrate decreased the levels of total cholesterol (-16 to -30%), LDL-cholesterol (-20 to -33%) and apoprotein B (-14 to -37%). HDL-cholesterol levels were variably affected depending on initial

levels (-15 to +28%). In eight hundred and fifty four (854) patients with mixed hyperlipidemia

(Type IIb), more variable decreases were observed in total (-3 to -36%) and LDL-cholesterol levels

(-11 to -29%), as well as substantial decreases in triglyceride levels (-19 to -67%). In five hundred and seven (507) patients with hypertriglyceridemia (Type IV), marked decreases of triglycerides (-

30 to -70%) and VLDL-triglycerides (-47 to -70%) were obtained following fenofibrate treatment.

Results observed in short-term trials were maintained over long-term treatment periods.

European studies

Non-micronized formulation

Thirty-one (31) short-term studies of up to twelve (12) months duration, and six (6) long-term trials of up to six (6) yearn duration were conducted in Europe, involving two thousand four hundred and forty nine (2449) patients. In most studies, the recommended fenofibrate dose of 300 mg daily, administered in three equally divided doses, was used; occasionally, this dose was increased to 400 mg or 600 mg, or reduced to 200 mg daily depending on patient response.

Micronized formulation

Specific clinical studies were performed with a micronized formulation.

The first clinical trial, a double blind comparative trial with micronized fenofibrate (one 200 mg capsule per day), non-micronized fenofibrate (100 mg three times daily) and matched placebo, of 3 months treatment duration, demonstrated comparable clinical response on all lipidic parameters with both the intent-to-treat and efficacy analysis.

The results of this study indicate that the fenofibrate treatments, 3 x 100 mg or 1 x 200 mg micronized, are significantly more active than the placebo on lipid parameters: cholesterol, triglycerides, LDL-cholesterol fraction and apolipoprotein B. The two treatments did not present any noticeable activity on the HDL-cholesterol or apolipoprotein A1 concentrations when they were subnormal at T0.

In the intent-to-treat analysis, the two treatments showed equivalent success levels of 73.4 % for 3 x

100 mg fenofibrate and 71.9 % for 1 x 200 mg micronized fenofibrate and significantly greater than that observed in the placebo group (14.8 %).

In the analysis of efficacy, the two treatments decreased the mean cholesterol concentrations by more than 15% versus the placebo group and this difference was significant (p <0.0001).

Concerning triglycerides, the difference between the means for each of the fenofibrate groups and the placebo group is greater than the comparison value (30 % of placebo).

The second clinical trial conducted in Germany was established to evaluate the general acceptability associated with efficacy on lipid parameters of micronized fenofibrate. From patients evaluated for efficacy, there were 45.1% patients with type IIa and 69.6% patients with type IIb classified as good responders on total cholesterol at T3. The total number of good responders for triglycerides

(patients type IIb and IV) was 71-4% at T3 and 77.7% at T12. The treatment effect was consistent throughout the 12 months of the study.

After 3 months of treatment the mean value of total cholesterol was lowered in patients with type IIa from 311.4 mg/dL to 258.3 mg/dL with a mean decrease of 17 %. In patients with type IIb the mean value of total cholesterol lowered from 328.0 mg/dL to 266.5 mg/dL with a mean decrease of 18.6

%.

After 3 months of treatment the mean value of triglycerides was lowered in patients with type IIb from 254.8 mg/dL to 165.7 mg/dL with a mean decrease of 34.4 %. In patients with type IV the mean value of triglycerides was lowered from 383.8 mg/dL to 231.1 mg/dL with a mean decrease of

37.9 % after 3 months of treatment.

TOXICOLOGY

Acute toxicity

Results from studies in mice, rats, hamsters and dogs indicate a low toxicity for fenofibrate with the highest administered doses (3200 to 24000 mg/kg), resulting in no deaths over the 7-day observation period. Autopsy findings were negative.

Chronic toxicity studies

Rats with normal or high cholesterol diet were treated for 7 days by gavage with fenofibrate at 0, 3,

10, 30, 100 and 300 mg/kg/day or clofibrate at 20,60, 200 and 600 mg/kg/day. SGOT levels were raised in treated rats but SGPT levels remained within the normal range for rats on normal diet and were only slightly elevated in rats on the high cholesterol diet. Dose related hepatomegaly and proliferation of peroxisomes occurred, at doses above 30 mg/kg/day. In a second but similar study of drug metabolizing enzymes, rats were treated daily by gavage for 7 days with fenofibrate at 0 or

100 mg/kg or clofibrate 200 mg/kg. The absence of significant change in the parameters measured suggests that the mechanisms resulting in hepatomegaly caused by both fibrates had little effect on cell organelles involved in drug metabolism and protein synthesis. In a third study in rats, oral doses of fenofibrate (0 to 1000 mg/kg) were given for 3 months. Depression of blood lipids was seen at all dose levels. SGOT and SGPT values were increased at 500 and 1000 mg/kg. Hepatomegaly was a consistent finding at all dose levels reaching a maximum of 78 % increase in weight compared to controls but appeared to regress rapidly. There were no other significant findings in the histological examination.

A 7-month study in dogs with 50 and 100 mg/kg(day and a 24-month study with 25 mg/kg/day were carried out. None of the dogs died but there was substantial weight loss associated with cholelithiasis and some interstitial nephritis. No important changes were observed in the biological parameters. Livers were apparently normal.

Fenofibrate (0, 12, 50 or 500 mg/kg) or clofibrate (200 mg/kg) was administered via a banana preparation, during 12 months to Rhesus monkeys. No fenofibrate related effect with regard to

toxicity was noted in any of the test groups during the study. No evidence of compound-related histomorphologic alterations was present in the animals sacrificed. The Rhesus monkey resembles man where biopsy studies show no signs of peroxisome proliferation during up to 2 years of fenofibrate treatment.

Carcinogenicity studies

Five rodent feeding studies have shown that target organs for tumorigenic effects of fenofibrate are liver, pancreas and testis.

Mice showed increased liver weight with intrahepatic cholestasis and some degenerative changes but not liver tumors with 50 mg/kg/day for 22 months.

Dose-related increases in liver and kidney weight were seen in mice treated with 10 to 200 mg/kg/day of fenofibrate for 80 weeks.

Gross hepatomegaly associated with cholestasis was seen at the high dose level and in clofibrate

(200 mg/kg/day) treated mice with occasional cholangitis and periportal fibrosis. Neoplastic lesions were confined to the liver with significant increases in hepatocellular carcinoma at the high dose of fenofibrate in both sexes. Hepatocellular adenomas were also increased in males. In clofibratetreated mice there was an excess of hepatic adenomas in females but not in males.

Both fenofibrate and clofibrate were found to be associated with an increased incidence of hepatocellular hypertrophy, lobular dysplasia and Kupffer cell pigmentation in another long-term toxicity study (93 weeks) on mice. In both sexes the incidence of total hepatic neoplasms and

carcinomas was significantly increased by the high dose of fenofibrate (200 mg/kg). At the intermediate dose (60 mg/kg) the combined tumor incidence was almost significant in males but not in females, while incidence of carcinomas was not significantly increased in males and absent in females. Also, clofibrate (400 mg/kg) significantly increased the total tumor incidence but not carcinomas in males; females were unaffected.

Rats which received fenofibrate (0, 10, 45 or 200 mg/kg/day) or clofibrate (200 mg/kg/day) mixed with their diet for a 2-year period showed no significant differences in mortality over the study period. Significant increases in incidences of hepatocellular carcinoma were found in the high dose fenofibrate group of animals of both sexes, in mid dose fenofibrate males, and in clofibrate treated males. Mid-dose fenofibrate males and clofibrate treated males and females also showed significantly increased incidence of hepatocellular adenomas. Well differentiated pancreatic acinar cell carcinomas and adenomas were increased in a dose related manner in the fenofibrate treated males, and higher incidences were also evident in the clofibrate males.

The chronic toxicity and carcinogenicity of fenofibrate was further studied in rats (0,10 and 60 mg/kg/day) in order to compare treatment-related responses with those produced by clofibrate (400 mg/kg/day) and gemfibrozil (250 mg/kg/day) during 117 weeks of treatments. The absolute and relative weights of the liver were increased in all treatment groups except with 10 mg/kg fenofibrate.

Although comparatively low, an incidence of hepatocellular carcinoma was observed in gemfibrozil treated rats, and neoplastic nodules were also found in the livers of 50% of the males which survived up to the termination of the study. Fewer neoplastic nodules were seen in the dofibratetreafed rats but these animals had a high incidence of hepatocellular carcinoma at termination. A significantly

increased incidence of pancreatic acinar cell adenoma was seen in the 60 mg/kg fenofibrate males, while this increase in females was not significant. A significant increase in acinar adenoma and a slight increase in acinar carcinoma occurred with clofibrate (400 mg/kg) and some adenomas were seen in gemfibrozil-treated rats. There was some excess of benign interstitial cell tumors of the testis in all treatment groups except the group that received 10 mg/kg of fenofibrate.

Reproduction and teratology studies

There was no evidence of any increase in malformation frequency in mice, rabbits and rats after administration of fenofibrate compared to that seen in controls. Examination of offspring from fenofibrate treated dams and those having received clofibrate did not disclose any significant abnormalities when compared to offspring from the controls.

With the highest dose levels at which the mothers were adversely affected, there was evidence of embryotoxicity in rats and rabbits.

Genetic toxicity studies

Gene mutations: In vitro tests for mutagenicity with either fenofibrate or fenofibric acid in the presence or absence of activating rat or human microsomal enzyme preparations, have all given negative results. Thus, fenofibric acid was without effect on gene mutation frequency in bacteria

(Ames), yeast and mouse lymphoma cells in culture.

In a second mouse lymphoma cell comparative study, there was no response to clofibric acid while some increased response to fenofibric acid at the highest concentration used was discounted due to

poor relative growth. Similar activity was seen with gemfibrozil at toxic concentrations in the absence of metabolic activation. In conclusion, all three fibrates were found to be non-mutagenic on the protocol criteria, both in the absence and presence of metabolic activation.

Chromosome aberrations: Some trace of an increased but not significant incidence of aberrations was seen in an Th vitro mouse lymphoma cell multiple end point assay.

Chromosome aberrations as such were not seen in a more recent comparative in vitro study with

CHO cells when testing clofibric acid and gemfibrozil as well as fenofibric acid. However, clofibric acid did have a marginal effect in increasing sister chromatid exchange frequency.

The absence of excision repair in human originated HeLa cells incubated with a wide range of concentrations of fenofibric acid with or without SR, reaffirmed the essentially non-genotoxic nature of the product.

Direct effects on DNA: The ability to bind covalently to target organ DNA is a property common to chemical substances which act by direct initiation of the carcinogenic process at the nuclear level.

This type of genotoxic activity can be studied in vivo by DNA assay in rodents treated with the radiolabelled drug.

Although binding of fenofibric and clofibric acids to proteins was readily observed, no binding to

DNA was demonstrated after oral administration of C14-labelled fenofibric or clofibric acid. The

data therefore exclude somatic mutations as responsible for the known hepatocarcinogenic activity of these fibrates in rodents.

In a second in vivo test the effects of fenofibric acid were compared with those of clofibric acid and gemfibrozil on DNA synthesis in mouse testicular tissue, as measured by the incorporation of

3H4hymidine. Any response is representative of changes in DNA synthesis in any testicular cells such as germ, Sertoli, Leydig or interstitial cells undergoing scheduled or unscheduled synthesis.

Both fenofibric acid and gemfibrozil caused modest increases in thymidine incorporation above control values. Clofibrate caused some inhibition of the incorporation of thymidine into DNA at the two lowest doses with a small increase at the highest. No positive control substance was used but it would be assumed that, for example, genotoxic alkylating agents might cause a decrease in incorporation due to an inhibition of DNA synthesis. Such inhibition or cell cycle delay is well known for such agents.

The increase in DNA synthesis as observed in mouse testicular tissue with fenofibric acid and gemfibrozil is difficult to evaluate in the absence of a positive control or historical data for this recently developed test, nevertheless such an effect might be anticipated of such agents which are known to cause peroxisome proliferation and which produce increased cell turnover. The occurrence of increased cell turnover would be in keeping with a non-genotoxic but promoting mode of such compounds in mice.

In a rat primary hepatocyte unscheduled DNA synthesis (UDS) assay in vitro, gemfibrozil, clofibric acid and fenofibric acid showed a negative response. None caused nuclear labelling significantly different from the control and no dose-related trends were evident.

Cell growth or malignant transformation in vitro : fenofibric acid was without effect on growth or malignant transformation of cultured mammalian cell lines.

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