Lipidil EZ

Administration of fenofibrate with ezetimibe is effective in improving serum total-C, LDL-C, Apo-B, TG, HDL-C, and non-HDL-C in patients with mixed hyperlipidemia.

Clinical studies have demonstrated that elevated levels of total-C, low density lipoprotein cholesterol (LDL-C) and apolipoprotein B (Apo B; the major protein constituent of LDL), promote atherosclerosis in humans. In addition, decreased levels of high density lipoprotein cholesterol (HDL-C) are associated with the development of atherosclerosis. Epidemiologic studies have established that cardiovascular morbidity and mortality vary directly with the level of total-C and LDL-C and inversely with the level of HDL-C. Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including very low density lipoproteins (VLDL), intermediate density lipoproteins (IDL), and remnants, can also promote atherosclerosis. The effects of fenofibrate given with ezetimibe on cardiovascular morbidity and mortality have not been established.

In patients with severe renal impairment, 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.

Safety and effectiveness have not been established in pediatric patients.

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.

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. Coadministration 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.

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.

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 fenofibrate stopped in the case of severe alteration of laboratory parameters.

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).

The safety and effectiveness of fenofibrate co-administered with ezetimibe have been evaluated in a clinical study (see Warnings, Precautions and Adverse Effects). Co-administration of ezetimibe with other fibrates has not been studied (see ezetimibe Product Monograph). Co-administration of ezetimibe with fibrates other than fenofibrate is not recommended until use in patients is studied.

In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. This increase is not considered clinically significant.

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.)

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.

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 hypoalbuminemia. 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.

Patient 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.

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.

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 lipid response is not obtained in three months, LIPIDIL EZ should be discontinued.

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.

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.

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 coadministered with multiple doses of atorvastatin.

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).

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

Coadministration 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 co-administration of ezetimibe with fibrates other than fenofibrate has not been studied. Therefore, co-administration of ezetimibe and fibrates other than fenofibrate is not recommended (see Drug Interactions, and Product Monograph for ezetimibe).

If cholelithiasis is suspected in a patient receiving ezetimibe and LIPIDIL EZ, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered (see Adverse Effects).

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.

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 coadministration of simvastatin, indicating that fenofibric acid concentrations are not significantly affected by the addition of a 40 mg dose of simvastatin.

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.

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. 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.

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 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.

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

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.

Each yellow, oblong, film-coated tablet (NanoCrystal Formulation), embossed with the Fournier logo on one side and 48 on the other, contains: fenofibrate 48 mg. Nonmedicinal ingredients: colloidal silicon dioxide, crospovidone, docusate sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate and sucrose; coating: D&C Blue #2/Indigo carmine FCF Aluminum Lake, D&C yellow #6/sunset yellow FCF Aluminum Lake, D&C Yellow #10 Aluminum Lake, lecithin, polyvinyl alcohol, talc and titanium dioxide. Blister packs of 30. Store at 15-30°C. Protect from light and moisture.

Each white, oblong, film-coated tablet (NanoCrystal Formulation), embossed with the Fournier logo on one side and 145 on the other, contains: fenofibrate 145 mg. Nonmedicinal ingredients: colloidal silicon dioxide, crospovidone, docusate sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate and sucrose; coating: polyvinyl alcohol, soybean lecithin, talc, titanium dioxide and xanthan gum. Blister packs of 30. Store at 15-30°C. Protect from light and moisture.

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 every 3 months for the first 12 months and at least yearly thereafter. LIPIDIL EZ (fenofibrate) should be discontinued if abnormalities persist and/or AST and ALT levels increase to more than 3 times the upper limit of normal.

When ezetimibe is initiated in a patient already taking LIPIDIL EZ, liver function tests should be considered at initiation of ezetimibe therapy and then as indicated. When ezetimibe is initiated at the same time as LIPIDIL EZ, liver function tests should be performed at initiation of therapy according to the above recommendations (see Adverse Effects).

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. Coadministration 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.

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 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.

When LIPIDIL EZ is to be administered with ezetimibe, the ezetimibe Product Monograph should be consulted.

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.

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.

When LIPIDIL EZ is to be administered with ezetimibe, the ezetimibe Product Monograph should also be consulted.

In a clinical study involving 625 patients treated for up to 12 weeks and 576 patients treated for up to 1 year, co-administration of fenofibrate and ezetimibe was well tolerated. This study was not designed to compare treatment groups for infrequent events. Incidence rates (95% CI) for clinically important elevations (>3 ULN, consecutive) in serum transaminases were 4.5% (1.9, 8.8) and 2.7% (1.2, 5.4) for fenofibrate monotherapy and ezetimibe co-administered with fenofibrate, respectively, adjusted for treatment exposure. Corresponding incidence rates for cholecystectomy were 0.6% (0.0, 3.1) and 1.7% (0.6, 0.4) for fenofibrate monotherapy and ezetimibe co-administered with fenofibrate, respectively (see Warnings, Precautions and Drug Interactions). There were no CPK elevations >10×ULN in either treatment group in this study. No cases of myopathy, rhabdomyolysis, or pancreatitis were reported in this 12 weeks study.

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).

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 (e.g. jaundice) indicative of hepatitis occur, laboratory tests are to be conducted for verification and fenofibrate discontinued, if applicable (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.

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.

The recommended dose of ezetimibe is 10 mg once daily orally in combination with LIPIDIL EZ. LIPIDIL EZ in combination with ezetimibe, may be taken with or without food, preferably at the same time each day.