Lipidil Micro (Fenofibrate – Micronized)

LIPIDIL MICRO®

Fournier

Fenofibrate (Micronized)

Lipid Metabolism Regulator

Action And Clinical Pharmacology: Fenofibrate lowers elevated serum lipids by decreasing the low density lipoprotein (LDL) fraction rich in cholesterol and the very low density lipoprotein (VLDL) fraction rich in triglycerides. In addition, fenofibrate increases the high density lipoprotein (HDL) cholesterol fraction.

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

The mechanism of action of fenofibrate has not been definitely established. Work carried out to date suggests that fenofibrate enhances the liver elimination of cholesterol as bile salts, inhibits the biosynthesis of triglycerides and enhances the catabolism of VLDL by increasing the activity of lipoprotein lipase, has an inhibitory effect on the biosynthesis of cholesterol by modulating the activity of HMG-CoA reductase.

Pharmacokinetics: After oral administration with food, fenofibrate is rapidly hydrolyzed into fenofibric acid, the active metabolite.

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. In man it is mainly excreted through the kidney. Half-life is about 20 hours. In patients with severe renal failure, significant accumulation was observed with a large increase in the half-life. Therefore, the dose of fenofibrate may need to be reduced, depending on the rate of creatinine clearance.

The long half-life led Laboratoires Fournier to develop a once daily formulation. The micronized formulation of fenofibrate (Lipidil Micro) offers in the order of 33% greater bioavailability than the nonmicronized fenofibrate formulation. Thus, a single 200 mg capsule daily of Lipidil Micro is bioequivalent to three 100 mg capsules of nonmicronized fenofibrate. In comparison with nonmicronized fenofibrate formulation, the absorption of micronized fenofibrate is less influenced by fat content of the diet.

Indications And Clinical Uses: As an adjunct to diet and other therapeutic measures for: 1. 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). 2. 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.

Micronized fenofibrate alone may not be an 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 (at least an equivalent of the American Heart Association (AHA) Step 1 diet), weight reduction and an exercise program; and for patients with diabetes mellitus, good diabetic control.

Contra-Indications: Hepatic or severe renal dysfunction
Pregnancy and Lactation: The drug should not be used in pregnant or lactating patients.

Fenofibrate is not indicated for the treatment of Type I hyperlipoproteinemia.

Manufacturers’ Warnings In Clinical States: 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.

Children: 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.

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.

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

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.

Fenofibrate clinically and pharmacologically shows similarities with clofibrate. Physicians prescribing fenofibrate should also be familiar with the risks and benefits of clofibrate.

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.

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.

CNS: 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).

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 Overdose: Symptoms and Treatment: 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 micronized fenofibrate is one 200 mg capsule daily taken with the main meal.

Availability And Storage: Each orange, hard gelatin capsule contains: micronized fenofibrate 200 mg. Nonmedicinal ingredients: lactose, magnesium stearate, pregelatinized starch, reticulated polyvinyl pyrrolidone and sodium laurylsulfate. Boxes of 30.

Keep at room temperature. Avoid excessive humidity.

LIPIDIL MICRO® Fournier Fenofibrate (Micronized) Lipid Metabolism Regulator

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