Colestrim film-coated tablet also contains the following inactive ingredients: Lactose, starch, croscarmellose sodium, crospovidone, povidone, sodium lauryl sulfate, magnesium stearate, purified talc, opadry AMG, purified water.
Colestrim Supra tablet contains the following inactive ingredients: Anhydrous lactose, hypromellose, sodium lauryl sulphate, simethicone emulsion 30%, croscarmellose sodium, magnesium stearate, purified water.
Colestrim Supra is a lipid regulating agent available as tablets for oral administration.
Fenofibrate is 1 methylethyl-2-[4-(4-chlorobenzoyl) phenoxy] 2 methylpropanoate. Its molecular formula is C5H2O4Cl and its molecular weight is 360.8.
Pharmacology: Pharmacodynamics: Mechanism of Action: Fenofibrate is a fibric acid derivative whose lipid modifying effects reported in humans are medicated via activation of peroxisome proliferated receptor type α (PPAR). Through activation of PPAR, fenofibrate increases the lipolysis and elimination of atherogenic triglyceride rich particles from plasma by activating lipoprotein lipase and reducing production of apoprotein CIII (an inhibitor of lipoprotein lipase activity). The resulting fall in triglycerides (TGs) produces an alteration in the size and composition of low density lipoprotein (LDL) from small, dense particles (which are thought to be atherogenic due to their susceptibility to oxidation) to large buoyant particles. Those larger particles have a greater affinity for cholesterol receptors and are catabolized rapidly. Activation of PPAR also induces an increase in the synthesis of apoproteins AI and AII and high density lipoprotein (HDL) cholesterol.
The previously stated effects of fenofibrate on lipoproteins leads to a reduction in very low density fractions (VLDL and LDL) containing apoprotein AI and AII (Apo I and Apo II).
In addition, through modulation of synthesis and the catabolism of VLDL fractions, fenofibrate increases the LDL clearance and reduces small dense LDL, the levels of which are elevated in the atherogenic lipoprotein phenotype, a common disorder in patients at risk for coronary heart disease.
Fenofibrate also reduces serum uric acid levels in hyperuricemic and normal individuals by increasing the urinary excretion of uric acid.
Clinical Studies: 160-mg: During clinical trials with fenofibrate, total-C was reduced by 20-25%, triglycerides by 40-55% and HDL-cholesterol (HDL-C) was increased by 10-30%.
In hypercholesterolaemic patients, where LDL-cholesterol (LDL-C) levels are reduced by 20-35%, the overall effect on cholesterol results in a decrease in the ratios of total cholesterol (total-C) to HDL-C, LDL-C to HDL-C, or apoprotein B (Apo B) to Apo AI, all of which are markers of atherogenic risk. Because of its significant effect on LDL-C and TGs, treatment with fenofibrate should be beneficial in hypercholesterolaemic patients, with or without hypertriglyceridaemia, including secondary hyperlipoproteinaemia eg, type 2 diabetes mellitus.
Extravascular deposits of cholesterol (tendinous and tuberous xanthoma) may be markedly reduced or even entirely eliminated during fenofibrate therapy.
Patients with raised levels of fibrinogen treated with fenofibrate have shown significant reductions in this parameter, as have those with raised levels of lipoprotein (a).
Other inflammatory markers eg, C-reactive protein are reduced with fenofibrate treatment. The uricosuric effect of fenofibrate leading to reduction in uric acid levels of approximately 25% should be of additional benefit in those dyslipidaemic patients with hyperuricaemia.
Fenofibrate has been shown to possess an anti-aggregatory effect on platelets in animals and in a clinical study, which showed a reduction in platelet aggregation induced by ADP, arachidonic acid and epinephrine. The effect of fenofibrate on coronary heart disease morbidity and non-cardiovascular mortality has not been established.
Pharmacokinetics: 145-mg: Plasma concentrations of fenofibric acid after administration one 145-mg tablet is equivalent under fed conditions to 1 micronized fenofibrate 200 mg capsule.
Fenofibrate is a prodrug of the active chemical moiety fenofibric acid. It is converted by ester hydrolysis in the body to fenofibric acid which is the active constituent measurable in the circulation.
Absorption: Fenofibrate is well-absorbed from the gastrointestinal tract. Peak plasma levels of fenofibric acid occur within 6-8 hrs after administration.
145-mg: Following oral administration in healthy volunteers, approximately 60% of a single dose of radiolabelled fenofibrate appeared in urine, primarily as fenofibric acid and its glucuronate conjugate and 25% was excreted in the feces.
Exposure to fenofibric acid in plasma, as measured by peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) is not significantly different when a single fenofibrate 145 mg dose is administered under fasting or nonfasting conditions.
160-mg: The absorption of fenofibrate tablets is increased by approximately 35% under fed as compared to fasting conditions.
Distribution: Serum protein binding was approximately 99% in normal and hyperlipidemic subjects.
145-mg: Upon multiple dosing of fenofibrate, fenofibric acid steady-state is achieved within 9 days. Plasma concentrations of fenofibric acid at steady-state are approximately double of those following a single dose.
160-mg: In healthy volunteers, steady-state plasma levels of fenofibric acid were shown to be achieved within 5 days of dosing and did not demonstrate accumulation across time following multiple dose administration.
Metabolism: Following oral administration, fenofibrate is rapidly hydrolyzed by esterases to the active metabolite, fenofibric acid, no unchanged fenofibrate is detected in plasma.
Fenofibric acid is primarily conjugated with glucuronic acid and then excreted in urine. A small amount of fenofibric acid is reduced at the carbonyl moiety to a benzhydrol metabolite which is, in turn, conjugated with glucuronic acid and excreted in urine.
In vivo metabolism data indicate that neither fenofibrate nor fenofibric acid undergo oxidate metabolism (eg, cytochrome P450) to a significant extent.
Elimination: After absorption, fenofibrate is mainly excreted in the urine in the form of metabolites, primarily fenofibric acid and fenofibric acid glucuronide.
145-mg: After administration of radiolabelled fenofibrate, approximately 60% of the dose appeared in the urine and 26% was excreted in the feces.
Fenofibric acid is eliminated with a half-life (t½) of 20 hrs, allowing once daily dosing.
160-mg: Following oral administration in healthy volunteers, approximately 60% of a single dose of radiolabeled fenofibrate appeared in the urine, primarily as fenofibric acid and its glucuronate conjugate and 25% was excreted in the feces. Fenofibric acid is eliminated with a t½ of 20 hrs, allowing once-daily administration in a clinical setting.
Special Populations: Elderly: In elderly volunteers 77-87 years, the oral clearance of fenofibric acid following a single oral dose of fenofibrate was 1.2 L/hr, which compares to 1.1 L/hr in young adults. This indicates that a similar dosage regimen can be used in elderly with normal renal function, without increasing accumulation of Colestrim/Colestrim Supra or metabolites.
Race: The influence of race on the pharmacokinetics of fenofibrate has not been studied. However, fenofibrate is not metabolized by enzymes known for exhibiting inter-ethnic variability.
Renal Impairment: 145-mg: The pharmacokinetics of fenofibric acid was examined in patients with mild, moderate and severe renal impairment. Patients with severe renal impairment [estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2] showed 2.7-fold increase in exposure for fenofibric acid and increased accumulation of fenofibric acid during chronic dosing compared to that of healthy subjects. Patients with mild to moderate renal impairment (eGFR 30-59 mL/min/1.73 m2) had similar exposure but an increase in the t½ for fenofibric acid compared to that of healthy subjects. Based on these findings, the use of Colestrim Supra should be avoided in patients who have severe renal impairment and dose reduction is required in patients having mild to moderate renal impairment.
160-mg: In patients with severe renal impairment [creatinine clearance (CrCl) <500 mL/min] the rate of clearance of fenofibric acid is greatly reduced and the drug accumulated during chronic dosage. However, in patients having moderate renal impairment (CrCl <50-90 mL/min). The oral clearance and oral volume of distribution of fenofibric acid are increased compared to healthy adults (2.1 L/hr and 95 L versus 1.1 L/hr and 30 L, respectively). Therefore, the dosage of fenofibrate should be minimized in patients who have severe renal impairment, while no modification is required in patients having moderate renal impairment.
Hepatic Impairment: No pharmacokinetic studies have been conducted in patients with hepatic impairment.
Primary Hypercholesterolemia or Mixed Dyslipidemia: Colestrim/Colestrim Supra is indicated as adjunctive therapy to diet to reduce elevated LDL-C, total-C, TGs and Apo B and to increase HDL-C in adult patients with primary hypercholesterolemia or mixed dyslipidemia.
160-mg: Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol when response to diet and non-pharmacological interventions alone has been adequate.
Severe Hypertriglyceridemia: Colestrim/Colestrim Supra is also indicated as adjunctive therapy to diet for treatment of adult patients with severe hypertriglyceridemia (Fredrickson types IV and V hyperlipidemia).
145-mg: Improving glycemic control in diabetic patients showing fasting chylomicronemia will usually obviate the need for pharmacologic intervention.
Markedly elevated levels of serum triglycerides (eg, >2,000 mg/dL) may increase risk of developing pancreatitis. The effect of fenofibrate therapy on reducing this risk has not been adequately studied.
160-mg: General Recommendations: Drug therapy is not indicated for patients with type I hyperlipoproteinemia, who have elevations of chylomicrons and plasma triglycerides, but who have normal levels of very low-density lipoprotein (VLDL). Inspection of plasma refrigerated for 14 hrs is helpful in distinguishing types I, IV and V hyperlipoproteinemia.
The initial treatment for dyslipidemia is dietary therapy specific for type of lipoprotein abnormality. Excess body weight and excess alcohol intake may be important factors in hypertriglyceridemia and should be addressed prior to any drug therapy. Physical exercise can be important ancillary measure. Disease contributory to hyperlipidemia eg, hypothyroidism or diabetes mellitus should be looked for adequately treated. Estrogen therapy, thiazide diuretics and β-blockers, are sometimes associated with massive rise in plasma triglycerides, especially in subjects with familial hypertriglyceridemia.
The use of drug should be considered only when reasonable attempts have been made to obtain satisfactory results with non-drug methods. If the decision is made to use drugs, the patient should be instructed that this does not reduce the importance of adhering to diet.
General: Patients should be placed on an appropriate lipid-lowering diet before receiving Colestrim Supra and should continue this diet during treatment with Colestrim Supra.
The initial treatment for dyslipidemia is dietary therapy specific for the type of lipoprotein abnormality. Excess body weight and excess alcoholic intake may be important factors in hypertriglyceridemia and should be addressed prior to any drug therapy. Physical exercise can be an important ancillary measure, diseases contributory to hyperlipidemia eg, hypothyroidism or diabetes mellitus should be looked for and adequately treated. Estrogen therapy, thiazide diuretics and β-blockers, are sometimes associated with massive rises in plasma triglycerides, especially in subjects with familial hypertriglyceridemia. In such cases, discontinuation of the specific etiologic agent may obviate the need for specific drug therapy of hypertriglyceridemia.
Lipid levels should be monitored periodically and consideration should be given to reducing the dosage of Colestrim Supra if lipid levels fall significantly as follows the targeted range.
If an adequate response has not been achieved after several months (eg, 3 months), complementary or different therapeutic measures should be considered.
Primary Hypercholesterolemia or Mixed Dyslipidemia: 1 tab containing fenofibrate 145- and 160-mg taken once daily. Patients currently one 160 mg tab can be changed to 1 fenofibrate 145 mg tab without further dose adjustment.
Severe Hypertriglyceridemia: Initial Dose: 145-mg: 145 mg/day. Maximum Dose: 145 mg once daily.
Dosage should be individualized according to patient response and should be adjusted if necessary following repeat lipid determinations at 4-8 week intervals.
Elderly: Dose selection for the elderly should be made on the basis of renal function.
Administration: Colestrim Supra tab can be given without regard to meals.
Colestrim tablets should be given with meals, thereby optimizing the bioavailability of the medication.
There is no specific treatment for overdosage with fenofibrate. General supportive care of the patients is indicated, including monitoring of vital signs and observation of clinical status, should an overdosage occur. If indicated, elimination of unabsorbed Colestrim Supra should be achieved by emesis or gastric lavage, usual precautions should be achieved by emesis or gastric lavage and usual precautions should be observed to maintain the airway. Because fenofibrate is highly bound to plasma proteins, hemodialysis should not be considered.
Hypersensitivity to fenofibrate or fenofibric acid or to any of the excipients of Colestrim Supra. Patients with severe renal impairment, including those receiving dialysis; active liver disease, including those with primary biliary cirrhosis and unexplained persistent liver function abnormalities; preexisting gallbladder disease.
Use in lactation: Fenofibrate should not be used in nursing mothers.
145-mg: A decision should be made whether to discontinue nursing or to Colestrim Supra, taking into account the importance of Colestrim Supra to the mother.
160-mg: Because of the potential for tumorigenicity seen in animal studies, a decision should be made whether to discontinue nursing or to discontinue Colestrim.
145-mg: Secondary cause of hypercholesterolemia eg, as uncontrolled type 2 diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemia, obstructive liver disease, pharmacological treatment, alcoholism, should be adequately treated before fenofibrate is initiated.
For hyperlipidaemic patients taking estrogens or contraceptives containing oestrogens it should be ascertained whether the hyperlipidaemia is of primary or secondary nature (possible elevation of lipid values caused by oral oestrogen).
Liver Function: As with other lipid lowering agents, increases have been reported in transaminase levels in some patients. In the majority of cases these elevations were transient, minor and asymptomatic. It is recommended that transaminase levels are monitored every 3 months during the first 12 months of treatment and thereafter, periodically. Attention should be paid to patients who develop increase in transaminase levels and therapy should be discontinue if [aspartate aminotransferase (ASAT) serum glutamic oxaloacetic transaminase (SGOT)] and alanine aminotransferase (ALAT) [serum glutamic pyruvic transaminase (SGPT)] levels increase to >3 times the upper limit of normal range. When symptoms indicative of hepatitis occur (eg, jaundice, pruritus), laboratory tests are to be conducted for verification and discontinuation of fenofibrate therapy may be considered.
Pancreas: 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.
Muscle: Muscle toxicity, including very rare cases of rhabdomyolysis, has been reported with administration of fibrates and other lipid-lowering agents. Patients with hypoalbuminemia and renal insufficiency in their personal history have a higher incidence of myotoxicity. Muscle toxicity should be suspected in patients presenting diffuse myalgia, myositis, muscular cramps and weakness and/or marked increases creatinine phosphokinase (CPK) (levels exceeding 5 times the upper normal range). In such cases treatment with fenofibrate should be stopped.
Patients with pre-disposing factors for myopathy and/or rhabdomyolysis including >70 years, personal or familial history of hereditary muscular disorders, renal impairment, hypoalbuminaemia, hypothyroidism ang high alcohol intake, may be at increased risk of developing rhabdomyolysis. For these patients, the putative benefits and risk of fenofibrate therapy should be carefully weighed up.
The risk of muscle toxicity may be increased if Colestrim Supra is administered with another fibrate or an HMG-CoA reductase inhibitor (statins), especially in cases of preexisting muscular disease. Consequently, the co-prescription of fenofibrate with a statin should be reserved to patients with severe combined dyslipidemia and high cardiovascular risk without any history of muscular disease. This combination therapy should be used with caution and patients should be monitored closely for signs of muscle toxicity.
Renal Function: Treatment should be interrupted in case of an increase in creatinine levels >50% and upper limit of normal (ULN). It is recommended that creatinine is measured during the first 3 months after initiation of treatment and thereafter, periodically. Colestrim Supra contains lactose therefore, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency of glucose-galactose malabsorption should not take Colestrim Supra.
Colestrim Supra contains sucrose therefore, patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption of sucrase-isomaltase insufficiency should not take Colestrim Supra.
Colestrim Supra tablet should not be taken in patients allergic to soya lecithin or related due to the risk of hypersensitivity reactions.
160-mg: Initial Therapy: Laboratory studies should be done to ascertain that the lipid levels are consistently abnormal before instituting fenofibrate therapy. Every attempt should be made to control serum lipids with appropriate diet, exercise, weight loss in obese patients and control of any medical problems eg, diabetes mellitus and hypothyroidism that are contributing to the lipid abnormalities. Medications known to exacerbate hypertriglyceridemia (blockers, thiazides, estrogens) should be discontinued or changed if possible, prior to consideration of triglyceride lowering the drug therapy.
Continued Therapy: Periodic determination of serum lipids should be obtained during the initial therapy in order to establish the lowest effective dose of fenofibrate. Therapy should be withdrawn in patients who do not have an adequate response after 2 months of treatment with the maximum recommended dose of 160 mg/day.
Pancreatitis: Pancreatitis has been reported in patients taking fenofibrate, gemfibrozil and clofibrate. The occurrence may represent a failure of efficacy in patients with severe hypertriglyceridemia, a direct drug effect, or a secondary phenomenon medicated through biliary tract stone or sludge formation with obstruction of the common bile duct.
Hypersensitivity Reactions: Acute hypersensitivity reactions include severe skin rashes requiring patient hospitalization and treatment with steroids have occurred very rarely during treatment with fenofibrate, including rare spontaneous reports of Stevens-Johnson syndrome and toxic epidermal necrolysis.
Hematological Changes: Mild to moderate hemoglobin, hematocrit and white blood cell decreases have been observed in patients following initiation of fenofibrate therapy. However, these levels stabilize during long-term administration. Extremely rare spontaneous reports of thrombocytopenia and agranulocytosis have been received during post-marketing surveillance. Periodic blood counts are recommended during the first 12 months of fenofibrate administration.
Liver Function: Fenofibrate at doses equivalent to 107-160 mg/day has been associated with increase in serum transaminases. When transaminase determinations were followed either after discontinuation treatment or during continued treatment, a return to normal limits was usually observed. The incidence of increase in transaminases related to fenofibrate therapy appears to be dose-related.
Hepatocellular, chronic active and cholestatic hepatitis associated with fenofibrate therapy have been reported after exposure to weeks to several years. In extremely rare cases, cirrhosis has been reported in association with chronic active hepatitis. Regular periodic monitoring of liver function including serum ALT (SGPT) should be performed for the duration of therapy with fenofibrate and therapy discontinued if enzyme levels persist >3 times the normal limit.
Skeletal Muscle: The use of fibrates alone, including fenofibrate may occasionally be associated with myopathy. Treatment with drugs of the fibrate class has been associated on rare occasions with rhabdomyolysis, usually in patients with impaired renal function. Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevations 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 occur or myopathy is diagnosed.
Cholelithiasis: Fenofibrate, like clofibrate and gemfibrozil, may increase cholesterol excretion into the bile, leading to cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated; fenofibrate therapy should be discontinued if gallstones are found.
Special Populations: Renal Impairment: The use of Colestrim Supra should be avoided in patients who have severe renal impairment. Dose reduction is required in patients with mild to moderate renal impairment. Monitoring renal function in patients with renal impairment is recommended.
Hepatic Impairment: The use of Colestrim Supra has not been evaluated in subjects with hepatic impairment.
Effects on the Ability to Drive or Operate Machinery: Fenofibrate tablets 145 mg has no influence on the ability to drive and use machines.
Use in pregnancy: Pregnancy Category C: Safety in pregnant women has not been established. There are no adequate and well-controlled studies of fenofibrate in pregnant women. Fenofibrate should not be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Use in lactation: Fenofibrate should not be used in nursing mothers. A decision should be made whether to discontinue Colestrim, taking into account the importance of Colestrim to the mother.
Use in children: Safety and effectiveness have not been established in pediatric patients.
Use in the elderly: Fenofibric acid is known to be substantially excreted by the kidney and the risk of adverse reactions to Colestrim Supra may be greater in patients with impaired renal function. Fenofibric acid exposure is not influenced by age. Since elderly patients have a higher incidence of renal impairment, dose selection for the elderly should be made on the basis of renal function. Elderly patients with normal renal function should require no dose modifications. Consider monitoring renal function in elderly patients taking Colestrim Supra.
Use in pregnancy: Pregnancy Category C: Safety in pregnant women has not been established. There are no adequate and well-controlled studies of fenofibrate in pregnant women. Fenofibrate should not be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Use in lactation: Fenofibrate should not be used in nursing mothers.
145-mg: A decision should be made whether to discontinue nursing or to Colestrim Supra, taking into account the importance of Colestrim Supra to the mother.
160-mg: Because of the potential for tumorigenicity seen in animal studies, a decision should be made whether to discontinue nursing or to discontinue Colestrim.
The adverse effects are mild and fugitive: Common (1/100, <1/10):
Gastrointestinal: Digestive, gastric or intestinal disorders (abdominal pain, nausea, vomiting, diarrhea, flatulence).
Hepatobiliary: Moderately elevated levels or serum transaminases.
Uncommon (1/1,000, <1/100):
Liver: Development of gallstones.
Skin: Rashes, pruritus, urticaria or photosensitivity reactions.
Testing: Increases in serum creatinine and urea.
Rare (1/10,000, <1/1,000):
Hair: Alopecia.
Muscle: Diffuse myalgia, myositis, muscular cramps and weakness.
Blood: Decreased haemoglobin and leukocytes.
Nervous System: Sexual asthenia.
Very Rare (<1/10,000):
Gastrointestinal: Cases of pancreatitis have been reported during treatment with fenofibrate.
Liver: Episodes of hepatitis. When symptoms (eg, jaundice, pruritus) indicative of hepatitis occur, laboratory tests are to be conducted for verification and fenofibrate discontinued, if applicable.
Skin: Cutaneous photosensitivity with erythema, vesiculation or nodulation on parts of the skin exposed to sunlight or artificial UV light (eg, sunlamp). In individual cases (even after many months of uncomplicated use).
Muscle: Rhabdomyolysis.
Respiratory: Interstitial pneumopathies.
Inform the physician in case of any adverse reactions related to drug use.
Oral Anticoagulants: Fenofibrate enhances oral anticoagulant effect and may increase risk of bleeding. It is recommended that the dose of anticoagulants is reduced by about ⅓ at the start of treatment and then gradually adjusted if necessary according to international normalize ratio (INR) monitoring. Therefore, this combination is not recommended.
Cyclosporin: Some severe cases of reversible renal function impairment have been reported during concomitant administration of fenofibrate and cyclosporin. The renal function of these patients must therefore, be closely monitored and the treatment with fenofibrate stopped in the case of severe alternation of laboratory parameters.
HMG-CoA Reductase Inhibitors and Other Fibrates: The risk of serious muscle toxicity is increased if a fibrate is used concomitantly with HMG-CoA reductase inhibitors or other fibrates. Such combination therapy should be used with caution and patients monitored closely for signs of muscle toxicity.
Cytochrome P-450 Enzymes: In vitro using human liver microsomes indicate that fenofibrate and fenofibric acid are not inhibitors of cytochrome (CYP) 450 isoforms CYP3A4, CYP2D6, CYP2E1 or CYP1A2. They are weak inhibitors of CYP2C19 and CYP2A6 and mild to moderate inhibitors of CYP2C9 at therapeutic concentrations.
Patients co-administered fenofibrate and CYP2C19, CYP2A6 and especially CYP2C9 metabolised drugs with a narrow therapeutic index should be carefully monitored and if necessary dose adjustment of these drugs is recommended.
Store below 30°C in a dry place. Protect from light and moisture.
Shelf-Life: 145-mg: 3 years.
160-mg: 30 months.
C10AB05 - fenofibrate ; Belongs to the class of fibrates. Used in the treatment of hyperlipidemia.
Colestrim FC tab 160 mg x 30's. Colestrim Supra tab (white to off-white biconvex, oblong, debossed with "F" on one side and "145" on the other side) 145 mg x 3 x 10's.
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