FENOFIBRIC ACID Drug Interactions: What You Need to Know

INTERACTIONS Table 2 presents clinically important drug interactions with fenofibric acid delayed-release capsules.

Table

2.

Clinically Important Drug

Interactions with Fenofibric acid delayed-release capsules Statins Clinical Impact: Fibrates may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of fibrates with statins. Intervention: Consider if the benefit of using fenofibric acid delayed-release capsules concomitantly with statin therapy outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dosage titration of statin therapy.

Colchicine Clinical

Impact: Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with fenofibrates. Intervention: Consider if the benefit of using colchicine concomitantly with fenofibric acid delayed-release capsules outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dosage titration of colchicine.

Coumarin Anticoagulants Clinical

Impact: Fibrates may cause potentiation of coumarin-type anticoagulant effects with prolongation of the PT/INR. Intervention: Caution should be exercised when coumarin anticoagulants are given in conjunction with fenofibric acid delayed-release capsules. The dosage of the anticoagulants should be reduced to maintain the PT/INR at the desired level to prevent bleeding complications. Frequent PT/INR determinations are advisable until it has been definitely determined that the PT/INR has stabilized Immunosuppressants Clinical Impact: Immunosuppressants such as cyclosporine and tacrolimus can produce nephrotoxicity with decreases in creatinine clearance and rises in serum creatinine, and because renal excretion is the primary elimination route of fibrate drugs including fenofibric acid delayed-release capsules, there is a risk that an interaction will lead to deterioration of renal function. Intervention: The benefits and risks of using fenofibric acid delayed-release capsules with immunosuppressants and other potentially nephrotoxic agents should be carefully considered, and the lowest effective dosage employed and renal function monitored. Bile-Acid Binding Resins Clinical Impact: Bile-acid binding resins may bind other drugs given concurrently. Intervention: In patients taking a bile acid resin, administer fenofibric acid delayed-release capsules at least 1 hour before or 4 to 6 hours after the bile acid resin to avoid impeding its absorption. Consider if the benefit of concomitant use of statins or colchicine outweighs the increased risk of myopathy and rhabdomyolysis. Monitor patients for signs and symptoms of myopathy ( 7 ). Exercise caution in concomitant treatment with coumarin anticoagulants. Reduce the dosage of coumarin to maintain the PT/INR at the desired level to prevent bleeding complications ( 7 ). Consider the benefits and risks of concomitant use with immunosuppressants and other potentially nephrotoxic agents. Use the lowest effective dosage and monitor renal function ( 7 ). Administer fenofibric acid delayed-release capsules at least 1 hour before or 4 to 6 hours after a bile acid resin to avoid impeding its absorption ( 7 ).

Fenofibric acid delayed-release capsules are contraindicated in patients with: Severe renal impairment, including those with end-stage renal disease (ESRD) and those receiving dialysis [see Clinical Pharmacology ( 12.3 )] . Active liver disease, including those with unexplained persistent liver function abnormalities [see Warnings and Precautions ( 5.2 )] . Pre-existing gallbladder disease [see Warnings and Precautions ( 5.5 )] . Hypersensitivity to fenofibric acid, fenofibrate, or any of the excipients in fenofibric acid delayed-release capsules. Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported with fenofibrate [see Warnings and Precautions ( 5.9 )] . Severe renal impairment, including those with end-stage renal disease (ESRD) and those receiving dialysis ( 4 ). Active liver disease including those with unexplained persistent liver function abnormalities ( 4 ). Pre-existing gallbladder disease ( 4 ). Hypersensitivity to fenofibric acid, fenofibrate, or any of the excipients in fenofibric acid delayed-release capsules ( 4 , 5.9 ).

AND PRECAUTIONS Hepatotoxicity: Serious drug-induced liver injury, including liver transplantation and death, has been reported with fenofibrates, including fenofibric acid delayed-release capsules. Monitor patient’s liver function, including serum ALT, AST, and total bilirubin, at baseline and periodically for the duration of therapy. Discontinue if signs or symptoms of liver injury develop or if elevated enzyme levels persist ( 5.2 ). Myopathy and Rhabdomyolysis: Have been reported in patients taking fenofibrates. Risks are increased during co-administration with a statin, in geriatric patients, and in patients with renal impairment or hypothyroidism. Discontinue fenofibric acid delayed-release capsules if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected. Temporarily discontinue fenofibric acid delayed-release capsules in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis. Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing the fenofibric acid delayed-release capsules dosage. Instruct patients to promptly report any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever ( 5.3 ). Increases in Serum Creatinine: Monitor renal function in patients with renal impairment taking fenofibric acid delayed-release capsules. Consider monitoring renal function in patients at risk for renal impairment ( 5.4 ). Cholelithiasis: Fenofibrate may increase cholesterol excretion into the bile, leading to cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated ( 5.5 ).

Hypersensitivity

Reactions: Acute hypersensitivity reactions, including anaphylaxis and angioedema, and delayed hypersensitivity reactions, including severe cutaneous adverse drug reactions have been reported postmarketing. Some cases were life-threatening and required emergency treatment. Discontinue fenofibric acid delayed-release capsules and treat appropriately if reactions occur ( 5.9 ).

5.1 Mortality and Coronary Heart Disease Morbidity Fenofibrate did not reduce cardiovascular disease morbidity or mortality in two large, randomized controlled trials of patients with type 2 diabetes mellitus <span class="opacity-50 text-xs">[see Clinical Studies (14.4) ]</span> . Because of chemical, pharmacological, and clinical similarities between fenofibrates, including fenofibric acid delayed-release capsules; pemafibrate; clofibrate; and gemfibrozil; the findings in 5 large randomized, placebo-controlled clinical trials with these other fibrate drugs may also apply to fenofibric acid delayed-release capsules. Pemafibrate did not reduce cardiovascular disease morbidity or mortality in a large, randomized, placebo-controlled trial of patients with type 2 diabetes mellitus on background statin therapy <span class="opacity-50 text-xs">[see Clinical Studies (14.4) ]</span> . In the Coronary Drug Project, a large trial conducted from 1965 to 1985 in men post myocardial infarction, there was no difference in mortality or nonfatal myocardial infarction between the clofibrate group and the placebo group after 5 years of treatment (NCT00000482). In a trial conducted by the World Health Organization (WHO) from 1965 to 1976, men without known coronary artery disease were treated with placebo or clofibrate for 5 years and followed for an additional 1 year. There was a statistically significant, higher age-adjusted all-cause mortality in the clofibrate group compared with the placebo group (5.70% vs. 3.96%, p ≤ 0.01). Excess mortality was due to a 33% increase in non-cardiovascular causes, including malignancy, post-cholecystectomy complications, and pancreatitis.

The Helsinki Heart

Study, conducted from 1982 to 1987, was a large (N = 4,081) trial of middle-aged men without a history of coronary artery disease. Subjects received either placebo or gemfibrozil for 5 years, with a 3.5-year open extension afterward. Total mortality was numerically but not statistically higher in the gemfibrozil randomization group versus placebo [95% confidence interval (CI) of the hazard ratio (HR) 0.91 to 1.64]. A secondary prevention component of the Helsinki Heart Study treated middle-aged men with gemfibrozil or placebo for 5 years. The HR for cardiac deaths was 2.2, 95% CI, 0.94 to 5.05.

5.2 Hepatotoxicity Serious drug-induced liver injury (DILI), including liver transplantation and death, has been reported with postmarketing use of fenofibrates, including fenofibric acid delayed-release capsules. DILI has been reported within the first few weeks of treatment or after several months of therapy and in some cases has reversed with discontinuation of fenofibric acid delayed-release capsules treatment. Patients with DILI have experienced signs and symptoms including dark urine, abnormal stool, jaundice, malaise, abdominal pain, myalgia, weight loss, pruritus, and nausea. Many patients had concurrent elevations of total bilirubin, serum alanine transaminase (ALT), and aspartate transaminase (AST). DILI has been characterized as hepatocellular, chronic active, and cholestatic hepatitis, and cirrhosis has occurred in association with chronic active hepatitis. In clinical trials, an intermediate daily dosage or the maximum recommended daily dosage of fenofibrate have been associated with increases in serum AST or ALT. The incidence of increases in transaminases may be dose related <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . Fenofibric acid delayed-release capsules are contraindicated in patients with active liver disease, including those with unexplained persistent liver function abnormalities. Monitor patient’s liver function, including serum ALT, AST, and total bilirubin, at baseline and periodically for the duration of therapy with fenofibric acid delayed-release capsules. Discontinue fenofibric acid delayed-release capsules if signs or symptoms of liver injury develop or if elevated enzyme levels persist (ALT or AST &gt; 3 times the upper limit of normal, or if accompanied by elevation of bilirubin). Do not restart fenofibric acid delayed-release capsules in these patients if there is no alternative explanation for the liver injury.

5.3 Myopathy and Rhabdomyolysis Fenofibric acid delayed-release capsules may cause myopathy [muscle pain, tenderness, or weakness associated with elevated creatine kinase (CK)] and rhabdomyolysis.

Risk

Factors for Myopathy Risk factors for myopathy include age 65 years or older, uncontrolled hypothyroidism, renal impairment, and concomitant use with certain other drugs [see Drug Interactions (7) and Use in Specific Populations (8.6) ]. Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis Data from observational studies indicate that the risk for rhabdomyolysis is increased when fibrates, including fenofibrates, are co-administered with a statin. Avoid concomitant use unless the benefit of further alterations in TG levels is likely to outweigh the increased risk of this drug combination [see Drug Interactions (7) , Clinical Pharmacology (12.3) , and Clinical Studies (14.4) ]. Cases of myopathy, including rhabdomyolysis, have been reported with fenofibric acid delayed-release capsules co-administered with colchicine. Consider whether the benefit of using colchicine concomitantly with fenofibric acid delayed-release capsules outweighs the increased risk of myopathy [see Drug Interactions (7) ] . Discontinue fenofibric acid delayed-release capsules if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected. Muscle symptoms and CK elevations may resolve if fenofibric acid delayed-release capsules are discontinued. Temporarily discontinue fenofibric acid delayed-release capsules in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis (e.g., sepsis; shock; severe hypovolemia; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy). Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing the fenofibric acid delayed-release capsules dosage. Instruct patients to promptly report any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever.

5.4 Increases in Serum Creatinine Increases in serum creatinine have been reported in patients receiving fenofibrates. These increases tend to return to baseline following discontinuation of fenofibric acid delayed-release capsules. The clinical significance of this finding is unknown. Monitor renal function in patients with renal impairment taking fenofibric acid delayed-release capsules. Renal monitoring should also be considered for patients taking fenofibric acid delayed-release capsules at risk for renal insufficiency such as geriatric patients and patients with diabetes. Fenofibric acid delayed-release capsules are contraindicated in patients with severe renal impairment, including those with end-stage renal disease (ESRD) and those receiving dialysis <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) , Use in Specific Populations (8.6) , and Clinical Pharmacology (12.3) ]</span>.

5.5 Cholelithiasis Fenofibrate may increase cholesterol excretion into the bile, leading to cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated. Fenofibric acid delayed-release capsules therapy should be discontinued if gallstones are found. Fenofibric acid delayed-release capsules are contraindicated in patients with pre-existing gallbladder disease.

5.6 Increased Bleeding Risk with Coumarin Anticoagulants Exercise caution when co-administering anticoagulants with fenofibric acid delayed-release capsules because of the potentiation of coumarin-type anticoagulant effects in prolonging the prothrombin time/International Normalized Ratio (PT/INR). To prevent bleeding complications, monitor the PT/INR frequently and adjust the dosage of the anticoagulant until the PT/INR has stabilized <span class="opacity-50 text-xs">[see Drug Interactions (7) ]</span> .

5.7 Pancreatitis Pancreatitis has been reported in patients taking fenofibrates. 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.

5.8 Hematologic Changes Mild to moderate hemoglobin, hematocrit, and white blood cell decreases have been observed in patients following initiation of therapy with fenofibrates. However, these levels stabilize during long-term administration. Thrombocytopenia and agranulocytosis have been reported in individuals treated with fenofibric acid delayed-release capsules. Periodic monitoring of red and white blood cell counts is recommended during the first 12 months of fenofibric acid delayed-release capsules administration.

5.9 Hypersensitivity Reactions Acute Hypersensitivity Anaphylaxis and angioedema have been reported with postmarketing use of fenofibrates. In some cases, reactions were life-threatening and required emergency treatment. If a patient develops signs or symptoms of an acute hypersensitivity reaction, advise them to seek immediate medical attention and discontinue fenofibric acid delayed-release capsules. Fenofibric acid delayed-release capsules are contraindicated in patients with a hypersensitivity to fenofibrate, fenofibric acid, or any of the ingredients in fenofibric acid delayed-release capsules.

Delayed Hypersensitivity

Severe cutaneous adverse drug reactions (SCAR), including Stevens-Johnson syndrome, Toxic Epidermal Necrolysis, and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have been reported with postmarketing use of fenofibrates, occurring days to weeks after treatment initiation. The cases of DRESS were associated with cutaneous reactions (such as rash or exfoliative dermatitis) and a combination of eosinophilia, fever, systemic organ involvement (renal, hepatic, or respiratory). Discontinue fenofibric acid delayed-release capsules and treat patients appropriately if SCAR is suspected.

5.10 Venothromboembolic Disease In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial, pulmonary embolus (PE) and deep vein thrombosis (DVT) were observed at higher rates in the fenofibrate- than the placebo-treated group.

Of

9,795 patients enrolled in FIELD, there were 4,900 in the placebo group and 4,895 in the fenofibrate group. For DVT, there were 48 events (1%) in the placebo group and 67 (1.4%) in the fenofibrate group (p = 0.074); and for PE, there were 32 (0.7%) events in the placebo group and 53 (1.1%) in the fenofibrate group (p = 0.022). In the Coronary Drug Project, a higher proportion of the clofibrate group experienced definite or suspected fatal or nonfatal pulmonary embolism or thrombophlebitis than the placebo group (5.2% vs. 3.3% at five years; p < 0.01). In the cardiovascular outcome trial with pemafibrate, pulmonary embolism was reported for 37 (0.7%) subjects in the pemafibrate group and 16 (0.3%) subjects in the placebo group. Deep vein thrombosis was reported for 36 (0.7%) subjects in the pemafibrate group and 13 (0.2%) subjects in the placebo group.

5.11 Paradoxical Decreases in HDL Cholesterol Levels There have been postmarketing and clinical trial reports of severe decreases in high-density lipoprotein cholesterol (HDL-C) levels (as low as 2 mg/dL) occurring in patients with and without diabetes initiated on fibrate therapy, including fenofibrate. The decrease in HDL-C is mirrored by a decrease in apolipoprotein A1. This decrease has been reported to occur within 2 weeks to years after initiation of fibrate therapy. The HDL-C levels remain depressed until fibrate therapy has been withdrawn; the response to withdrawal of fibrate therapy is rapid and sustained. The clinical significance of this decrease in HDL-C is unknown. Check HDL-C levels within the first few months after initiation of fenofibric acid delayed-release capsules. If a severely depressed HDL-C level is detected, discontinue fenofibric acid delayed-release capsules and monitor HDL-C until it has returned to baseline. Fenofibric acid delayed-release capsules should not be re-initiated.