Trilipix - Product Information
|Condition:||High Cholesterol, Hypertriglyceridemia|
|Class:||Fibric acid derivatives|
|Ingredients:||Fenofibric acid, hypromellose, povidone, water, hydroxylpropyl cellulose, colloidal silicon dioxide, sodium stearyl fumarate, methacrylic acid copolymer, talc, triethyl citrate, gelatin, titanium dioxide, and yellow iron oxide, black iron oxide and red iron oxide, FD&C Blue #2.|
Indications and Usage
Treatment of Severe Hypertriglyceridemia
Trilipix is indicated as adjunctive therapy to diet to reduce triglycerides (TG) in patients with severe hypertriglyceridemia. Improving glycemic control in diabetic patients showing fasting chylomicronemia will usually obviate the need for pharmacological intervention. Markedly elevated levels of serum triglycerides (e.g. > 2,000 mg/dL) may increase the risk of developing pancreatitis. The effect of Trilipix therapy on reducing this risk has not been adequately studied.
Treatment of Primary Hypercholesterolemia or Mixed Dyslipidemia
Trilipix is indicated as adjunctive therapy to diet to reduce elevated low-density lipoprotein cholesterol (LDL-C), total cholesterol (Total-C), triglycerides (TG), and apolipoprotein B (Apo B), and to increase high-density lipoprotein cholesterol (HDL-C) in patients with primary hypercholesterolemia or mixed dyslipidemia.
Limitations of Use
Fenofibrate at a dose equivalent to 135 mg of Trilipix did not reduce coronary heart disease morbidity and mortality in 2 large, randomized controlled trials of patients with type 2 diabetes mellitus [see Warnings and Precautions].
General Considerations for Treatment
Laboratory studies should be performed to establish that lipid levels are abnormal before instituting Trilipix therapy.
Every reasonable attempt should be made to control serum lipids with non-drug methods including appropriate diet, exercise, weight loss in obese patients, and control of any medical problems such as diabetes mellitus and hypothyroidism that may be contributing to the lipid abnormalities. Medications known to exacerbate hypertriglyceridemia (beta-blockers, thiazides, estrogens) should be discontinued or changed if possible, and excessive alcohol intake should be addressed before triglyceride-lowering drug therapy is considered. If the decision is made to use lipid-altering drugs, the patient should be instructed that this does not reduce the importance of adhering to diet.
Drug therapy is not indicated for patients who have elevations of chylomicrons and plasma triglycerides, but who have normal levels of VLDL.
Dosage and Administration
Patients should be placed on an appropriate lipid-lowering diet before receiving Trilipix and should continue this diet during treatment. Trilipix delayed release capsules can be taken without regard to meals. Patients should be advised to swallow Trilipix capsules whole. Do not open, crush, dissolve, or chew capsules. Serum lipids should be monitored periodically.
The initial dose of Trilipix is 45 to 135 mg once daily. Dosage should be individualized according to patient response, and should be adjusted if necessary following repeat lipid determinations at 4 to 8 week intervals. The maximum dose is 135 mg once daily.
Primary Hypercholesterolemia or Mixed Dyslipidemia
The dose of Trilipix is 135 mg once daily.
Impaired Renal Function
Treatment with Trilipix should be initiated at a dose of 45 mg once daily in patients with mild to moderate renal impairment and should only be increased after evaluation of the effects on renal function and lipid levels at this dose. The use of Trilipix should be avoided in patients with severely impaired renal function [see Use in Specific Populations and Clinical Pharmacology].
Dose selection for the elderly should be made on the basis of renal function [see Use in Specific Populations].
Dosage Forms and Strengths
- 45 mg capsules with a reddish brown to orange brown cap and a yellow body imprinted in black ink the number “45”.
- 45 mg capsules with a reddish brown to orange brown cap imprinted in white ink the “a” logo and a yellow body imprinted in black ink the number “45”.
- 135 mg capsules with a blue cap and a yellow body imprinted in black ink the number “135”.
- 135 mg capsules with a blue cap imprinted in white ink the “a” logo and a yellow body imprinted in black ink the number “135”.
Trilipix is contraindicated in:
- patients with severe renal impairment, including those receiving dialysis [see Clinical Pharmacology].
- patients with active liver disease, including those with primary biliary cirrhosis and unexplained persistent liver function abnormalities [see Warnings and Precautions].
- patients with preexisting gallbladder disease [see Warnings and Precautions].
- nursing mothers [see Use in Specific Populations].
- patients with hypersensitivity to fenofibric acid or fenofibrate [see Warnings and Precautions].
Warnings and Precautions
Mortality and Coronary Heart Disease Morbidity
The effect of Trilipix on coronary heart disease morbidity and mortality and non-cardiovascular mortality has not been established. Because of similarities between Trilipix and fenofibrate, clofibrate, and gemfibrozil, the findings in the following large randomized, placebo-controlled clinical studies with these fibrate drugs may also apply to Trilipix.
The Action to Control Cardiovascular Risk in Diabetes Lipid (ACCORD Lipid) trial was a randomized placebo-controlled study of 5518 patients with type 2 diabetes mellitus on background statin therapy treated with fenofibrate. The mean duration of follow-up was 4.7 years. Fenofibrate plus statin combination therapy showed a non-significant 8% relative risk reduction in the primary outcome of major adverse cardiovascular events (MACE), a composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular disease death (hazard ratio [HR] 0.92, 95% CI 0.79-1.08) (p=0.32) as compared to statin monotherapy. In a gender subgroup analysis, the hazard ratio for MACE in men receiving combination therapy versus statin monotherapy was 0.82 (95% CI 0.69-0.99), and the hazard ratio for MACE in women receiving combination therapy versus statin monotherapy was 1.38 (95% CI 0.98-1.94) (interaction p=0.01). The clinical significance of this subgroup finding is unclear.
The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study was a 5-year randomized, placebo-controlled study of 9795 patients with type 2 diabetes mellitus treated with fenofibrate. Fenofibrate demonstrated a non-significant 11% relative reduction in the primary outcome of coronary heart disease events (hazard ratio [HR] 0.89, 95% CI 0.75-1.05, p = 0.16) and a significant 11% reduction in the secondary outcome of total cardiovascular disease events (HR 0.89 [0.80-0.99], p = 0.04). There was a non-significant 11% (HR 1.11 [0.95, 1.29], p = 0.18) and 19% (HR 1.19 [0.90, 1.57], p = 0.22) increase in total and coronary heart disease mortality, respectively, with fenofibrate as compared to placebo.
In the Coronary Drug Project, a large study of post-myocardial infarction patients treated for 5 years with clofibrate, there was no difference in mortality seen between the clofibrate group and the placebo group. There was, however, a difference in the rate of cholelithiasis and cholecystitis requiring surgery between the two groups (3.0% vs. 1.8%).
In a study conducted by the World Health Organization (WHO), 5000 subjects without known coronary artery disease were treated with placebo or clofibrate for 5 years and followed for an additional one 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. This appeared to confirm the higher risk of gallbladder disease seen in clofibrate-treated patients studied in the Coronary Drug Project.
The Helsinki Heart Study was a large (N = 4081) study 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 higher in the gemfibrozil randomization group but did not achieve statistical significance (p = 0.19, 95% confidence interval for relative risk G:P = 0.91-1.64). Although cancer deaths trended higher in the gemfibrozil group (p = 0.11), cancers (excluding basal cell carcinoma) were diagnosed with equal frequency in both study groups. Due to the limited size of the study, the relative risk of death from any cause was not shown to be different than that seen in the 9 year follow-up data from WHO study (RR = 1.29). A secondary prevention component of the Helsinki Heart Study enrolled middle-aged men excluded from the primary prevention study because of known or suspected coronary heart disease. Subjects received gemfibrozil or placebo for 5 years. Although cardiac deaths trended higher in the gemfibrozil group, this was not statistically significant (hazard ratio 2.2, 95% confidence interval: 0.94-5.05).
Fibrates increase the risk of myositis or myopathy and have been associated with rhabdomyolysis. The risk for serious muscle toxicity appears to be increased in elderly patients and in patients with diabetes, renal failure, or hypothyroidism.
Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevations of CPK levels. Patients should promptly report unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. CPK levels should be assessed in patients reporting these symptoms, and Trilipix should be discontinued if markedly elevated CPK levels occur or myopathy or myositis is suspected or diagnosed.
Data from observational studies suggest that the risk for rhabdomyolysis is increased when fibrates are co-administered with a statin.
Cases of myopathy, including rhabdomyolysis, have been reported with fenofibrates co-administered with colchicine, and caution should be exercised when prescribing fenofibrate with colchicine [see Drug Interactions].
Trilipix at a dose of 135 mg once daily has been associated with increases in serum transaminases [AST (SGOT) or ALT (SGPT)]. In a pooled analysis of three 12-week, double-blind, controlled studies of Trilipix, increases in ALT and AST to > 3 times the upper limit of normal on two consecutive occasions occurred in 1.9% and 0.2%, respectively, of patients receiving Trilipix without other lipid-altering drugs. Increases in ALT and/or AST were not accompanied by increases in bilirubin or clinically significant increases in alkaline phosphatase.
In a pooled analysis of 10 placebo-controlled trials of fenofibrate, increases to > 3 times the upper limit of normal in ALT occurred in 5.3% of patients taking fenofibrate versus 1.1% of patients treated with placebo. The incidence of increases in transaminases observed with fenofibrate therapy may be dose related. In an 8-week dose-ranging study of fenofibrate in hypertriglyceridemia, the incidence of ALT or AST elevations ≥ 3 times the upper limit of normal was 13% in patients receiving dosages equivalent to 90 mg to 135 mg Trilipix once daily and was 0% in those receiving dosages equivalent to 45 mg Trilipix once daily or less, or placebo. Hepatocellular, chronic active, and cholestatic hepatitis observed with fenofibrate therapy have been reported after exposures of weeks to several years. In extremely rare cases, cirrhosis has been reported in association with chronic active hepatitis.
Baseline and regular monitoring of liver function, including serum ALT (SGPT) should be performed for the duration of therapy with Trilipix, and therapy discontinued if enzyme levels persist above 3 times the upper limit of normal.
Reversible elevations in serum creatinine have been reported in patients receiving Trilipix as well as patients receiving fenofibrate. In the pooled analysis of three 12-week, double-blind, controlled studies of Trilipix, increases in creatinine to > 2 mg/dL occurred in 0.8% of patients treated with Trilipix without other lipid-altering drugs. Elevations in serum creatinine were generally stable over time with no evidence for continued increases in serum creatinine with long-term therapy and tended to return to baseline following discontinuation of treatment. The clinical significance of these observations is unknown. Monitoring renal function in patients with renal impairment taking Trilipix is suggested. Renal monitoring should be considered for patients at risk for renal insufficiency, such as the elderly and those with diabetes.
Trilipix, like fenofibrate, clofibrate, and gemfibrozil, may increase cholesterol excretion into the bile, potentially leading to cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated. Trilipix therapy should be discontinued if gallstones are found.
Caution should be exercised when Trilipix is given in conjunction with oral coumarin anticoagulants. Trilipix may potentiate the anticoagulant effects of these agents resulting in prolongation of the prothrombin time/International Normalized Ratio (PT/INR). Frequent monitoring of PT/INR and dose adjustment of the oral anticoagulant are recommended until the PT/INR has stabilized in order to prevent bleeding complications [see Drug Interactions].
Pancreatitis has been reported in patients taking drugs of the fibrate class, including Trilipix. 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.
Mild to moderate hemoglobin, hematocrit, and white blood cell decreases have been observed in patients following initiation of Trilipix and fenofibrate therapy. However, these levels stabilize during long-term administration. Thrombocytopenia and agranulocytosis have been reported in individuals treated with fenofibrates. Periodic monitoring of red and white blood cell counts are recommended during the first 12 months of Trilipix administration.
Acute hypersensitivity reactions such as Stevens-Johnson syndrome and toxic necrolysis requiring patient hospitalization and treatment with steroids have been reported in individuals treated with fenofibrates.
In the 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%) in the fenofibrate group (p = 0.074); and for PE, there were 32 (0.7%) events in the placebo group and 53 (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 PE or thrombophlebitis than the placebo group (5.2% vs. 3.3% at five years; p < 0.01).
Paradoxical Decreases in HDL Cholesterol Levels
There have been postmarketing and clinical trial reports of severe decreases in HDL cholesterol levels (as low as 2 mg/dL) occurring in diabetic and non-diabetic patients initiated on fibrate therapy. 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. It is recommended that HDL-C levels be checked within the first few months after initiation of fibrate therapy. If a severely depressed HDL-C level is detected, fibrate therapy should be withdrawn, and the HDL-C level monitored until it has returned to baseline, and fibrate therapy should not be re-initiated.
Clinical Trials Experience
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
Fenofibric acid is the active metabolite of fenofibrate. Adverse events reported by 2% or more of patients treated with fenofibrate and greater than placebo during double-blind, placebo-controlled trials are listed in Table 1. Adverse events led to discontinuation of treatment in 5.0% of patients treated with fenofibrate and in 3.0% treated with placebo. Increases in liver tests were the most frequent events, causing discontinuation of fenofibrate treatment in 1.6% of patients in double-blind trials.
(N = 439)
(N = 365)
|BODY AS A WHOLE|
|Abnormal Liver Tests||7.5%||1.4%|
|Increased Creatine Phosphokinase||3.0%||1.4%|
* Dosage equivalent to 135 mg Trilipix
Clinical trials with Trilipix did not include a placebo-control arm. However, the adverse event profile of Trilipix was generally consistent with that of fenofibrate. The following adverse events not listed above were reported in ≥ 3% of patients taking Trilipix alone:
Gastrointestinal Disorders: Diarrhea, dyspepsia
General Disorders and Administration Site Conditions: Pain
Infections and Infestations: Nasopharyngitis, sinusitis, upper respiratory tract infection
Musculoskeletal and Connective Tissue Disorders: Arthralgia, myalgia, pain in extremity
Nervous System Disorders: Dizziness
The following adverse events have been identified during postapproval use of fenofibrate: rhabdomyolysis, pancreatitis, renal failure, muscle spasms, acute renal failure, hepatitis, cirrhosis, anemia, asthenia, and severely depressed HDL-cholesterol levels.
Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Potentiation of coumarin-type anticoagulant effect has been observed with prolongation of the PT/INR.
Caution should be exercised when oral coumarin anticoagulants are given in conjunction with Trilipix. The dosage of the anticoagulant 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 [see Warnings and Precautions].
Bile Acid Binding Resins
Since bile acid binding resins may bind other drugs given concurrently, patients should take Trilipix at least 1 hour before or 4 to 6 hours after a bile acid resin to avoid impeding its absorption.
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 drugs of the fibrate class including Trilipix, there is a risk that an interaction will lead to deterioration of renal function. The benefits and risks of using Trilipix with immunosuppressants and other potentially nephrotoxic agents should be carefully considered, and the lowest effective dose employed.
Cases of myopathy, including rhabdomyolysis, have been reported with fenofibrates co-administered with colchicine, and caution should be exercised when prescribing fenofibrate with colchicine.
Use in Specific Populations
Pregnancy Category: C
The safety of Trilipix in pregnant women has not been established. There are no adequate and well controlled studies of Trilipix in pregnant women. Trilipix should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
In pregnant rats given oral dietary doses of 14, 127, and 361 mg/kg/day from gestation day 6-15 during the period of organogenesis, adverse developmental findings were not observed at 14 mg/kg/day (less than 1 times the maximum recommended human dose [MRHD], based on body surface area comparisons; mg/m2). At higher multiples of human doses evidence of maternal toxicity was observed.
In pregnant rabbits given oral gavage doses of 15, 150, and 300 mg/kg/day from gestation day 6-18 during the period of organogenesis and allowed to deliver, aborted litters were observed at 150 mg/kg/day (10 times the MRHD, based on body surface area comparisons; mg/m2). No developmental findings were observed at 15 mg/kg/day (at less than 1 times the MRHD, based on body surface area comparisons; mg/m2).
In pregnant rats given oral dietary doses of 15, 75, and 300 mg/kg/day from gestation day 15 through lactation day 21 (weaning), maternal toxicity was observed at less than 1 times the MRHD, based on body surface area comparisons; mg/m2.
Trilipix should not be used in nursing mothers. A decision should be made whether to discontinue nursing or to discontinue the drug taking into account the importance of the drug to the mother.
The safety and effectiveness of Trilipix in pediatric patients have not been established.
Trilipix is substantially excreted by the kidney as fenofibric acid and fenofibric acid glucuronide, and the risk of adverse reactions to this drug 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 [see Dosage and Administration and Clinical Pharmacology]. Elderly patients with normal renal function should require no dose modifications. Consider monitoring renal function in elderly patients taking Trilipix.
The use of Trilipix should be avoided in patients who have severe renal impairment [see Contraindications]. Dose reduction is required in patients with mild to moderate renal impairment [see Dosage and Administration and Clinical Pharmacology]. Monitoring renal function in patients with renal impairment is recommended.
The use of Trilipix has not been evaluated in subjects with hepatic impairment [see Contraindications and Clinical Pharmacology].
There is no specific treatment for overdose with Trilipix. General supportive care of the patient is indicated, including monitoring of vital signs and observation of clinical status, should an overdose occur. If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage; usual precautions should be observed to maintain the airway. Because Trilipix is highly bound to plasma proteins, hemodialysis should not be considered.
How Supplied/Storage and Handling
Trilipix (fenofibric acid) delayed release capsules 45 mg:
- A reddish brown to orange brown cap and a yellow body imprinted in black ink the number “45”, available in bottles of 90 (NDC 0074-3161-90).
- A reddish brown to orange brown cap imprinted in white ink the “a” logo and a yellow body imprinted in black ink the number “45”, available in bottles of 90 (NDC 0074-9642-90).
Trilipix (fenofibric acid) delayed release capsules 135 mg:
- A blue cap and a yellow body imprinted in black ink the number “135”, available in bottles of 90 (NDC 0074-3162-90).
- A blue cap imprinted in white ink the “a” logo and a yellow body imprinted in black ink the number “135”, available in bottles of 90 (NDC 0074-9189-90).
Store at 25°C (77°F); excursions permitted to 15°-30°C (59° to 86°F) [See USP controlled room temperature]. Keep out of the reach of children. Protect from moisture.
Patient Counseling Information
See Consumer Medicine Information
Patients should be advised:
- of the potential benefits and risks of Trilipix.
- to read the Consumer Medicine Information before starting Trilipix therapy and to reread it each time the prescription is renewed.
- of medications that should not be taken in combination with Trilipix.
- to continue to follow an appropriate lipid-modifying diet while taking Trilipix.
- to take Trilipix once daily, without regard to food, at the prescribed dose, swallowing each capsule whole.
- to return for routine monitoring.
- to inform their physician of all medications, supplements, and herbal preparations they are taking and any change to their medical condition. Patients should also be advised to inform their physicians prescribing a new medication that they are taking Trilipix.
- to inform their physician of any muscle pain, tenderness, or weakness; onset of abdominal pain; or any other new symptoms.
AbbVie Inc. 2016
Manufactured for AbbVie Inc., North Chicago, IL 60064, U.S.A. by Fournier Laboratories Ireland Limited, Anngrove, Carrigtwohill Co. Cork, Ireland, or AbbVie LTD, Barceloneta, PR 00617.
03-B361 June, 2016