Drug Safety-related Labeling Changes (SrLC)

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FENOGLIDE (NDA-022118)

(FENOFIBRATE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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06/06/2025 (SUPPL-14)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:

FENOGLIDE is contraindicated in patients with:

• Severe renal impairment, including those with end-stage renal disease (ESRD) and those receiving dialysis [see Clinical Pharmacology (12.3)].

. . .

• Pre-existing gallbladder disease [see Warnings and Precautions (5.5)].

• Hypersensitivity to fenofibrate, fenofibric acid or any of the excipients in FENOGLIDE. Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported with fenofibrate [see Warnings and Precautions (5.9)].

5 Warnings and Precautions

5.1 Mortality and Coronary Heart Disease Morbidity

Additions and/or revisions underlined:

Fenofibrate did not reduce cardiovascular disease morbidity or mortality in two large, randomized controlled trials of patients with type 2 diabetes mellitus [see Clinical Studies (14.4)].

. . .

Because of chemical, pharmacological, and clinical similarities between fenofibrates, including FENOGLIDE; pemafibrate; clofibrate; and gemfibrozil; the findings in 5 large randomized, placebo-controlled clinical trials with these other fibrate drugs may also apply to FENOGLIDE.

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 [see Clinical Studies (14.4)].

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.

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.

. . .

 

5.2 Hepatotoxicity

Additions and/or revisions underlined:

. . .

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 [see Adverse Reactions (6.1)].

. . .

 

5.3 Myopathy and Rhabdomyolysis

Additions and/or revisions underlined:

FENOGLIDE 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 FENOGLIDE co-administered with colchicine. Consider whether the benefit of using colchicine concomitantly with FENOGLIDE outweighs the increased risk of myopathy [see Drug Interactions (7)].

Discontinue FENOGLIDE if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected. Muscle symptoms and CK elevations may resolve if FENOGLIDE is discontinued. Temporarily discontinue FENOGLIDE 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 FENOGLIDE 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

Subsection title revised

Additions and/or revisions underlined:

. . .

Renal monitoring should also be considered for patients taking FENOGLIDE at risk for renal insufficiency such as geriatric patients and patients with diabetes. FENOGLIDE is contraindicated in patients with severe renal impairment, including those with end-stage renal disease (ESRD) and those receiving dialysis [see Dosage and Administration (2.3), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

 

5.5 Cholelithiasis

Additions and/or revisions underlined:

. . .

FENOGLIDE is contraindicated in patients with pre-existing gallbladder disease.

 

5.6 Increased Bleeding Risk with Coumarin Anticoagulants

Subsection title revised

 

5.9 Hypersensitivity Reactions

Additions and/or revisions underlined:

. . .

FENOGLIDE is contraindicated in patients with a hypersensitivity to fenofibrate, fenofibric acid, or any of the ingredients in FENOGLIDE.

 

5.10 Venothromboembolic Disease

Additions and/or revisions underlined:

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 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.

6 Adverse Reactions

Addition of the following to the bulleted line listing:

. . .

• Myopathy and Rhabdomyolysis [see Warnings and Precautions (5.3)]

• Increases in Serum Creatinine [see Warnings and Precautions (5.4)]

• Cholelithiasis [see Warnings and Precautions (5.5)]

• Increased Bleeding Risk with Coumarin Anticoagulants [see Warnings and Precautions (5.6)]

. . .

• Hematologic Changes [see Warnings and Precautions (5.8)]

. . .

Paradoxical Decreases in HDL Cholesterol Levels [see Warnings and Precautions (5.11)]

 

6.1 Clinical Trials Experience

Extensive changes; please refer to label for complete information

 

6.2 Postmarketing Experience

Additions and/or revisions underlined:

The following adverse reactions have been identified during post approval use of fenofibrate. Because these reactions 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.

Blood: Anemia, white blood cell decreases

Gastrointestinal: Pancreatitis

General: Asthenia

Hepatobiliary: Increased total bilirubin, hepatitis, cirrhosis

Immune System: Anaphylaxis, angioedema

Lipid Disorders: Severely depressed HDL-cholesterol levels

Musculoskeletal: Myalgia, muscle spasms, rhabdomyolysis, arthralgia

Renal and Urinary: Acute renal failure

Respiratory: Interstitial lung disease

Skin and Subcutaneous Tissue: Photosensitivity reactions days to months after initiation. This may occur in patients who report a prior photosensitivity reaction to ketoprofen.

7 Drug Interactions

Extensive changes; please refer to label for complete information

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of FENOGLIDE have not been established in pediatric patients with severe hypertriglyceridemia or primary hyperlipidemia.

 

8.5 Geriatric Use

Additions and/or revisions underlined:

Assess renal function in geriatric patients and follow contraindications and dosing recommendations for patients with renal impairment [see Contraindications (4), Warnings and Precautions (5.3, 5.4) and Use in Specific Populations (8.6)].

While fenofibric acid exposure is not influenced by age, geriatric patients are more likely to have renal impairment, and fenofibric acid is substantially excreted by the kidney [see Clinical Pharmacology (12.3)]. Consider monitoring renal function in geriatric patients taking FENOGLIDE.

 

8.6 Renal Impairment

Additions and/or revisions underlined

FENOGLIDE is contraindicated in patients with severe renal impairment (eGFR less than 30 mL/min/1.73m2), including those with end-stage renal disease (ESRD) and those receiving dialysis. Dosage reduction is required in patients with mild to moderate renal impairment [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)]. Patients with severe renal impairment have 2.7-fold higher exposure of fenofibric acid and increased accumulation of fenofibric acid during chronic dosing compared with healthy volunteers. Renal impairment is a risk factor for myopathy and rhabdomyolysis [see Warnings and Precautions (5.3, 5.4) and Clinical Pharmacology (12.3)].

 

8.7 Hepatic Impairment

Additions and/or revisions underlined

The use of FENOGLIDE has not been evaluated in patients with hepatic impairment. FENOGLIDE is contraindicated in patients with active liver disease, including those with unexplained persistent liver function abnormalities [see Clinical Pharmacology (12.3)].

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Patient Counseling Information

Additions and/or revisions underlined

Hepatotoxicity

Inform patients that FENOGLIDE may cause liver enzyme elevations and possibly liver failure. Advise patients to promptly report fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice [see Contraindications (4) and Warnings and Precautions (5.2)].

Myopathy and Rhabdomyolysis

Advise patients that FENOGLIDE may cause myopathy and rhabdomyolysis. Inform patients that the risk is also increased when taking certain types of medication and they should discuss all medication, both prescription and over the counter, with their healthcare provider. Instruct patients to inform other healthcare providers prescribing a new medication or increasing the dosage of an existing medication that they are taking FENOGLIDE. Instruct patients to promptly report any unexplained muscle pain, tenderness, or weakness particularly if accompanied by malaise or fever [see Warnings and Precautions (5.3) and Drug Interactions (7)].

Increased Bleeding Risk with Coumarin Anticoagulants

Inform patients that the concomitant use of FENOGLIDE with coumarin-type anticoagulants may increase the risk of bleeding. Advise patients if they are taking or planning to take coumarin-type anticoagulants to inform their healthcare providers and that increased monitoring may be necessary [see Warnings and Precautions (5.6) and Drug Interactions (7)].

Hypersensitivity Reactions

Inform patients that serious hypersensitivity reactions, such as anaphylaxis and angioedema, have been reported with fenofibrates. Advise patients to report immediately any signs or symptoms suggesting allergic reaction, and to discontinue drug until they have consulted prescribing physicians [see Warnings and Precautions (5.9)].

Pregnancy

Advise patients to inform their healthcare provider of a known or suspected pregnancy to discuss if FENOGLIDE should be discontinued [see Use in Specific Populations (8.1)].

Lactation

Advise patients that breastfeeding during treatment with FENOGLIDE is not recommended [see Use in Specific Populations (8.2)].

Missed Doses

If a dose is missed, advise patients to not take an extra dose and to resume treatment with the next dose.

06/03/2021 (SUPPL-13)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Hepatotoxicity

(Newly added section)

Serious drug-induced liver injury (DILI), including liver transplantation and death, have been reported postmarketing with FENOGLIDE. 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 FENOGLIDE 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, fenofibrate at doses equivalent to 87 mg to 130 mg fenofibrate daily (at the highest dose, comparable to FENOGLIDE, 120 mg) has been associated with increases in serum AST or ALT. The incidence of increases in transaminases may be dose related [see Adverse Reactions (6.1)].

FENOGLIDE is contraindicated in patients with active liver disease, including those with primary biliary cirrhosis and unexplained persistent liver function abnormalities [see Contraindications (4)]. Monitor patient’s liver function, including serum ALT, AST, and total bilirubin, at baseline and periodically for the duration of therapy with FENOGLIDE. Discontinue FENOGLIDE if signs or symptoms of liver injury develop or if elevated enzyme levels persist (ALT or AST

> 3 times the upper limit of normal, or if accompanied by elevation of bilirubin). Do not restart FENOGLIDE in these patients if there is no alternative explanation for the liver injury.

5.3 Myopathy and Rhabdomyolysis

(Section title revised)

6 Adverse Reactions

(Newly added information)

The following serious adverse reactions are described below and elsewhere in the labeling:

• Mortality and coronary heart disease morbidity [see Warnings and Precautions (5.1)]

• Hepatoxicity [see Warnings and Precautions (5.2)]

• Pancreatitis [see Warnings and Precautions (5.7)]

• Hypersensitivity Reactions [see Warnings and Precautions (5.9)]

• Venothromboembolic Disease [see Warnings and Precautions (5.10)]

6.1 Clinical Trials Experience

Increases in Liver Enzymes

(Newly added information)

In a pooled analysis of 10 placebo-controlled trials, increases to > 3 times the upper limit of normal in ALT occurred in 5.3% of patients taking fenofibrate at doses equivalent to 87 mg to 130 mg fenofibrate daily (at the highest dose, comparable to FENOGLIDE, 120 mg) versus 1.1% of patients treated with placebo. In an 8-week study, the incidence of ALT or AST elevations ? 3 times the upper limit of normal was 13% in patients receiving dosages equivalent to 87 mg to 130 mg fenofibrate daily and was 0% in those receiving dosages equivalent to 43 mg or less fenofibrate daily or placebo.

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

The following adverse reactions have been identified during post approval use of fenofibrate. Because these reactions 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:

myalgia, rhabdomyolysis, pancreatitis, acute renal failure, muscle spasms, hepatitis, cirrhosis, increased total bilirubin, anemia, arthralgia, decreases in hematocrit, white blood cell decreases, asthenia, severely depressed HDL cholesterol levels, and interstitial lung disease.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Patients should be advised:

to inform their physician of symptoms of liver injury (e.g., jaundice, abnormal pain, nausea, malaise, dark urine, abnormal stool, pruritus); any muscle pain, tenderness, or weakness; onset of abdominal pain; or any other new symptoms.

05/15/2019 (SUPPL-10)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Addition of interstitial lung disease to listing of reactions identified.

03/13/2019 (SUPPL-9)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)

Risk Summary

Limited available data with fenofibrate use in pregnant women are insufficient to determine a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, no evidence of embryo-fetal toxicity was observed with oral administration of fenofibrate in rats and rabbits during organogenesis at doses less than or equivalent to the maximum recommended clinical dose of 120 mg daily, based on body surface area (mg/m2). Adverse reproductive outcomes occurred at higher doses in the presence of maternal toxicity.

FENOGLIDE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

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, no adverse developmental findings were observed at 14 mg/kg/day (less than the clinical exposure at the maximum recommended human dose [MRHD] of 300 mg fenofibrate daily, equivalent to 120 mg FENOGLIDE daily, based on body surface area comparisons). Increased fetal skeletal malformations were observed at maternally toxic doses (361 mg/kg/day, corresponding to 12 times the clinical exposure at the MRHD) that significantly suppressed maternal body weight gain.

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, no adverse developmental findings were observed at 15 mg/kg/day (a dose that approximates the clinical exposure at the MRHD, based on body surface area comparisons). Aborted litters were observed at maternally toxic doses (greater than or equal to 150 mg/kg/day, corresponding to greater than or equal to 10 times the clinical exposure at the MRHD) that suppressed maternal body weight gain.

In pregnant rats given oral dietary doses of 15, 75, and 300 mg/kg/day from gestation day 15 through lactation day 21 (weaning), no adverse developmental effects were observed at 15 mg/kg/day (less than the clinical exposure at the MRHD, based on body surface area comparisons), despite maternal toxicity (decreased weight gain). Post-implantation loss was observed at greater than or equal to 75 mg/kg/day (greater than or equal to 2 times the clinical exposure at the MRHD) in the presence of maternal toxicity (decreased weight gain). Decreased pup survival was noted at 300 mg/kg/day (10 times the clinical exposure at the MRHD), which was associated with decreased maternal body weight gain/maternal neglect.

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)

Risk Summary

There is no available information on the presence of fenofibrate in human milk, effects of the drug on the breastfed infant, or the effects on milk production. Fenofibrate is present in the milk of rats, and is therefore likely to be present in human milk. Because of the potential for serious adverse reactions in breastfed infants, such as disruption of infant lipid metabolism, women should not breastfeed during treatment with FENOGLIDE and for 5 days after the final dose.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Patients should be advised:

•             to return to their physician’s office for routine monitoring.

•             not to breastfeed during treatment with FENOGLIDE and for 5 days after the final dose.

05/18/2018 (SUPPL-7)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.9 Hypersensitivity Reactions

(subsection revised, additions underlined)

 

Acute Hypersensitivity

Anaphylaxis and angioedema have been reported postmarketing with fenofibrate.. 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 fenofibrate.

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 postmarketing, occurring days to weeks after initiation of fenofibrate. 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 espiratory). Discontinue fenofibrate and treat patients appropriately if SCAR is suspected.

6 Adverse Reactions

6.1 Clinical Trials Experience

(additions underlined)

…

Urticaria was seen in 1.1 vs. 0%, and rash in 1.4 vs. 0.8% of fenofibrate and placebo patients respectively in controlled trials.

6.2 Postmarketing Experience

(additions underlined)

The following adverse reactions have been identified during post approval use of fenofibrate. Because these reactions 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:

Myalgia, rhabdomyolysis, pancreatitis, acute renal failure, muscle spasms, hepatitis, cirrhosis, anemia, arthralgia, decreases in hematocrit, white blood cell decreases, asthenia, and severely depressed HDL cholesterol levels.

Photosensitivity reactions have occurred days to months after initiation; in some of these cases, patients reported a prior photosensitivity reaction to ketoprofen.