Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

TRIGLIDE (NDA-021350)

(FENOFIBRATE)

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

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06/03/2021 (SUPPL-23)

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 Triglide. 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 Triglide 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 134 mg to 200 mg fenofibrate daily (the high dose equivalent to 160 mg Triglide) 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)].

Triglide 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 Triglide. Discontinue Triglide 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 Triglide in these patients if there is no alternative explanation for the liver injury.

5.3 Myopathy and Rhabdomyolysis

(Section title revised)

(Additions and/or revisions underlined)

Fenofibrates increase the risk of 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 insufficiency, or hypothyroidism.

Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevations of creatine phosphokinase (CPK) 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 Triglide therapy should be discontinued if markedly elevated CPK levels occur or myopathy/myositis is suspected or diagnosed.

Data from observational studies indicate that the risk for rhabdomyolysis is increased when fibrates, in particular gemfibrozil, are co-administered with a statin. The combination should be avoided unless the benefit of further alterations in lipid levels is likely to outweigh the increased risk of this drug combination [see Clinical Pharmacology (12.3)].

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 (7.4)].

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

(Newly added information)

Increases in Liver Enzymes

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 versus 1.1% of patients treated with placebo. In an 8-week study, the incidence of ALT or AST elevations > or equal to 3 times the upper limit of normal was 13% in patients receiving dosages equivalent to 134 mg to 200 mg fenofibrate daily (the high dose equivalent to 160 mg Triglide) and was 0% in those receiving dosages equivalent to 34 mg or 67 mg micronized 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, muscle spasms, acute renal failure, hepatitis, cirrhosis, increased total bilirubin, anemia, arthralgia, 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)

Advise patients to promptly report symptoms of liver injury (e.g., jaundice, abnormal pain, nausea, malaise, dark urine, abnormal stool, pruritus); any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever; onset of abdominal pain or other symptoms consistent with gallstones or pancreatitis; or any other new symptoms.

05/15/2019 (SUPPL-22)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Addition of interstitial lung disease to listing of reactions identified.

05/18/2018 (SUPPL-20)

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, 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 respiratory). 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)

myalgia, rhabdomyolysis, pancreatitis, muscle spasms, acute renal failure, hepatitis, cirrhosis, anemia, arthralgia, 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.