Drug Safety-related Labeling Changes (SrLC)

Get Email Alerts | Guide

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.

ULORIC (NDA-021856)

(FEBUXOSTAT)

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

Download Data

Expand all

04/17/2023 (SUPPL-15)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Cardiovascular Death

Additions and/or revisions underlined:

In a cardiovascular (CV) outcome study, gout patients with established CV disease treated with ULORIC had a higher rate of CV death compared to those treated with allopurinol. Sudden cardiac death was the most common cause of adjudicated CV deaths, 2.7% in the ULORIC group (83 of 3,098) as compared to 1.8% in the allopurinol group (56 of 3,092). ULORIC was similar to allopurinol for nonfatal myocardial infarction (MI), nonfatal stroke and unstable angina with urgent coronary revascularization [see Clinical Studies (14.2)].

Because of the increased risk of CV death, ULORIC should only be used in patients who have an inadequate response to a maximally titrated dose of allopurinol, who are intolerant to allopurinol, or for whom treatment with allopurinol is not advisable [see Indications and Usage(1)].

Consider the risks and benefits of ULORIC when deciding to prescribe or continue patients on ULORIC. Consider use of prophylactic low-dose aspirin therapy in patients with a history of CV disease. Monitor patients for the development of CV events. Inform patients about the symptoms of serious CV events and the steps to take if they occur.

5.3 Hepatic Effects

Additions and/or revisions underlined:

Cases of fatal and nonfatal hepatic failure in patients taking ULORIC have been reported. During randomized controlled studies, transaminase elevations greater than three times the upper limit of normal (ULN) were observed (AST: 2%, 2%, and ALT: 3%, 2% in ULORIC and allopurinol-treated patients, respectively). No dose-effect relationship for these transaminase elevations was noted [see Clinical Pharmacology (12.3)].

Obtain a liver test panel (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and total bilirubin) as a baseline before initiating ULORIC.

Measure liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. In this clinical context, if the patient presents abnormal liver tests (ALT or AST greater than three times the upper limit of the reference range), interrupt ULORIC treatment while investigating the probable cause.

Permanently discontinue ULORIC if liver injury is confirmed, and no alternate etiology can be found.

Permanently discontinue ULORIC in patients who have serum ALT or AST greater than three times the reference range with serum total bilirubin greater than two times the reference range without alternative etiologies because they are at risk for severe drug-induced liver injury. For patients with lesser elevations of serum ALT or bilirubin and with an alternate probable cause, treatment with ULORIC can be used with close monitoring.

5.4 Serious Skin Reactions

Additions and/or revisions underlined:

Serious skin and hypersensitivity reactions, including Stevens-Johnson Syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS) and toxic epidermal necrolysis (TEN) have been reported postmarketing in patients taking ULORIC. Discontinue ULORIC if serious skin reactions are suspected [see Patient Counseling Information (17)]. Many of these patients had reported previous similar skin reactions to allopurinol. ULORIC should be used with close monitoring in these patients.

7 Drug Interactions

7.1 Xanthine Oxidase Substrate Drugs

Newly added information:

…

A drug interaction study of ULORIC and azathioprine, also metabolized by XO, showed an increase in exposure of 6-mercaptopurine which may lead to toxicity [see Clinical Pharmacology (12.3)].

…

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

CV Death

Inform patients that gout patients with established CV disease treated with ULORIC had a higher rate of CV death compared to those treated with allopurinol in a CV outcomes study. Inform all patients of the higher rate of CV death with ULORIC compared to allopurinol. Alert all patients (those with and without CV disease) for the development of signs and symptoms of CV events and to seek medical care promptly should they occur [see Warnings and Precautions (5.1)].

Gout Flares

Inform patients that after initiation of ULORIC an increase in gout flares can occur and that is not reason to stop taking the medication. Instruct patients that it is recommended to initiate and continue gout prophylaxis therapy for six months while taking ULORIC [see Warnings and Precautions (5.2)].

Hepatic Effects

Inform patients that hepatic effects, including fatal ones, have occurred in patients treated with ULORIC. Instruct them to inform their healthcare provider if they experience liver injury symptoms [see Warnings and Precautions (5.3)].

…

02/21/2019 (SUPPL-13)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Cardiovascular Death

(Newly added subsection)

In a cardiovascular (CV) outcome study (ClinicalTrials.gov identifier NCT01101035), gout patients with established CV disease treated with ULORIC had a higher rate of CV death compared to those treated with allopurinol. The CV outcomes study in patients with gout (CARES) was a randomized, double-blinded, allopurinol-controlled, non-inferiority study conducted to evaluate the risk of major adverse cardiovascular events (MACE) in patients with gout who were treated with ULORIC. The study enrolled patients who had a history of major CV disease, cerebrovascular disease or diabetes mellitus with micro- and/or macrovascular disease. The primary endpoint was the time to first occurrence of MACE defined as the composite of CV death, nonfatal MI, nonfatal stroke, or unstable angina with urgent coronary revascularization. The study was designed to exclude a prespecified risk margin of 1.3 for the hazard ratio of MACE. Results showed that ULORIC was non-inferior to allopurinol for the primary endpoint of MACE [Hazard Ratio: 1.03, 95% Confidence Interval (CI): 0.89, 1.21]. However, there was a significant increase in CV deaths in patients treated with ULORIC (134 [1.5 per 100 patient-years]) compared to patients treated with allopurinol (100 [1.1 per 100 patient-years]) [Hazard Ratio: 1.34, 95% CI: 1.03, 1.73]. Sudden cardiac death was the most common cause of adjudicated CV deaths in the ULORIC group (83 of 3,098; 2.7%) as compared to the allopurinol group (56 of 3,092; 1.8%). ULORIC was similar to allopurinol for nonfatal MI, nonfatal stroke and unstable angina with urgent coronary revascularization .

Consider the risks and benefits of ULORIC when deciding to prescribe or continue patients on ULORIC. Consider use of prophylactic low-dose aspirin therapy in patients with a history of CV disease. Physicians and patients should remain alert for the development of adverse CV event signs and symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur.

6 Adverse Reactions

6 ADVERSE REACTIONS

(Newly added subsection)

The following serious adverse reactions are described elsewhere in the prescribing information:

Cardiovascular Death
Hepatic Effects

Serious Skin Reactions

6.1 Clinical Trials Experience

(Newly added subsection)

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In Phase 2 and 3 clinical studies, a total of 2757 patients with hyperuricemia and gout were treated with ULORIC 40 mg or 80 mg daily. For ULORIC 40 mg, 559 patients were treated for greater than or equal to 6 months. For ULORIC 80 mg, 1377 patients were treated for greater than or equal to?6 months, 674 patients were treated for greater than or equal to 1 year and 515 patients were treated for ?2 years. In the CARES study, a total of 3098 patients were treated with ULORIC 40 mg or 80 mg daily; of these, 2155 patients were treated for greater than or equal to? greater than or equal to?1 year and 1539 were treated for greater than or equal to?2 years.

…

In the CARES study, liver function abnormalities and diarrhea were reported in more than 1% of patients treated with ULORIC, although not at a rate more than 0.5% greater than allopurinol.

8 Use in Specific Populations

8.2 Lactation

(Newly added subsection)

…

Safety and effectiveness of ULORIC in pediatric patients have not been established.

8.5 Geriatric Use

(Newly added subsection)

No dose adjustment is necessary in elderly patients. Of the total number of patients in Studies 1, 2, and 3 (clinical studies of ULORIC in the treatment of gout), 16% were 65 and over, while 4% were 75 and over. Comparing patients in different age groups, no clinically significant differences in safety or effectiveness were observed but greater sensitivity of some older individuals cannot be ruled out. The Cmax and AUC24 of febuxostat following multiple oral doses of ULORIC in geriatric patients (?65 years) were similar to those in younger patients.

8.6 Renal Impairment

(Newly added subsection)

No dose adjustment is necessary in patients with mild to moderate renal impairment (Clcr 30 to 89 mL/min). For patients with severe renal impairment (Clcr 15 to 29 mL/min), the recommended dosage of ULORIC is limited to 40 mg once daily.

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

17 PATIENT COUNSELING INFORMATION

(Newly added subsection)

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

CV Death

Inform patients that gout patients with established CV disease treated with ULORIC had a higher rate of CV death compared to those treated with allopurinol in a CV outcomes study. Inform all patients of the higher rate of CV death with ULORIC compared to allopurinol. Instruct all patients (those with and without CV disease) to be alert for the development of signs and symptoms of CV events.

Gout Flares

Inform patients that after initiation of ULORIC there was an increased frequency of gout flares. Instruct patients that it is recommended to initiate and continue gout prophylaxis therapy for six months while taking ULORIC.

Hepatic Effects

Inform patients that hepatic effects have occurred in patients treated with ULORIC and instruct them to inform their healthcare provider if they experience liver injury symptoms.

Serious Skin Reactions

Inform patients that serious skin and hypersensitivity reactions have occurred in patients treated with ULORIC. Instruct patients to discontinue ULORIC if they develop symptoms of these reactions.

MEDICATION GUIDE

(Newly added subsection; please refer to the label for changes)

02/06/2018 (SUPPL-12)

Approved Drug Label (PDF)

5 Warnings and Precautions

Newly added subsection:

5.4 Serious Skin Reactions

Postmarketing reports of serious skin and hypersensitivity reactions, including Stevens-Johnson Syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS) and toxic epidermal necrolysis (TEN) have been reported in patients taking ULORIC. Discontinue ULORIC if serious skin reactions are suspected. Many of these patients had reported previous similar skin reactions to allopurinol. ULORIC should be used with caution in these patients.

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

Blood and Lymphatic System Disorders: agranulocytosis, eosinophilia.

Skin and Subcutaneous Tissue Disorders: generalized rash, Stevens-Johnson Syndrome, hypersensitivity skin reactions, erythema multiforme, drug reaction with eosinophilia and systemic symptoms, toxic epidermal necrolysis.

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

PATIENT COUNSELING INFORMATION

Addition of the following:

Some serious skin and allergic reactions such as rash, skin reddening, pain, swelling or blistering of lips, eyes or mouth, skin peeling and flu-like symptoms have been reported in patients taking ULORIC. Patients who had previous reactions to allopurinol may be at greater risk for these skin conditions.

PATIENT INFORMATION

Format has been revised; please refer to label.

08/15/2017 (SUPPL-11)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

PLLR conversion; revised as below:

Risk Summary

Limited available data with ULORIC use in pregnant women are insufficient to inform a drug associated risk of adverse developmental outcomes. No adverse developmental effects were observed in embryo-fetal development studies with oral administration of febuxostat to pregnant rats and rabbits during organogenesis at doses that produced maternal exposures up to 40 and 51 times, respectively, the exposure at the maximum recommended human dose (MRHD). No adverse developmental effects were observed in a pre- and postnatal development study with administration of febuxostat to pregnant rats from organogenesis through lactation at an exposure approximately 11 times the MRHD.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Animal Data

In an embryo-fetal development study in pregnant rats dosed during the period of organogenesis from gestation Days 7 – 17, febuxostat was not teratogenic and did not affect fetal development or survival at exposures up to approximately 40 times the MRHD (on an AUC basis at maternal oral doses up to 48 mg/kg/day). In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation Days 6 – 18, febuxostat was not teratogenic and did not affect fetal development at exposures up to approximately 51 times the MRHD (on an AUC basis at maternal oral doses up to 48 mg/kg/day).

In a pre- and postnatal development study in pregnant female rats dosed orally from gestation Day 7 through lactation Day 20, febuxostat had no effects on delivery or growth and development of offspring at a dose approximately 11 times the MRHD (on an AUC basis at a maternal oral dose of 12 mg/kg/day). However, increased neonatal mortality and a reduction in neonatal body weight gain were observed in the presence of maternal toxicity at a dose approximately 40 times the MRHD (on an AUC basis at a maternal oral dose of 48 mg/kg/day).

Febuxostat crossed the placental barrier following oral administration to pregnant rats and was detected in fetal tissues.

8.2 Lactation

PLLR conversion; revised as below:

Risk Summary

There are no data on the presence of febuxostat in human milk, the effects on the breastfed infant, or the effects on milk production. Febuxostat is present in rat milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ULORIC and any potential adverse effects on the breastfed child from ULORIC or from the underlying maternal condition.

Data

Animal Data

Orally administered febuxostat was detected in the milk of lactating rats at up to approximately 7 times the plasma concentration.

8.6 Renal Impairment

Additions and/or revisions underlined:

… For patients with severe renal impairment (Cl cr 15 to 29 mL/min), the dose of ULORIC is limited to 40 mg once daily.