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.

ARAVA (NDA-020905)

(LEFLUNOMIDE)

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

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06/28/2024 (SUPPL-33)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.6 Skin Ulcers

Newly added subsection:

Skin ulcers may occur in patients during therapy with leflunomide. If leflunomide-associated skin ulcer is suspected or if skin ulcers persist despite appropriate therapy, leflunomide discontinuation and an accelerated drug elimination procedure should be considered [see Warnings and Precautions (5.3)]. The decision to resume leflunomide following skin ulcers should be based on clinical judgment of adequate wound healing.

6 Adverse Reactions

Additions and/or revisions underlined:

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

Hepatotoxicity [see Warnings and Precautions (5.2)]
Immunosuppression [see Warnings and Precautions (5.4)]
Bone marrow suppression [see Warnings and Precautions (5.4)]
Serious infections [see Warnings and Precautions (5.4)]
Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reactions with eosinophilia and systemic symptoms [see Warnings and Precautions (5.5)]
Skin ulcers [see Warnings and Precautions (5.6)]
Peripheral neuropathy [see Warnings and Precautions (5.8)]
Interstitial lung disease [see Warnings and Precautions (5.9)]

8 Use in Specific Populations

8.3 Females and Males of Reproductive Potential

Additions and/or revisions underlined:

ARAVA may cause fetal harm if administered during pregnancy [see Use in Specific Populations (8.1)].

Pregnancy Testing

Exclude pregnancy prior to initiation of treatment with ARAVA in females of reproductive potential. Advise females to notify their healthcare provider immediately if pregnancy occurs or is suspected during treatment [see Warnings and Precautions (5.1, 5.3) and Use in Specific Populations (8.1)].

Contraception

Females

Females of reproductive potential should use effective contraception while taking ARAVA. If ARAVA is discontinued, use of contraception should be continued until it is verified that plasma concentrations of teriflunomide are less than 0.02 mg/L (0.02 mcg/mL, the level expected to have minimal fetal risk, based on animal data).

Females of reproductive potential who wish to become pregnant should discontinue ARAVA and undergo an accelerated elimination procedure. Effective contraception should be used until it is verified that plasma concentrations of teriflunomide are less than 0.02 mg/L (0.02 mcg/mL) [see Warnings and Precautions (5.1, 5.3) and Use in Specific Populations (8.1)].

Males

Teriflunomide, the active metabolite of ARAVA, is detected in human semen. Animal studies to specifically evaluate the risk of male mediated fetal toxicity have not been conducted. To minimize any possible risk, men not wishing to father a child and their female partners should use effective contraception. Men wishing to father a child should discontinue use of ARAVA and either undergo an accelerated elimination procedure or wait until verification that the plasma teriflunomide concentration is less than 0.02 mg/L (0.02 mcg/mL) [see Warnings and Precautions (5.3)].

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of ARAVA in pediatric patients have not been established.

The safety and effectiveness of ARAVA in the treatment of polyarticular course juvenile idiopathic arthritis (JIA) was evaluated in a single multicenter, double-blind, active-controlled trial in 94 pediatric patients (1:1 randomization) with polyarticular course juvenile idiopathic arthritis (JIA) as defined by the American College of Rheumatology (ACR). In this population, ARAVA treatment was found not to be effective.

The safety of ARAVA was studied in 74 patients with polyarticular course JIA ranging in age from 3-17 years (47 patients from the active-controlled study and 27 from an open-label safety and pharmacokinetic study). The most common adverse events included abdominal pain, diarrhea, nausea, vomiting, oral ulcers, upper respiratory tract infections, alopecia, rash, headache, and dizziness. Less common adverse events included anemia, hypertension, and weight loss. Fourteen pediatric patients experienced ALT and/or AST elevations, nine between1.2 and 3-fold the upper limit of normal, and five between 3 and 8-fold the upper limit of normal.

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Serious Skin Reactions

Advise patients of the possibility of rare, serious skin reactions. Instruct patients to promptly seek medical attention if they develop a skin rash, mucous membrane lesions, or skin ulcers.

Investigations

Advise patients of the potential hepatotoxic effects of ARAVA and of the need for monitoring liver enzymes. Instruct patients to report if they develop symptoms such as unusual tiredness, abdominal pain or jaundice.
Advise patients that they may develop a lowering of their blood counts and should have frequent hematologic monitoring. This is particularly important for patients who are receiving other immunosuppressive therapy concurrently with ARAVA, who have recently discontinued such therapy before starting treatment with ARAVA, or who have had a history of a significant hematologic abnormality. Instruct patients to promptly report if they notice symptoms consistent with pancytopenia, such as easy bruising or bleeding, recurrent infections, fever, paleness or unusual tiredness.
Inform patients about the early warning signs of interstitial lung disease and ask them to contact their physician promptly if these symptoms appear or worsen during therapy.

10/18/2016 (SUPPL-31)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Post Marketing Experience (addition underlined)

Gastrointestinal: acute hepatic necrosis, colitis, including microscopic colitis, hepatitis, jaundice/cholestasis, pancreatitis; severe liver injury such as hepatic failure

Respiratory: interstitial lung disease, including interstitial pneumonitis and pulmonary fibrosis, which may be fatal; pulmonary hypertension;