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.

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

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07/28/2023 (SUPPL-74)

5 Warnings and Precautions

5.8 Pulmonary Arterial Hypertension

(Newly added subsection)

Cases of pulmonary arterial hypertension (PAH) have been reported with interferon beta products, including EXTAVIA. PAH has occurred in patients treated with interferon beta products in the absence of other contributory factors. Many of the reported cases required hospitalization, including one case with interferon beta in which the patient underwent a lung transplant. PAH has developed at various time points after initiating therapy with interferon beta products and may occur several years after starting treatment.

Patients who develop unexplained symptoms (e.g., dyspnea, new or increasing fatigue) should be assessed for PAH. If alternative etiologies have been ruled out and a diagnosis of PAH is confirmed, discontinue treatment and manage as clinically indicated.

6 Adverse Reactions

(Additions and/or revisions underlined)

The following serious adverse reactions are discussed in more details in other sections of labeling:

· Hepatic Injury [see Warnings and Precautions (5.1)]

· Anaphylaxis and Other Allergic Reactions [see Warnings and Precautions (5.2)]

· Depression and Suicide [see Warnings and Precautions (5.3)]

· Congestive Heart Failure [see Warnings and Precautions (5.4)]

· Injection Site Reactions Including Necrosis [see Warnings and Precautions (5.5)]

· Leukopenia [see Warnings and Precautions (5.6)]

· Thrombotic Microangiopathy [see Warnings and Precautions (5.7)]

· Pulmonary Arterial Hypertension [see Warnings and Precautions (5.8)]

· Flu-like Symptom Complex [see Warnings and Precautions (5.9)]

· Seizures [see Warnings and Precautions (5.10)]

· Drug-induced Lupus Erythematosus [see Warnings and Precautions (5.11)]

6.3 Postmarketing Experience

(Additions and/or revisions underlined)

The following adverse reactions have been identified during postapproval use of interferon beta-1b. 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 and lymphatic system disorders: Anemia, Thrombocytopenia, Hemolytic anemia

Endocrine disorders: Hypothyroidism, Hyperthyroidism, Thyroid dysfunction

Metabolism and nutrition disorders: Triglyceride increased, Anorexia, Weight decrease, Weight increase

Psychiatric disorders: Anxiety, Confusion, Emotional lability

Nervous system disorders: Convulsion, Dizziness, Psychotic symptoms Cardiac disorders: Cardiomyopathy, Palpitations, Tachycardia Vascular disorders: Vasodilatation

Respiratory, thoracic, and mediastinal disorders: Bronchospasm, Pulmonary Arterial Hypertension

Gastrointestinal disorders: Diarrhea, Nausea, Pancreatitis, Vomiting

Hepatobiliary disorders: Hepatitis, Gamma GT increased

Skin and subcutaneous tissue disorders: Alopecia, Pruritus, Skin discoloration, Urticaria

Musculoskeletal and connective tissue disorders: Arthralgia, Drug-induced lupus erythematosus

Reproductive system and breast disorder: Menorrhagia

General disorders and administration site conditions: Fatal capillary leak syndrome*

*The administration of cytokines to patients with a preexisting monoclonal gammopathy has been associated with the development of this syndrome.

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

17 PATIENT COUNSELING INFORMATION

…

(Additions and/or revisions underlined)

Pulmonary Arterial Hypertension

Inform patients that PAH has occurred in patients treated with interferon beta products, including EXTAVIA. Instruct patients to promptly report any new symptoms such as new or increasing fatigue or shortness of breath to their healthcare provider [see Warnings and Precautions (5.8)].

…

Drug-induced Lupus Erythematosus

Advise patients that drug-induced lupus erythematosus has been reported during the use of EXTAVIA. Inform patients of the symptoms of rash, redness of the skin on the face, joint pain, fever, and weakness, and instruct patients to report them immediately to their healthcare provider [see Warnings and Precautions (5.11)].

…

Medication Guide

(Extensive changes; please refer to label for complete information)

11/03/2021 (SUPPL-73)

5 Warnings and Precautions

5.5 Injection Site Reactions Including Necrosis (formerly Injection Site Necrosis and Reactions)

Additions and/or revisions underlined:

Injection site reactions, including injection site necrosis, can occur with the use of interferon beta products, including EXTAVIA. Injection site necrosis (ISN) was reported in 4% of interferon beta-1b-treated patients in controlled clinical trials (compared to 0% on placebo) [see Adverse Reactions (6.1)] …

… Approximately 69% of patients experienced injection site reactions during the first three months of treatment, compared to approximately 40% at the end of the studies.

Injection site abscesses and cellulitis have been reported in the postmarketing setting with use of interferon beta products including EXTAVIA. Some cases required treatment with hospitalization for surgical drainage and intravenous antibiotics. Periodically evaluate patient understanding and use of aseptic self-injection techniques and procedures, particularly if injection site necrosis has occurred. Patients should be advised of the importance of rotating injection sites with each dose. Whether to discontinue therapy following a single site of necrosis is dependent on the extent of necrosis. For patients who continue therapy with EXTAVIA after injection site necrosis has occurred, avoid administration of EXTAVIA into the affected area until it is fully healed. If multiple lesions occur, change injection site, or discontinue therapy until healing occurs.

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

MEDICATION GUIDE

What are the possible side effects of EXTAVIA?

EXTAVIA may cause serious side effects. Call your healthcare provider right away if you have any of the serious side effects of EXTAVIA, including:

Additions and/or revisions underlined:

Injection site problems. Serious skin reactions can happen in some people, including areas of severe damage to skin and the tissue below the skin (necrosis). These reactions can happen anywhere you inject EXTAVIA. Symptoms of injection site problems may include swelling, redness, or pain at the injection site, fluid drainage from the injection site, and breaks in your skin or blue-black skin discoloration. Call your healthcare provider right away if an injection site becomes swollen and painful or the area looks infected. You may have a skin infection or an area of severe skin damage (necrosis) requiring treatment by a healthcare provider.

10/02/2020 (SUPPL-70)

5 Warnings and Precautions

Thrombotic Microangiopathy

(Additions and/or revisions underlined)

Cases have been reported several weeks to years after starting interferon beta products. If clinical symptoms and laboratory findings consistent with TMA occur and a relationship to EXTAVIA is suspected, discontinue treatment and manage as clinically indicated.

6 Adverse Reactions

6.3 Postmarketing Experience

(Additions and/or revisions underlined)

Blood and lymphatic system disorders: Anemia, Thrombocytopenia, Hemolytic anemia

08/16/2019 (SUPPL-67)

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

Medication Guide

Additions and/or revisions underlined:

What is EXTAVIA?

EXTAVIA is a prescription medicine used to treat relapsing forms of multiple sclerosis, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. EXTAVIA is similar to certain interferon proteins that are produced in the body.

What should I tell my healthcare provider before taking EXTAVIA? Before you take EXTAVIA, tell your healthcare provider if you:

· have or have had depression (sinking feeling or sadness), anxiety (feeling uneasy, nervous, or fearful for no reason) or trouble sleeping

12/11/2018 (SUPPL-66)

8 Use in Specific Populations

8.1 Pregnancy

8.2 Lactation

PLLR conversion; extensive changes. Please refer to label for complete information.

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Pregnancy

Advise patients to notify their healthcare provider if they are pregnant or plan to become pregnant.

05/12/2016 (SUPPL-62)

5 Warnings and Precautions

Anaphylaxis and Other Allergic Reactions (addition of paragraph)

The removable rubber cap of the diluent (Sodium Chloride, 0.54% Solution) pre-filled syringe contains natural rubber latex, which may cause allergic reactions and should not be handled by latex-sensitive individuals. The safe use of EXTAVIA pre-filled syringe in latex-sensitive individuals has not been studied.

Drug-induced Lupus Erythematosus (addition of section)

Cases of drug-induced lupus erythematosus have been reported with some interferon beta products, including EXTAVIA. Signs and symptoms of drug-induced lupus reported in EXTAVIA-treated patients have included rash, serositis, polyarthritis, nephritis, and Raynaud’s phenomenon. Cases have occurred with positive serologic testing (including positive anti-nuclear and/or anti-double-stranded DNA antibody testing). If EXTAVIA-treated patients develop new signs and symptoms characteristic of this syndrome, EXTAVIA therapy should be stopped.

6 Adverse Reactions

Drug Induced Lupus Erythematosus (addition)

Post Marketing Experience (addition to subsection)

Musculoskeletal and connective tissue disorders: drug-induced lupus erythematosus

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

PCI

Anaphylaxis and Other Allergic Reactions (addition of sentence)
Inform latex-sensitive patients that the removable rubber cap of the diluent pre-filled syringe contains natural rubber latex.