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.

AVONEX (BLA-103628)

(INTERFERON BETA-1A)

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

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07/28/2023 (SUPPL-5269)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.8 Pulmonary Arterial Hypertension

(Newly added subsection)

Cases of pulmonary arterial hypertension (PAH) have been reported in patients treated with interferon beta products, including AVONEX. 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 detail in other sections of labeling:

Depression, Suicide, and Psychotic Disorders [see Warnings and Precautions (5.1)]
Hepatic Injury [see Warnings and Precautions (5.2)]
Anaphylaxis and Other Allergic-Reactions [see Warnings and Precautions (5.3)]
Injection Site Reactions Including Necrosis [see Warnings and Precautions (5.4)]
Congestive Heart Failure [see Warnings and Precautions (5.5)]
Decreased Peripheral Blood Counts [see Warnings and Precautions (5.6)]
Thrombotic Microangiopathy [see Warnings and Precautions (5.7)]
Pulmonary Arterial Hypertension [see Warnings and Precautions (5.8)]
Seizures [see Warnings and Precautions (5.9)]
Autoimmune Disorders [see Warnings and Precautions (5.10)]
Laboratory Tests [see Warnings and Precautions (5.11)]

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

The following additional adverse reactions have been identified during post-approval use of AVONEX. 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.

Hemolytic anemia
Menorrhagia and metrorrhagia
Pulmonary Arterial Hypertension
Rash (including vesicular rash)
Rare cases of injection site abscess or cellulitis requiring surgical intervention

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

See FDA-approved patient labeling (Medication Guide and Patient’s Instructions for Use).

Instruct patients to carefully read the supplied AVONEX Medication Guide and caution patients not to change the AVONEX dose or schedule of administration without medical consultation.

Inform patients that the tip cap of the AVONEX Prefilled Syringe and AVONEX PEN contains natural rubber latex which may cause allergic reactions.

Instruction on Self-injection Technique and Procedures

Provide appropriate instruction for methods of self-injection of AVONEX, including careful review of the AVONEX Medication Guide. Instruct patients in the use of aseptic technique when administering AVONEX.

Inform patients that an appropriately qualified healthcare professional should show them or their caregiver how to prepare and inject AVONEX before administering the first dose. An appropriately qualified healthcare professional should watch the first AVONEX injection given.

Tell patients not to re-use needles or syringes and instruct patients on safe disposal procedures. Inform patients to dispose of used needles and syringes in a puncture-resistant container and instruct the patient regarding safe disposal of full containers.

Advise patients:

· of the importance of rotating areas of injection with each dose to minimize the likelihood of injection site reactions. [see Warnings and Precautions (5.4) and Choose an Injection Site section of the Medication Guide].

· NOT to inject area of the body where the skin is irritated, reddened, bruised, infected or scarred in any way

· to check the injection site after 2 hours for redness, swelling, or tenderness

· contact their healthcare provider if they have a skin reaction and it does not clear up in a few days

Pregnancy

Advise patients to notify their healthcare provider if they become pregnant during treatment or plan to become pregnant [see Use in Specific Populations (8.1)].

…

Congestive Heart Failure

(Additions and/or revisions underlined)

Advise patients that worsening of pre-existing congestive heart failure has been reported in patients using AVONEX. Advise patients of symptoms of worsening cardiac condition, and instruct patients to report them immediately to their physician [see Warnings and Precautions (5.5)].

Pulmonary Arterial Hypertension

Inform patients that PAH has occurred in patients treated with interferon beta products, including AVONEX. 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)].

11/03/2021 (SUPPL-5266)

Approved Drug Label (PDF)

5 Warnings and Precautions

Newly added subsection:

5.4 Injection Site Reactions Including Necrosis

Injection site reactions, including injection site necrosis, can occur with the use of interferon beta products, including AVONEX. In controlled clinical trials, injection site reactions (e.g., injection site pain, bruising or erythema) occurred in 18% of patients receiving AVONEX and 13% in the placebo group. These reactions included injection site inflammation (6%), injection site pain (8%), injection site mass (<1%), nonspecific reactions.

Injection site abscesses and cellulitis and injection site necrosis have been reported in the postmarketing setting with interferon beta products, including AVONEX. 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. Whether to discontinue

therapy following a single site of necrosis is dependent on the extent of necrosis. For patients who continue therapy with AVONEX after injection site necrosis has occurred, avoid administration of AVONEX into the affected area until it is fully healed. If multiple lesions occur, change injection site or discontinue therapy until healing occurs.

6 Adverse Reactions

Newly added to the bulleted line listing:

Injection Site Reactions Including Necrosis [see Warnings and Precautions (5.4)]

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

MEDICATION GUIDE

What are the possible side effects of AVONEX? AVONEX can cause serious side effects including:

Newly added information:

Injection site reactions. AVONEX may cause redness, pain, itching, or swelling at the place where your injection was given. 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.

PATIENT COUNSELING INFORMATION

Instruction on Self-injection Technique and Procedures

Additions and/or revisions underlined:

Advise patients:

of the importance of rotating areas of injection with each dose to minimize the likelihood of injection site reactions. [see Warnings and Precautions (5.4) and Choose an Injection Site section of the Medication Guide].

Newly added information:

Injection Site Reactions Including Necrosis

Advise patients that injection site reactions can occur and that the reactions can include injection site necrosis. Instruct patients to report promptly any break in the skin that is associated with blue-black discoloration, swelling, or drainage of fluid from the injection site [see Warnings and Precautions (5.4)].

03/27/2020 (SUPPL-5263)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

(addition underlined)

…

Hemolytic anemia

…

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion)

Risk Summary

Data from a large population-based cohort study, as well as other published studies over several decades, have not identified a drug-associated risk of major birth defects with the use of interferon beta products during early pregnancy. Findings regarding a potential risk for low birth weight or miscarriage with the use of interferon beta products in pregnancy have been inconsistent (see Data). In a study in pregnant monkeys, administration of interferon beta during pregnancy resulted in an increased rate of abortion at doses greater than those used clinically (see Data).

In the U.S. 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. The background risk of major birth defects and miscarriage for the indicated population is unknown.

Data

Human Data

The majority of observational studies reporting on pregnancies exposed to interferon beta products did not identify an association between the use of interferon beta products during early pregnancy and an increased risk of major birth defects.

In a population-based cohort study conducted in Finland and Sweden, data were collected from 1996--2014 in Finland and 2005--2014 in Sweden on 2,831 pregnancy outcomes from women with MS. 797 pregnancies were in women exposed to interferon beta only. No evidence was found of an increased risk of major birth defects among women with MS exposed to interferon beta products compared to women with MS that were unexposed to any non-steroid therapy for MS (n=1,647) within the study. No increased risks were observed for miscarriages and ectopic pregnancies, though there were limitations in obtaining complete data capture for these outcomes, making the interpretation of the findings more difficult.

Two small cohort studies that examined pregnancies exposed to interferon beta products (without differentiating between subtypes of interferon beta products) suggested that a decrease in mean birth weight may be associated with interferon beta exposure during pregnancy, but this finding was not confirmed in larger observational studies. Two small studies observed an increased prevalence of miscarriage, although the finding was only statistically significant in one study. Most studies enrolled patients later in pregnancy which made it difficult to ascertain the true percentage of miscarriages. In one small cohort study a significantly increased risk of preterm birth following interferon beta exposure during pregnancy was observed.

Animal Data

In pregnant monkeys given interferon beta at 100 times the recommended weekly human dose (based upon a body surface area [mg/m2] comparison), no adverse effects on embryofetal development were observed. Abortifacient activity was evident following 3 to 5 doses at this level. No abortifacient effects were observed in monkeys treated at 2 times the recommended weekly human dose (based upon mg/m2).

8.2 Lactation

(PLLR conversion)

Risk Summary

Limited published literature has described the presence of interferon beta-1a products in human milk at low levels. There are no data on the effects of interferon beta-1a on milk production.

Therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for AVONEX and any potential adverse effects on the breastfed infant from AVONEX or from the underlying maternal condition.

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

MEDICATION GUIDE

(additions and revisions, please refer to label for complete information)

PATIENT COUNSELING INFORMATION

(additions underlined)

…

Pregnancy

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

…

07/12/2019 (SUPPL-5264)

Approved Drug Label (PDF)

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

MEDICATION GUIDE

What is AVONEX?

Additions and/or revisions underlined:

AVONEX is a prescription medicine used to treat relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.