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.

RENFLEXIS (BLA-761054)

(INFLIXIMAB-ABDA)

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

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12/26/2023 (SUPPL-21)

Approved Drug Label (PDF)

4 Contraindications

Additions and revisions underlined:

The use of RENFLEXIS at doses >5 mg/kg is contraindicated in patients with moderate or severe heart failure [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)].

RENFLEXIS is contraindicated in patients with a previous severe hypersensitivity reaction to infliximab products or any of the inactive ingredients of RENFLEXIS or any murine proteins [severe hypersensitivity reactions have included anaphylaxis, hypotension, and serum sickness] [see Warnings and Precautions (5.7) and Adverse Reactions (6.1)].

5 Warnings and Precautions

5.13 Vaccinations and Use of Live Vaccines/Therapeutic Infectious Agents

Newly added information:

Vaccinations

Prior to initiating RENFLEXIS in pediatric and adult patients, update vaccinations in accordance with current vaccination guidelines.

5.5 Heart Failure

Additions and revisions underlined:

The use of RENFLEXIS at doses >5 mg/kg is contraindicated in patients with moderate or severe heart failure. A randomized, double-blind, placebo-controlled study evaluated the use of infliximab (5 mg/kg or 10 mg/kg at Weeks 0, 2, and 6) in patients with moderate or severe heart failure [New York Heart Association (NYHA) Functional Class III/IV]. Compared to patients who received placebo, there was a higher rate of mortality and a higher risk of hospitalization at Week 28 due to heart failure in patients who received the 10 mg/kg infliximab dose, and higher rates of cardiovascular adverse events in patients who received infliximab doses of 5 mg/kg and 10 mg/kg.

There have been post-marketing reports of new onset and worsening heart failure, with and without identifiable precipitating factors (e.g., pre-existing cardiovascular disease), in patients treated with infliximab products. Some of these patients have been under 50 years of age.

If a decision is made to administer RENFLEXIS (< or =5 mg/kg) to patients with moderate or severe heart failure or to administer RENFLEXIS (any approved dose) to patients with mild heart failure, they should be closely monitored during therapy, and RENFLEXIS should be discontinued if new or worsening symptoms of heart failure appear [see Contraindications (4) and Adverse Reactions (6.1)].

6 Adverse Reactions

6.1 Clinical Trials Experience

Extensive changes; please refer to label

6.2 Immunogenicity

Extensive changes; please refer to label

6.3 Postmarketing Experience

Extensive changes; please refer to label

7 Drug Interactions

7.1 Other Biological Products

Newly added subsection:

The combination of RENFLEXIS with other biological products used to treat the same conditions as RENFLEXIS is not recommended [see Warnings and Precautions (5.10)].

8 Use in Specific Populations

8.1 Pregnancy

Extensive changes; please refer to label

8.5 Geriatric Use

Extensive changes; please refer to label

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

Medication Guide

Additions and revisions underlined:

It is not known if RENFLEXIS is safe and effective in children under 6 years of age.

What should I tell my doctor before starting treatment with RENFLEXIS?

Your doctor will assess your health before each treatment.

Tell your doctor about all of your medical conditions, including if you:

have an infection (see “What is the most important information I should know about RENFLEXIS?”).
have other liver problems including liver failure.
have heart failure or other heart conditions. If you have heart failure, it may get worse while you receive RENFLEXIS.
have or have had any type of cancer.
have had phototherapy (treatment with ultraviolet light or sunlight along with a medicine to make your skin sensitive to light) for psoriasis. You may have a higher chance of getting skin cancer while receiving RENFLEXIS.
have COPD, a specific type of lung disease. Patients with COPD may have an increased risk of getting cancer while receiving RENFLEXIS.
have or have had a condition that affects your nervous system such as:
- multiple sclerosis, or Guillain-Barré syndrome, or
- if you experience any numbness or tingling, or
- if you have had a seizure.
have recently received or are scheduled to receive a vaccine. Adults and children receiving RENFLEXIS should not receive live vaccines (for example, the Bacille Calmette-Guérin [BCG] vaccine) or treatment with a weakened bacteria (such as BCG for bladder cancer). Adults and children should have all of their vaccines brought up to date before starting treatment with RENFLEXIS.
are pregnant or plan to become pregnant, are breastfeeding or plan to breastfeed. You and your doctor should decide if you should receive RENFLEXIS while you are pregnant or breastfeeding.
What are the possible side effects of RENFLEXIS?
RENFLEXIS can cause serious side effects, including:
See “What is the most important information I should know about RENFLEXIS?”. Serious Infections

Some patients, especially those 65 years and older have had serious infections while receiving infliximab products, such as RENFLEXIS. These serious infections include TB and infections caused by viruses, fungi, or bacteria that have spread throughout the body or cause infections in certain areas (such as skin).

PATIENT COUNSELING INFORMATION

Extensive changes; please refer to label

06/26/2019 (SUPPL-9)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(extensive additions, please refer to label)

8 Use in Specific Populations

8.4 Pediatric Use

(additions underlined)

The safety and effectiveness of infliximab products have been established in pediatric patients 6 to 17 years of age for induction and maintenance treatment of Crohn’s disease or ulcerative colitis. However, infliximab products have not been studied in children with Crohn’s disease or ulcerative colitis <6 years of age.

…

Pediatric Ulcerative Colitis

The safety and effectiveness of infliximab products for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients aged 6 years and older with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy are supported by evidence from adequate and well-controlled studies of infliximab in adults. Additional safety and pharmacokinetic data were collected in 60 pediatric patients aged 6 years and older. The effectiveness of infliximabin inducing and maintaining mucosal healing could not be established. Although 41 patients had a Mayo endoscopy subscore of 0 or 1 at the Week 8 endoscopy, the induction phase was open-label and lacked a control group. Only 9 patients had an optional endoscopy at Week 54.

In the pediatric UC trial, approximately half of the patients were on concomitant immunomodulators (AZA, 6-MP, MTX) at study start. Due to the risk of HSTCL, a careful risk-benefit assessment should be made when RENFLEXIS is used in combination with other immunosuppressants.

The longer term (greater than 1 year) safety and effectiveness of infliximab products in pediatric ulcerative colitis patients have not been established in clinical trials.

…

03/21/2019 (SUPPL-4)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Serious Infections

Addition of the following to the Opportunistic infections listing:

Cryptococcosis, salmonellosis

5.2 Malignancies

Addition of the following:

Cervical Cancer

A population-based retrospective cohort study using data from Swedish national health registries found a 2 to 3-fold increase in the incidence of invasive cervical cancer in women with rheumatoid arthritis treated with infliximab compared to biologics-naïve patients or the general population, particularly those over 60 years of age. A causal relationship between infliximab products and cervical cancer cannot be excluded. Periodic screening should continue in women treated with RENFLEXIS.

5.7 Hypersensitivity

Addition of the following to Most hypersensitivity reactions sentence:

Anaphylaxis

Newly added subsection:

5.8 Cardiovascular and Cerebrovascular Reactions During and After Infusion

Serious cerebrovascular accidents, myocardial ischemia/infarction (some fatal), hypotension, hypertension, and arrhythmias have been reported during and within 24 hours of initiation of infliximab infusion. Cases of transient visual loss have been reported during or within 2 hours of infusion of infliximab. Monitor patients during infusion and if serious reaction occurs, discontinue infusion. Further management of reactions should be dictated by signs and symptoms.

6 Adverse Reactions

6.2 Post-Marketing Experience

Additions and/or revisions underlined:

… The following adverse reactions, some with fatal outcome, have been reported during post- approval use of infliximab products: neutropenia, agranulocytosis (including infants exposed in utero to infliximab products), interstitial lung disease … serious infections [see Warnings and Precautions (5.1)], malignancies, including leukemia, melanoma , Merkel cell carcinoma, and cervical cancer.

Infusion-related Reactions

In post-marketing experience, cases of anaphylactic reactions, including anaphylactic shock, laryngeal/pharyngeal edema …

… Cases of transient visual loss have been reported in association with infliximab products during or within 2 hours of infusion. Cerebrovascular accidents, myocardial ischemia/infarction (some fatal), and arrhythmia occurring within 24 hours of initiation of infusion have also been reported.

8 Use in Specific Populations

8.1 Pregnancy

Clinical Considerations

Fetal/Neonatal adverse reactions

Addition of the following sentence to the end of this section:

Cases of agranulocytosis in infants exposed in utero have also been reported.

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

MEDICATION GUIDE

Newly added information following Heart Failure:

Other Heart Problems

Some patients have experienced a heart attack (some of which led to death), low blood flow to the heart, or abnormal heart rhythm within 24 hours of beginning their infusion of an infliximab product. Symptoms may include chest discomfort or pain, arm pain, stomach pain, shortness of breath, anxiety, lightheadedness, dizziness, fainting, sweating, nausea, vomiting, fluttering or pounding in your chest, and/or a fast or a slow heartbeat. Tell your doctor right away if you have any of these symptoms.