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.

NULOJIX (BLA-125288)

(BELATACEPT)

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

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07/28/2021 (SUPPL-101)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.10 Risk of Rejection with Conversion From a CNI Based Maintenance Regimen

New subsection added

Conversion of patients receiving a CNI based maintenance regimen to a NULOJIX based maintenance regimen increases the risk of acute rejection. In two randomized controlled studies, kidney transplant recipients at least six months post-transplant and stable on a CNI based regimen who were converted to a belatacept based regimen experienced higher rejection rates mostly during the first year post-conversion than patients maintained on their CNI based regimens. Conversion of stable kidney transplant recipients from a CNI based maintenance therapy to a belatacept based maintenance therapy is not recommended unless the patient is CNI intolerant.

04/13/2018 (SUPPL-75)

Approved Drug Label (PDF)

6 Adverse Reactions

6.3 Long-Term Extension Studies

Newly created subsection:

After completion of the 36-month studies, patients remaining on randomized therapy in Study 1 and Study 2 were eligible for enrollment in the long-term extension studies. No new adverse reactions were observed in the extension studies.

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

Pregnancy Exposure Registry

…

Risk Summary

The data with NULOJIX use in pregnant women are insufficient to inform on drug-associated risk. Belatacept is known to cross the placenta of animals. Administration of belatacept to pregnant rats and rabbits during the period of organogenesis was not teratogenic at exposures approximately 16 and 19 times greater than that observed at the maximum recommended human dose (MRHD) of 10 mg per kg body weight administered over the first month of treatment, based on area under the concentration-time curve (AUC). In a pre- and postnatal development study in rats, treatment-related infections in dams were associated with increased pup mortality, presumably secondary to deteriorating maternal health, at exposures 3 times higher than that observed at MRHD.

The background risk of major birth defects and miscarriage for the indicated population is unknown; however, in the U.S. general population, the estimated background risk of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies.

Data

Animal Data

In embryo-fetal development studies, daily intravenous administration of belatacept to pregnant rats and rabbits throughout the period of organogenesis did not produce adverse fetal effects at doses up to 200 mg per kg and 100 mg per kg, respectively (16 and 19 times the MRHD exposure, based on AUC). In a pre- and postnatal development study, daily intravenous administration of belatacept to rats from Day 6 of gestation through Day 20 of the lactation period was associated with maternal toxicity (infections) in a small percentage of dams at doses …

In pups that survived, there were no abnormalities or malformations at doses up to 200 mg per kg (19 times the MRHD exposure, based on AUC).

8.2 Lactation

Newly created subsection:

Risk Summary

There are no data on the presence of NULOJIX in human milk or the effects of NULOJIX on breastfed infants or human milk production to inform risk of NULOJIX to an infant during lactation. Belatacept is excreted in rat milk after intravenous administration, and it is possible that the drug will be present in human milk. However, absorption of intact belatacept from the nursing infant’s gastrointestinal tract has not been studied. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NULOJIX and any potential adverse effects on the breastfed child from NULOJIX or from the underlying maternal conditions.

11/09/2017 (SUPPL-74)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.9 Coadministration with Anti-Thymocyte Globulin

(new subsection added)

In postmarketing experience in de novo kidney transplant recipients, some with other predisposing risk factors for venous thrombosis of the renal allograft, venous thrombosis of the renal allograft has occurred when the initial dose of anti-thymocyte globulin, as immunosuppressive induction, was coadministered (at the same or nearly the same time) with the first dose of belatacept. In such patients, the coadministration (at the same or nearly the same time) of anti-thymocyte globulin and belatacept may pose a risk for venous thrombosis of the renal allograft. If anti-thymocyte globulin (or any other cell-depleting induction treatment) and belatacept will be administered concomitantly, a twelve-hour interval between the two administrations is suggested.

6 Adverse Reactions

6.2 Postmarketing Experience

(additions underlined)

…

Vascular Disorder: Venous Thrombosis of the Renal Allograft

7 Drug Interactions

7.3 Anti-Thymocyte Globulin

(new subsection added)

Coadministration (at the same or nearly the same time) of anti-thymocyte globulin (or any other cell-depleting induction treatment) and belatacept in de novo kidney transplant recipients, especially those with other predisposing risk factors for venous thrombosis of the renal allograft, may pose a risk for venous thrombosis of the renal allograft.

02/02/2017 (SUPPL-70)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Studies Experience

Infusion Reactions

Additions and/or revisions underlined:

There have been no reports of anaphylaxis or drug hypersensitivity in patients treated with NULOJIX in Studies 1 and 2 up to three years of follow-up. However, milder infusion-related reactions within one hour of infusion were reported in 5% of patients treated with the recommended dose of NULOJIX, similar to the placebo rate. The most frequent reactions were hypotension and hypertension. A case of anaphylaxis was reported in the postmarketing experience.

New-Onset Diabetes After Transplantation

Other Adverse Reactions

In these sections, all greater than or equal to signs have been replaced with epsilon signs

6.2 Postmarketing Experience

Newly added subsection:

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.

Immune System Disorder: Anaphylaxis

Spontaneous reports during the postmarketing experience included a case of anaphylaxis, which was observed in a kidney transplant patient whose belatacept therapy had been interrupted for two months during treatment of a systemic varicella infection. When belatacept therapy was resumed, within five minutes after the start of the belatacept infusion the patient developed a generalized rash, pruritus, hypotension, atrial fibrillation, respiratory distress and syncope, requiring medical treatment. Another belatacept infusion was attempted one month later, but was terminated when the patient experienced more pronounced symptoms of anaphylaxis and required medical treatment.

8 Use in Specific Populations

8.1 Pregnancy

In this section, all greater than or equal to signs have been replaced with epsilon signs.