Drug Safety-related Labeling Changes (SrLC)
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Guide
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.
ADCETRIS (BLA-125388)
(BRENTUXIMAB VEDOTIN)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
02/11/2025 (SUPPL-108)
06/14/2023 (SUPPL-107)
11/10/2022 (SUPPL-106)
10/15/2019 (SUPPL-100)
11/16/2018 (SUPPL-99)
5 Warnings and Precautions
5.1 Peripheral Neuropathy(subsection revised, additions and revisions underlined)
ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative.
In studies of ADCETRIS as monotherapy, 62% of patients experienced any grade of
neuropathy. The median time to onset of any grade was 3 months (range, 0–12). Of the patients who experienced neuropathy, 62% had complete resolution, 24% had partial improvement, and 14% had no improvement at the time of their last evaluation. The median time from onset to resolution or improvement of any grade was 5 months (range, 0–45). Of the patients who reported neuropathy, 38% had residual neuropathy at the time of their last evaluation [Grade 1 (27%), Grade 2 (9%), Grade 3 (2%)].
In ECHELON-1 (Study 5), 67% of patients treated with ADCETRIS + AVD experienced any grade of neuropathy. The median time to onset of any grade was 2 months (range, 0–7), of Grade 2 was 3 months (range, 0–6) and of Grade 3 was 4 months (range, <1–7). The median time from onset to resolution or improvement of any grade was 2 months (range, 0–32), of Grade 2 was 3 months (range, 0–28), and of Grade 3 was 4 months (range, 0–32). Of these patients, 43% had complete resolution, 24% had partial improvement (a decrease in severity by one or more grades from worst grade), and 33% had no improvement at the time of their last evaluation. Of the patients with residual neuropathy at the time of their last evaluation (57%), patients had Grade 1 (36%), Grade 2 (16%), Grade 3 (4%), or Grade 4 (<1%) neuropathy.In ECHELON-2 (Study 6), 52% of patients treated with ADCETRIS + CHP experienced new or worsening peripheral neuropathy of any grade (by maximum grade, 34% Grade 1, 15% Grade 2, 3% Grade 3, < 1% Grade 4). The peripheral neuropathy was predominantly sensory (94% sensory, 16% motor) and had a median onset time of 2 months (range, <1–5). At last evaluation, 50% had complete resolution of neuropathy, 12% had partial improvement, and 38% had no improvement. The median time to resolution or improvement overall was 4 months (range, 0–45). Of patients with residual neuropathy at their last evaluation, the neuropathy was Grade 1 in 72%, Grade 2 in 25%, and Grade 3 in 3%.
…
(additions underlined)
Fatal
and serious cases of febrile neutropenia have been reported with ADCETRIS.
Prolonged (?1 week) severe neutropenia and Grade 3 or Grade 4 thrombocytopenia
or anemia can occur with ADCETRIS.
Start primary prophylaxis with G-CSF beginning with Cycle 1 for patients who receive ADCETRIS in combination with chemotherapy for previously untreated Stage III or IV cHL or previously untreated PTCL
…
6 Adverse Reactions
6.1 Clinical Trial Experience(extensive additions, please refer to label)
8 Use in Specific Populations
8.5 Geriatric Use(additions underlined)
…
In the clinical trial of ADCETRIS in combination with CHP for patients with previously untreated, CD30-expressing PTCL (Study 6: ECHELON-2), 31% of ADCETRIS + CHP-treated patients were age 65 or older. Among older patients, 74% had adverse reactions equal or greater than Grade 3 and 49% had serious adverse reactions. Among patients younger than age 65, 62% had adverse reactions equal or greater than Grade 3 and 33% had serious adverse reactions. Older age was a risk factor for febrile neutropenia, occurring in 29% of patients who were age 65 or older versus 14% of patients less than age 65.
…
03/20/2018 (SUPPL-97)
5 Warnings and Precautions
5.1 Peripheral Neuropathy(additions underlined)
…
In a study of ADCETRIS as combination therapy (Study 5, ECHELON-1) 67% of patients treated with ADCETRIS + AVD experienced any grade of neuropathy. The median time to onset of any grade was 8 weeks (range, 0–29), of Grade 2 was 14 weeks (range, 0–28) and of Grade 3 was 16 weeks (range, 1–29). The median time from onset to resolution or improvement of any grade was 10 weeks (range, 0–139), of Grade 2 was 12 weeks (range, 0–123), and of Grade 3 was 17 weeks (range, 0–139). Of these patients, 43% had complete resolution, 24% had partial improvement (a decrease in severity by one or more grade from worst grade) and 33% had no improvement at the time of their last evaluation. Of the patients with residual neuropathy at the time of their last evaluation (57%), patients reported Grade 1 (36%), Grade 2 (16%), Grade 3 (4%), or Grade 4 (1 patient) neuropathy. Median time of overall study follow-up was 84.3 weeks (range, 0–194).
Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness. Patients
experiencing new or worsening peripheral neuropathy may require a delay, change in dose, or discontinuation of ADCETRIS.
(additions underlined)
Fatal and serious cases of febrile neutropenia have been
reported with ADCETRIS. Prolonged (?1 week)
severe neutropenia and Grade 3 or Grade 4 thrombocytopenia or anemia can occur with
ADCETRIS.
Start primary prophylaxis with G-CSF beginning with Cycle 1 for previously untreated patients who receive ADCETRIS in combination with chemotherapy for Stage III or IV.
Monitor complete blood counts prior to each dose of ADCETRIS. Monitor more frequently for patients with Grade 3 or 4 neutropenia. Monitor patients for fever. If Grade 3 or 4 neutropenia develops, consider dose delays, reductions, discontinuation, or G-CSF prophylaxis with subsequent ADCETRIS doses.
6 Adverse Reactions
6.1 Clinical Trial Experience(extensive additions and revisions, please refer to label)
8 Use in Specific Populations
8.1 Pregnancy(additions underlined)
Risk Summary
ADCETRIS can cause fetal harm based on the findings from animal studies and the drug’s mechanism of action. In animal reproduction studies, administration of brentuximab vedotin to pregnant rats during organogenesis at doses similar to the clinical dose of 1.8 mg/kg every three weeks caused embryo-fetal toxicities, including congenital malformations (see Data). The available data from case reports on ADCETRIS use in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes. Advise a pregnant woman of the potential risk to a fetus.
…
In the clinical trial of ADCETRIS in combination with chemotherapy for patients with previously untreated Stage III or IV cHL, (Study 5: ECHELON-1), 9% of ADCETRIS + AVD-treated patients were aged 65 or older. Older age was a risk factor for febrile neutropenia, occurring in 39% of patients aged 65 or older vs. 17% of patients less than age 65, who received ADCETRIS + AVD.. The ECHELON-1 trial did not contain sufficient information on patients aged 65 and over to determine whether they respond differently from younger patients.
Other clinical trials of ADCETRIS in cHL (Studies 1 and 3: AETHERA) and sALCL (Study 2) did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.
In the clinical trial of ADCETRIS in pcALCL or CD30-expressing MF (Study 4: ALCANZA), 42% of ADCETRIS-treated patients were aged 65 or older. No meaningful differences in safety or efficacy were observed between these patients and younger patients.
11/09/2017 (SUPPL-94)
5 Warnings and Precautions
5.1 Peripheral Neuropathy(subsection revised, additions underlined)
ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative.
In studies of ADCETRIS as monotherapy, 62% of patients experienced any grade of neuropathy. The median time to onset of any grade was 13 weeks (range, 0–52). Of the patients who experienced neuropathy, 62% had complete resolution, 24% had partial improvement, and 14% had no improvement at the time of their last evaluation. The median time from onset to resolution or improvement of any grade was 21 weeks (range, 0–195). Of the patients who reported neuropathy, 38% had residual neuropathy at the time of their last evaluation [Grade 1 (27%), Grade 2 (9%), Grade 3 (2%)].
Monitor
patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia,
paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness.
Patients experiencing new or worsening peripheral neuropathy may require a
delay, change in dose, or discontinuation of ADCETRIS.
(additions underlined)
Acute pancreatitis, including fatal outcomes,has been reported. Other fatal and serious gastrointestinal (GI) complications include perforation, hemorrhage, erosion, ulcer, intestinal obstruction, enterocolitis, neutropenic colitis, and ileus. Lymphoma with preexisting GI involvement may increase the risk of perforation. In the event of new or worsening GI symptoms, including severe abdominal pain, perform a prompt diagnostic evaluation and treat appropriately.
6 Adverse Reactions
6.1 Clinical Trial Experience(extensive additions and revisions, please refer to label)
(additions underlined)
As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to ADCETRIS in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.
…
8 Use in Specific Populations
8.1 Pregnancy(additions underlined)
Risk Summary
…
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.
(additions underlined)
Clinical trials of ADCETRIS in cHL (Studies 1 and 3: AETHERA) and sALCL (Study 2) did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.
In the clinical trial of ADCETRIS in pcALCL or CD30-expressingMF (Study 4: ALCANZA), 42% of ADCETRIS-treated patients were aged 65 or older. No meaningful differences in safety or efficacy were observed between these patients and younger patients.
(additions underlined)
Avoid the use of ADCETRIS in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment.
Dosage reduction is required in patients with mild (Child-Pugh A) hepatic impairment.