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.

ZYNYZ (BLA-761334)

(RETIFANLIMAB-DLWR)

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

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05/18/2026 (SUPPL-9)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Severe and Fatal Immune-Mediated Adverse Reactions

Additions and/or revisions underlined:

…

Other: Myocarditis-Myositis-Myasthenia Gravis (or Myasthenia-Like) Overlap Syndrome, reported as the co-occurrence of either two or all three adverse reactions.

03/30/2026 (SUPPL-8)

Approved Drug Label (PDF)

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

MEDICATION GUIDE

Additions and/or revisions underlined:

…

How will I receive ZYNYZ?

Your healthcare provider will give you ZYNYZ into your vein through an intravenous (IV) line over 30 minutes.

ZYNYZ is usually given every 3 weeks or every 4 weeks depending on the dose you are receiving.

…

12/17/2025 (SUPPL-5)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1Severe and Fatal Immune-Mediated Adverse Reactions

Extensive changes; please refer to label for complete information

5.2 Infusion-Related Reactions

Additions and/or revisions underlined:

A severe infusion-related reaction (Grade 3) occurred in 5 (0.8%) of 606 patients receiving ZYNYZ [see Adverse Reactions (6.1)]. Monitor patients for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion or permanently discontinue ZYNYZ based on severity of reaction [see Dosage and Administration (2.2)].

…

6 Adverse Reactions

6.1 Clinical Trials Experience

Extensive changes to Table 7 and Table 8; please refer to label for complete information

Additions and/or revisions underlined:

…

The safety population described in Warnings and Precautions reflects exposure to ZYNYZ

500 mg as an intravenous infusion every 4 weeks in combination with carboplatin and paclitaxel in 154 patients with SCAC enrolled in the POD1UM-303 trial, and as a single agent in

94 patients with SCAC in the POD1UM-202 trial, 107 patients with MCC in the POD1UM-201 trial, and 251 patients with other solid tumors. All patients received ZYNYZ until disease progression or unacceptable toxicity; those in the POD1UM-202 and POD1UM-201 trials received ZYNYZ for up to 24 months and those in the POD1UM-303 trial received ZYNYZ for up to 12 months. The median duration of exposure of the pooled monotherapy population was 5.4 months (range: 1 day to 27 months).

…

Merkel Cell Carcinoma (MCC)

Metastatic or Recurrent Locally Advanced MCC: ZYNYZ as a Single Agent

The safety of ZYNYZ was evaluated in 107 patients enrolled in the POD1UM-201 trial with metastatic or recurrent locally advanced MCC [see Clinical Studies (14.2)]. Patients received ZYNYZ 500 mg intravenously every 4 weeks until disease progression, unacceptable toxicity, or up to 24 months. The median duration of exposure was 10.3 months (range: 1 day to 25 months).

Serious adverse reactions occurred in 26% of patients receiving ZYNYZ. The most frequent serious adverse reactions (greater than or equal to 2% of patients) were fatigue, arrhythmia, and pneumonitis.

Permanent discontinuation of ZYNYZ due to an adverse reaction occurred in 21% of patients. These included asthenia, colitis, demyelinating polyneuropathy, diarrhea, drug hypersensitivity, eosinophilic fasciitis, hepatitis, hypophysitis, increased transaminases, infusion-related reaction, pancreatitis, polyarthritis, radiculopathy, toxic epidermal necrolysis, and tubulointerstitial nephritis (1 patient each).

Dosage interruptions due to an adverse reaction occurred in 39% of patients who received ZYNYZ. Adverse reactions or laboratory abnormalities that required dosage interruption in > 2% of patients who received ZYNYZ were increased transaminases, increased lipase, increased amylase, and pyrexia.

The most common (greater than or equal to 10%) adverse reactions that occurred in patients receiving ZYNYZ were musculoskeletal pain, fatigue, pruritus, diarrhea, rash, pyrexia, nausea, and constipation.

8 Use in Specific Populations

8.5 Geriatric Use

Additions and/or revisions underlined:

As a Single Agent

Of the 94 patients with locally recurrent or with metastatic SCAC treated with ZYNYZ in POD1UM-202, 49% were 65 years or older, and 11% were 75 years or older [see Clinical Studies (14.1)].

Of the 101 patients with metastatic or recurrent locally advanced MCC treated with ZYNYZ in POD1UM-201, 76% were 65 years or older, and 39% were 75 years or older [see Clinical Studies (14.2)].

…

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

MEDICATION GUIDE

Additions and/or revisions underlined:

…

What are the possible side effects of ZYNYZ?

…

The most common side effects of ZYNYZ when used alone in people with MCC include:

constipation

…

05/15/2025 (SUPPL-4)

Approved Drug Label (PDF)

5 Warnings and Precautions

Additions and/or revisions underlined:

5.1 Severe and Fatal Immune-Mediated Adverse Reactions

Immune-Mediated Colitis

. . .

ZYNYZ as a Single Agent: Immune-mediated colitis occurred in 1.6% (7/440) of patients receiving ZYNYZ, including Grade 4 (0.2%), Grade 3 (0.2%), and Grade 2 (0.7%). Colitis led to permanent discontinuation of ZYNYZ in 1 patient and withholding of ZYNYZ in 0.9% of patients. Systemic corticosteroids were required in 71% (5/7) of patients. Colitis resolved in 4 of the 7 patients. Of the 4 patients in whom ZYNYZ was withheld for colitis, 1 reinitiated ZYNYZ after symptom improvement; this patient did not have recurrence of colitis.

ZYNYZ in Combination with Carboplatin and Paclitaxel: Immune-mediated colitis occurred in 10% (16/154) of patients receiving ZYNYZ in combination with carboplatin and paclitaxel, including Grade 4 (0.6%), Grade 3 (2.6%), and Grade 2 (3.2%). Colitis led to permanent discontinuation of ZYNYZ in 2 patients and withholding of ZYNYZ in 2 patients. Systemic corticosteroids were required in 94% (15/16) of patients. Colitis resolved in 15 of the 16 patients. Of the 2 patients in whom ZYNYZ was withheld for colitis, both reinitiated ZYNYZ after symptom improvement; neither patient had a recurrence of colitis.

. . .

Immune-Mediated Endocrinopathies

. . .

ZYNYZ as a Single Agent: Adrenal insufficiency occurred in 0.7% (3/440) of patients receiving ZYNYZ, including Grade 3 (0.5%) and Grade 2 (0.2%). Adrenal insufficiency did not lead to permanent discontinuation of ZYNYZ. ZYNYZ was withheld for 1 patient with adrenal insufficiency. All patients required systemic corticosteroids. Adrenal insufficiency resolved in 1 of the 3 patients.

ZYNYZ in Combination with Carboplatin and Paclitaxel: Adrenal insufficiency occurred in 5.8% (9/154) of patients receiving ZYNYZ in combination with carboplatin and paclitaxel, including Grade 3 and Grade 2 (1.9% each). Adrenal insufficiency led to permanent discontinuation of ZYNYZ in 1 patient and withholding of ZYNYZ in 3 patients. All patients required systemic corticosteroids. Adrenal insufficiency resolved in 4 of the 9 patients.

HypophysitisZYNYZ can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field cuts. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as clinically indicated.

Withhold or permanently discontinue ZYNYZ depending on severity [see Dosage and Administration (2.2)].

. . .

8 Use in Specific Populations

8.1 Geriatric Use

Additions and/or revisions underlined:

In Combination with Carboplatin and Paclitaxel

Of the 154 patients with inoperable locally recurrent or metastatic SCAC treated with ZYNYZ in combination with carboplatin and paclitaxel in POD1UM-303, 38% were 65 years or older, and

9% were 75 years or older [see Clinical Studies (Section 14.1)]. No overall differences in safety or effectiveness were observed between these patients and younger patients.

As a Single Agent

Of the 94 patients with locally recurrent or with metastatic SCAC treated with ZYNYZ in POD1UM-202, 49% were 65 years or older, and 11% were 75 years or older [see Clinical Studies (14.1)].

Of the 65 patients with metastatic or recurrent locally advanced MCC treated with ZYNYZ in POD1UM-201, 79% were 65 years or older, and 37% were 75 years or older [see Clinical Studies (14.2)].

Clinical studies of ZYNYZ as a single agent did not include sufficient numbers of younger adult patients to determine if patients 65 years of age and older respond differently than younger adult patients.

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

. . .

Other immune-mediated adverse reactions:

Advise patients that immune-mediated adverse reactions can occur and may involve any organ system, and to contact their healthcare provider immediately for any new or worsening signs or symptoms [see Warnings and Precautions (5.1)].
Advise patients of the risk of solid organ transplant rejection and other transplant (including corneal graft) rejection [see Warnings and Precautions (5.1)].

. . .

MEDICATION GUIDE

Additions and/or revisions underlined:

. . .

Rejection of a transplanted organ or tissue. Your healthcare provider should tell you what signs and symptoms you should report and monitor you, depending on the type of organ or tissue transplant that you have had.

. . .

What is ZYNYZ?

ZYNYZ is a prescription medicine used to treat adults with:

a type of anal cancer called squamous cell carcinoma of the anal canal (SCAC).
- ZYNYZ may be used in combination with the chemotherapy medicines carboplatin and paclitaxel, as your first treatment, when your anal cancer:
  - has returned and cannot be removed by surgery, or
  - has spread.
- ZYNYZ may be used alone when your anal cancer:
  - has returned or has spread, and
  - you have received chemotherapy that contains platinum, and it did not work, is no longer working, or you could not tolerate it.
a type of skin cancer called Merkel cell carcinoma (MCC). ZYNYZ may be used alone to treat your skin cancer when it has spread or returned.

. . .

Before you receive ZYNYZ, tell your healthcare provider about all of your medical conditions, including if you:

have immune system problems such as Crohn’s disease, ulcerative colitis, or lupus
have received an organ or tissue transplant, including corneal transplant

. . .

The most common side effects of ZYNYZ when given with the chemotherapy medicines carboplatin and paclitaxel in people with SCAC include:

tiredness
constipation
numbness, pain, tingling or burning in your hands
bleeding or feet
rash
nausea
vomiting
hair loss
decreased appetite
diarrhea
itching
muscle and bone pain
stomach-area pain

The most common side effects of ZYNYZ when used alone in people with SCAC include:

tiredness
stomach-area pain
muscle and bone pain
shortness of breath
diarrhea
fever
infection
vomiting
rectal or genital-area pain
cough
bleeding
itching
urinary tract infection (UTI)
low levels of thyroid hormone
rash
headache
nausea
decreased weight
loss of appetite
constipation

The most common side effects of ZYNYZ when used alone in people with MCC include:

. . .

04/22/2024 (SUPPL-2)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Severe and Fatal Immune-Mediated Adverse Reactions

Additions and/or revisions underlined:

…

Other (Hematologic/Immune): hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection, other transplant (including corneal graft) rejection.