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.

OPDIVO QVANTIG (BLA-761381)

(NIVOLUMAB;HYALURONIDASE-NVHY)

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

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05/12/2026 (SUPPL-12)

Approved Drug Label (PDF)

5 Warnings and Precautions

WARNINGS AND PRECAUTIONS

5.1 Severe and Fatal Immune-Mediated Adverse Reactions

Additions and/or revisions underlined:

. . .

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of less than 1% (unless otherwise noted) in patients who received OPDIVO QVANTIG or intravenous nivolumab as a single agent or in combination with chemotherapy or immunotherapy, or were reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions.

. . .

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

. . .

6 Adverse Reactions

ADVERSE REACTIONS

6.2 Postmarketing Experience

Additions and/or revisions in underlined:

The following adverse reactions have been identified during post-approval use of intravenous nivolumab. 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.

. . .

Metabolism and nutrition disorders: tumor lysis syndrome

. . .

11/24/2025 (SUPPL-5)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of OPDIVO QVANTIG have been established in pediatric patients aged 12 years and older who weigh 30 kg or greater for the following indications:

Unresectable or metastatic melanoma [see Indications and Usage (1.2)]
Unresectable or metastatic melanoma following combination treatment with intravenous nivolumab and ipilimumab [see Indications and Usage (1.2)]
Completely resected Stage IIB, Stage IIC, Stage III, or Stage IV melanoma as adjuvant treatment [see Indications and Usage (1.3)]
Unresectable or metastatic MSI-H or dMMR CRC following combination treatment with intravenous nivolumab and ipilimumab [see Indications and Usage (1.9)]
MSI-H or dMMR mCRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, irinotecan [see Indications and Usage (1.9)]

Use of OPDIVO QVANTIG in pediatric patients for these indications is supported by evidence from adequate and well-controlled studies for intravenous nivolumab in adults and additional pharmacokinetic and safety data for intravenous nivolumab in pediatric patients 12 years and older who weigh 30 kg or greater [see Adverse Reactions (6.1) and Clinical Studies (14)]. Nivolumab exposure in pediatric patients 12 years and older who receive OPDIVO QVANTIG is predicted to be within range of those observed/predicted in adult patients at the recommended dosage [see Adverse Reactions (6.1), Clinical Pharmacology (12.3)].

The safety and effectiveness of OPDIVO QVANTIG have not been established for pediatric patients younger than 12 years old with melanoma or MSI-H or dMMR mCRC.

The safety and effectiveness of OPDIVO QVANTIG have not been established in pediatric patients for other approved adult indications [see Indications and Usage (1)].

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

MEDICATION GUIDE

Additions and/or revisions underlined:

. . .

What is OPDIVO QVANTIG?

OPDIVO QVANTIG is a prescription medicine used to treat:

. . .

adults and children 12 years of age and older who weigh 66 pounds (30 kg) or more with a type of skin cancer called melanoma.
. . .

adults and children 12 years of age and older who weigh 66 pounds (30 kg) or more with a type of colon or rectal cancer (colorectal cancer or CRC).

. . .

It is not known if OPDIVO QVANTIG is safe and effective in children younger than 12 years of age with melanoma or MSI-H or dMMR metastatic colorectal cancer.

It is not known if OPDIVO QVANTIG is safe and effective in children for the treatment of any other cancers that it is used to treat in adults.

. . .

10/27/2025 (SUPPL-1)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Severe and Fatal Immune-Mediated Adverse Reactions

Additions and/or revisions underlined:

…

Intravenous Nivolumab

Hypophysitis occurred in 0.6% (12/1994) of patients treated with single agent intravenous nivolumab, including Grade 3 (0.2%) and Grade 2 (0.3%). Hypophysitis led to permanent discontinuation of intravenous nivolumab in <0.1% and withholding of intravenous nivolumab in 0.2% of patients. Approximately 67% (8/12) of patients with hypophysitis received hormone replacement therapy, including systemic corticosteroids. Hypophysitis resolved in 42% of the 12 patients. Of the 3 patients in whom intravenous nivolumab was withheld for hypophysitis, 2 reinitiated intravenous nivolumab after symptom improvement; of these, none had recurrence of hypophysitis.

…

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

Hepatocellular Carcinoma

Unresectable or Metastatic Hepatocellular Carcinoma (HCC)

CHECKMATE-9DW

The safety of intravenous nivolumab 1 mg/kg in combination with ipilimumab was evaluated in CHECKMATE-9DW, a randomized, open-label trial in adult patients with unresectable or metastatic HCC [see Clinical Studies (14.10)]. Patients received intravenous nivolumab 1 mg/kg in combination with ipilimumab (n=332) or investigator’s choice of lenvatinib (n=275) or sorafenib (n=50) at the following dosage:

Intravenous nivolumab 1 mg/kg administered intravenously over 30 minutes in combination with ipilimumab 3 mg/kg administered intravenously over 30 minutes every 3 weeks, for a maximum of 4 doses, followed by single-agent intravenous nivolumab at 480 mg administered intravenously over 30 minutes every 4 weeks, or
Investigator’s choice:
- Lenvatinib 8 mg orally daily (if body weight <60 kg) or 12 mg orally daily (if body weight
  Greater than or equal to 60 kg), or
- Sorafenib 400 mg orally twice daily
  In the intravenous nivolumab 1 mg/kg and ipilimumab arm, the median duration of exposure to intravenous nivolumab 1 mg/kg was 4.7 months (range: <0.1 to 24.4 months), 45% were exposed for >6 months and 30% were exposed for >1 year.
  Serious adverse reactions occurred in 53% of patients treated with intravenous nivolumab 1 mg/kg in combination with ipilimumab. The most frequent non liver-related serious adverse reactions reported in greater than or equal to 2% of patients who received intravenous nivolumab 1 mg/kg in combination with ipilimumab were diarrhea/colitis (4.5%), gastrointestinal hemorrhage (3%), and rash (2.4%).
  Liver-related serious adverse reactions occurred in 17% of patients treated with intravenous nivolumab 1 mg/kg in combination with ipilimumab, including Grade 3-4 events in 16% of patients. The most frequently reported all grade liver-related serious adverse reactions occurring in greater than or equal to 1% of patients who received intravenous nivolumab 1 mg/kg in combination with ipilimumab were immune-mediated hepatitis (3%), increased AST/ALT (3%), hepatic failure (2.4%), ascites (2.4%), and hepatotoxicity (1.2%).
  Fatal adverse reactions occurred in 12 (3.6%) patients who received intravenous nivolumab 1 mg/kg in combination with ipilimumab; these included 4 (1.2%) patients who died due to immune-mediated or autoimmune hepatitis and 4 (1.2%) patients who died of hepatic failure.
  Permanent discontinuations of intravenous nivolumab 1 mg/kg due to an adverse reaction occurred in 27% of patients. Adverse reactions leading to permanent discontinuation of intravenous nivolumab 1 mg/kg in >1% of patients included immune-mediated hepatitis (1.8%), diarrhea/colitis (1.8%), hepatic failure (1.2%).
  Dosage interruptions of intravenous nivolumab 1 mg/kg due to an adverse reaction occurred in 62% of patients. Adverse reactions which required dosage interruption in >5% of patients included increased AST (13%), increased ALT (11%), and diarrhea/colitis (8%).
  The most common (>20%) adverse reactions were rash, pruritus, fatigue, and diarrhea.
  Tables 37 and 38 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-9DW.
  Please refer to label to view Table 37 and Table 38.
  …

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

MEDICATION GUIDE

Additions and/or revisions underlined:

…

What is the most important information I should know about OPDIVO QVANTIG?

OPDIVO QVANTIG is a medicine that may treat certain cancers by working with your immune system. OPDIVO QVANTIG can cause your immune system to attack normal organs and tissues in any area of your body and can affect the way they work. These problems can sometimes become severe or life-threatening and can lead to death. These problems may happen anytime during treatment or even after your treatment has ended. You may have more than one of these problems at the same time. Some of these problems may happen more often when OPDIVO QVANTIG is used in combination with another therapy.

…

What is OPDIVO QVANTIG?

OPDIVO QVANTIG is a prescription medicine used to treat adults with:

…

a type of liver cancer called hepatocellular carcinoma (HCC).
- OPDIVO QVANTIG may be used alone as your first treatment, after completing combination treatment with intravenous nivolumab and intravenous ipilimumab, when your liver cancer:

cannot be removed with surgery or has spread.

OPDIVO QVANTIG may be used alone, after completing combination treatment with intravenous nivolumab and ipilimumab, when your liver cancer:
- cannot be removed with surgery or has spread, and
- you have received prior treatment with sorafenib.
  …
  Before receiving OPDIVO QVANTIG, 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
have received or plan to receive a stem cell transplant that uses donor stem cells (allogeneic)
have received radiation treatment to your chest area in the past and have received other medicines that are like OPDIVO QVANTIG
…

10/27/2025 (SUPPL-2)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Severe and Fatal Immune-Mediated Adverse Reactions

Additions and/or revisions underlined:

…

Intravenous Nivolumab

…

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

MSI-H or dMMR Metastatic Colorectal Cancer

First-line Treatment of MSI-H or dMMR Metastatic Colorectal Cancer (mCRC)

CHECKMATE-8HW

The safety of intravenous nivolumab in combination with ipilimumab, or as a single agent, was evaluated in CHECKMATE-8HW, a randomized, open-label, three arm trial in immunotherapy naïve patients with MSI-H or dMMR mCRC [see Clinical Studies (14.11)]. Patients received one of the following:

Intravenous nivolumab 240 mg every 3 weeks and ipilimumab 1 mg/kg every 3 weeks for a maximum of 4 doses, then intravenous nivolumab 480 mg every 4 weeks
Intravenous nivolumab 240 mg every 2 weeks for 6 doses, then intravenous nivolumab 480 mg every 4 weeks
Investigator’s choice chemotherapy: mFOLFOX or FOLFIRI [see Clinical Studies (14.11)]
In the intravenous nivolumab and ipilimumab arm, the median duration of exposure to intravenous nivolumab was 20.5 months (range: 0 to 35.9 months), 70% patients were exposed for >6 months and 63% were exposed for >1 year. In the intravenous nivolumab arm, the median duration of exposure to intravenous nivolumab was 16.4 months (range: 0 to 36 months), 64% patients were exposed for >6 months and 54% were exposed for >1 year.
Serious adverse reactions occurred in 46% of patients receiving intravenous nivolumab in combination with ipilimumab, and 39% of patients receiving intravenous nivolumab alone. The most frequent serious adverse reactions reported in greater than or equal to 1% of patients who received intravenous nivolumab with ipilimumab were adrenal insufficiency (2.8%), hypophysitis (2.8%), diarrhea (2.0%), abdominal pain (2.0%), small intestinal obstruction (2.0%), pneumonia (1.7%), acute
kidney injury (1.4%), immune mediated enterocolitis (1.4%), pneumonitis (1.4%), colitis (1.1%), large intestinal obstruction (1.1%), and urinary tract infection (1.1%). The most frequent serious adverse reactions reported in >1% of patients who received intravenous nivolumab, as a single agent, were intestinal obstruction (2.3%), acute kidney injury (1.7%), COVID-19 (1.7%), abdominal pain (1.4%), diarrhea (1.4%), ileus (1.4%), subileus (1.4%), pulmonary embolism
(1.4%), adrenal insufficiency (1.1%) and pneumonia (1.1%).
Fatal adverse reactions occurred in 2 (0.6%) patients who received intravenous nivolumab in combination with ipilimumab; these included myocarditis, and pneumonitis (1 each). Fatal adverse reactions occurring in 3 (0.9%) patients who received intravenous nivolumab as a single agent; these included pneumonitis (n=2) and myasthenia gravis.
Intravenous nivolumab and/or ipilimumab were permanently discontinued in 19% of patients receiving the combination. The most frequent adverse reactions (>1%) leading to permanent discontinuation were adrenal insufficiency (1.4%), immune mediated enterocolitis (1.1%), and pneumonitis (1.1%). Intravenous nivolumab was permanently discontinued in 13% of patients receiving single agent intravenous nivolumab. Adverse reactions leading to the delay of intravenous nivolumab and/or ipilimumab occurred in 48% of patients receiving the combination; single agent intravenous nivolumab was delayed in 37% of patients due to adverse reactions.
The most common adverse reactions reported in greater than or equal to 20% of patients treated with intravenous nivolumab in combination with ipilimumab were fatigue, diarrhea, pruritus, abdominal pain, musculoskeletal pain, and nausea. The most common adverse reactions reported in greater than or equal to 20% of patients treated with intravenous nivolumab as a single agent, were fatigue, diarrhea, abdominal pain, pruritus, and musculoskeletal pain.
Tables 33 and 34 summarize selected adverse reactions and selected laboratory abnormalities for intravenous nivolumab in combination with ipilimumab and the single agent intravenous nivolumab arms respectively, in CHECKMATE-8HW.
Please refer to label to view Table 33 and Table 34.
…

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

MEDICATION GUIDE

Additions and/or revisions underlined:

…

What is the most important information I should know about OPDIVO QVANTIG?

…

What is OPDIVO QVANTIG?

OPDIVO QVANTIG is a prescription medicine used to treat adults with:

…

a type of colon or rectal cancer (colorectal cancer or CRC).
- OPDIVO QVANTIG may be used alone, after completing combination treatment with intravenous nivolumab and ipilimumab, when your colon or rectal cancer:
  - cannot be removed with surgery or has spread, and
  - is microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).
- OPDIVO QVANTIG may be used alone when your colon or rectal cancer:
  - has spread, and
  - is MSI-H or dMMR, and
  - you have received treatment with a fluoropyrimidine, oxaliplatin, and irinotecan, and it did not work or is no longer working.
    …
    Before receiving OPDIVO QVANTIG, 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
have received or plan to receive a stem cell transplant that uses donor stem cells (allogeneic)
have received radiation treatment to your chest area in the past and have received other medicines that are like OPDIVO QVANTIG
…

05/23/2025 (SUPPL-8)

Approved Drug Label (PDF)

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

MEDICATION GUIDE

Additions and/or revisions underlined:

. . .

OPDIVO QVANTIG is a prescription medicine used to treat adults with:

. . .

OPDIVO QVANTIG may be used in combination with chemotherapy that contains fluoropyrimidine and platinum as your first treatment when your esophageal cancer:
- is a type called squamous cell carcinoma, and
- cannot be removed with surgery, or has spread, and
- your tumors are positive for PD-L1.
OPDIVO QVANTIG may be used alone when your esophageal cancer:
- is a type called squamous cell carcinoma, and
- cannot be removed with surgery, and has come back or spread, and
- you have received chemotherapy that contains fluoropyrimidine and platinum.

cancer of the stomach (gastric cancer), cancer where the esophagus joins the stomach (gastroesophageal junction cancer), and a type of cancer in the esophagus called esophageal adenocarcinoma.
- OPDIVO QVANTIG may be used in combination with chemotherapy that contains fluoropyrimidine and platinum when your gastric, gastroesophageal junction, or esophageal cancer:
  - cannot be removed with surgery, or has spread, and
  - your tumors are positive for PD-L1.

. . .