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.

TIVDAK (BLA-761208)

(TISOTUMAB VEDOTIN-TFTV)

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

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11/12/2025 (SUPPL-10)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

Safety and effectiveness of TIVDAK in pediatric patients have not been established.

Nonclinical studies of tisotumab vedotin-tftv suggest a lack of anti-tumor activity and penetrance to brain based on limited in vivo data from tissue factor (TF)-expressing subcutaneous or orthotopic pediatric models of high- grade gliomas/glioblastomas (HGG/GBM) and diffuse intrinsic pontine glioma (DIPG).

04/29/2024 (SUPPL-7)

Approved Drug Label (PDF)

Boxed Warning

Additions and/or revisions underlined:

Conduct an ophthalmic exam, including an assessment of ocular symptoms, visual acuity, and slit lamp exam of the anterior segment of the eye prior to initiation of TIVDAK, prior to every cycle for the first nine cycles, and as clinically indicated. [see Dosage and Administration (2.2) and Warnings and Precautions (5.1)].

5 Warnings and Precautions

5.1 Ocular Adverse Reactions

Extensive changes; please refer to label for complete information

5.2 Peripheral Neuropathy

Additions and/or revisions underlined:

Peripheral neuropathy occurred in 39% of patients with cervical cancer treated with TIVDAK across clinical trials; 6% of patients experienced Grade 3 peripheral neuropathy. Peripheral neuropathy adverse reactions included peripheral sensory neuropathy (23%), peripheral neuropathy (5%), paresthesia (3.8%), peripheral sensorimotor neuropathy (3.3%), muscular weakness (2.8%), and peripheral motor neuropathy (2.4%). One patient with another tumor type treated with TIVDAK at the recommended dose developed Guillain-Barre syndrome.

The median time to onset of peripheral neuropathy was 2.4 months (range, 0-11.3). Of the patients who

experienced peripheral neuropathy, 18% had complete resolution and 21% had partial improvement (defined as a decrease in severity by one or more grades from the worst grade) at last follow up. Peripheral neuropathy led to discontinuation of TIVDAK in 7% of patients with cervical cancer.

…

5.3 Hemorrhage

Additions and/or revisions underlined:

Hemorrhage occurred in 51% of patients with cervical cancer treated with TIVDAK across clinical trials. The most common all grade hemorrhage adverse reaction was epistaxis (33%). Grade 3 hemorrhage occurred in 4% of patients.

The median time to onset of hemorrhage was 0.3 months (range, 0-10.4). Of the patients who experienced hemorrhage, 71% had complete resolution and 12% had partial resolution (defined as a decrease in severity by one or more grades from the worst grade) at last follow-up.

…

5.4 Pneumonitis

Additions and/or revisions underlined:

Severe, life-threatening, or fatal pneumonitis can occur in patients treated with antibody drug conjugates containing vedotin including TIVDAK. Among patients with cervical cancer treated with TIVDAK across clinical trials, 4 patients (0.9%) experienced pneumonitis, including 1 patient who had a fatal outcome.

…

5.5 Severe Cutaneous Adverse Reactions

Additions and/or revisions underlined:

Severe cutaneous adverse reactions, including events of fatal or life-threatening SJS, can occur in patients treated with TIVDAK. Severe cutaneous adverse reactions occurred in 1.6% of patients with cervical cancer treated with TIVDAK across clinical trials. Grade greater than or equal to 3 severe cutaneous adverse reactions occurred in 0.5% of patients, including 1 patient who had a fatal outcome.

…

6 Adverse Reactions

6.1 Clinical Trials Experience

Extensive changes; please refer to label for complete information

8 Use in Specific Populations

8.3 Females and Males of Reproductive Potential

Additions and/or revisions underlined:

Infertility

Females

Based on findings in animal studies with MMAE-containing antibody-drug conjugates (ADCs), TIVDAK may impair female fertility. The effect on fertility is reversible [see Nonclinical Toxicology (13.1)].

8.5 Geriatric Use

Additions and/or revisions underlined:

Of the 425 patients with cervical cancer treated with TIVDAK across clinical trials, 14% were greater than or equal to 65 years of age and 2.4% were greater than or equal to 75 years of age. Grade greater than or equal to 3 adverse reactions occurred in 60% of patients greater than or equal to 65 years and in 55% of patients <65 years. Drug was discontinued due to an adverse reaction in 25% of patients greater than or equal to 65 years and in 13% of patients <65 years. Clinical studies of TIVDAK did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger patients.

8.6 Hepatic Impairment

Additions and/or revisions underlined:

Avoid use of TIVDAK in patients with moderate or severe hepatic impairment [aspartate aminotransferase (AST) > 3 x upper limit of normal (ULN) or total bilirubin > 1.5 × ULN] [see Clinical Pharmacology (12.3)].

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Ocular Adverse Reactions

Inform patients about the eye exam they will receive with an eye care provider before starting TIVDAK, before each of the first nine cycles and as clinically indicated [see Warnings and Precautions (5.1)].

Inform patients about the ocular signs or symptoms the eye care provider will review before each cycle [see Warnings and Precautions (5.1)].

MEDICATION GUIDE

Additions and/or revisions underlined:

What is the most important information I should know about TIVDAK?

TIVDAK can cause serious side effects, including:

Eye problems. Eye problems are common with TIVDAK, and can also be severe. TIVDAK can cause changes to the surface of your eye that can lead to dry eyes, eye redness, eye irritation, corneal ulcers, blurred vision, and severe vision loss. Tell your healthcare provider if you develop new or worsening vision changes or eye problems during treatment with TIVDAK.

Your healthcare provider will send you to an eye specialist to check your eyes before you start treatment with TIVDAK, before each infusion for your first 9 infusions of TIVDAK, and as needed for any new or worsening signs or symptoms of eye problems.
Your healthcare provider will ask if you have any signs or symptoms of eye problems before each infusion. You will be referred to an eye specialist for any new or worsening signs or symptoms of eye problems.
Your healthcare provider will prescribe 3 different types of eye drops before you start treatment with TIVDAK. Bring the eye drops with you to each infusion and use them as directed by your healthcare provider to reduce your risk of eye problems:

Use 1 drop of steroid eye drops in each eye before each infusion and continue to use your eye drops 3 times a day for 3 days after each infusion.
Use vasoconstrictor eye drops right before each infusion.

Use lubricating eye drops throughout treatment and for 30 days after your last dose of TIVDAK.

…

The most common side effects of TIVDAK include:

• decreased red blood cell counts

• numbness or tingling in your hands or feet

• eye problems (conjunctival disorders)

• nausea

• tiredness

• changes in liver function blood tests

• nosebleed

• hair loss (alopecia)

• bleeding (hemorrhage)

TIVDAK may cause fertility problems in females and males, which may affect your ability to have children. Talk to your healthcare provider if this is a concern for you.

These are not all of the possible side effects of TIVDAK.

07/26/2023 (SUPPL-5)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 Severe Cutaneous Adverse Reactions

(Newly added subsection)

Severe cutaneous adverse reactions, including events of fatal or life-threatening SJS, can occur in patients treated with TIVDAK.

Monitor patients for signs or symptoms of severe cutaneous adverse reactions, which include target lesions, worsening skin reactions, blistering or peeling of the skin, painful sores in mouth, nose, throat, or genital area, fever or flu-like symptoms, and swollen lymph nodes. If signs or symptoms of severe cutaneous adverse reactions occur, withhold TIVDAK until the etiology of the reaction has been determined. Early consultation with a specialist is recommended to ensure greater diagnostic accuracy and appropriate management.

Permanently discontinue TIVDAK for confirmed Grade 3 or 4 severe cutaneous adverse reactions, including SJS [see Dosage and Administration (2.3)].

6 Adverse Reactions

(Additions and/or revisions underlined)

The following serious adverse reactions are described elsewhere in the labeling:

· Ocular Adverse Reactions [see Boxed Warning, Warnings and Precautions (5.1)]

· Peripheral Neuropathy [see Warnings and Precautions (5.2)]

· Hemorrhage [see Warnings and Precautions (5.3)]

· Pneumonitis [see Warnings and Precautions (5.4)]

· Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.5)]

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

17 PATIENT COUNSELING INFORMATION

Pneumonitis

· Advise patients to immediately report new or worsening respiratory symptoms [see Warnings and Precautions (5.4)].

(Additions and/or revisions underlined)

Severe Cutaneous Adverse Reactions

· Inform patients of the signs and symptoms of severe cutaneous adverse reactions, including life- threatening and potentially fatal SJS, which include target lesions, worsening skin reactions, blistering or peeling of the skin, painful sores in mouth, nose, throat, or genital area, fever or flu-like symptoms, and swollen lymph nodes. [see Warnings and Precautions (5.5)].

· Instruct patients to contact their healthcare provider to seek immediate medical attention for signs or symptoms of severe cutaneous adverse reactions, including SJS [see Warnings and Precautions (5.5)].