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.

COMETRIQ (NDA-203756)

(CABOZANTINIB S-MALATE)

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

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10/09/2025 (SUPPL-13)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Thromboembolic Events

Section title revision

5.6 Cardiac Failure

Newly added section:

COMETRIQ can cause severe and fatal cardiac failure [see Adverse Reactions (6.1)]. Cardiac failure occurred in 0.9% of patients treated with COMETRIQ as a single agent. Median time to onset of cardiac failure was 76 days (range: 60 days to 92 days).

Consider baseline and periodic evaluations of left ventricular ejection fraction. Monitor for signs and symptoms of cardiovascular events. Withhold and resume at a reduced dose upon recovery or permanently discontinue COMETRIQ depending on the severity [see Dosage and Administration (2.2)].

6 Adverse Reactions

Addition of the following to the bulleted line listing:

Cardiac Failure [see Warnings and Precautions (5.6)]

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

Other clinically relevant adverse reactions (all grades) that were reported in clinical trials include: cardiac failure (<1%) and hepatitis cholestatic (<1%).

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

PATIENT COUNSELING INFORMATION

Newly added information:

…

Cardiac failure: Advise patients that COMETRIQ can cause cardiac failure. Advise patients to immediately contact their healthcare provider for signs and symptoms of cardiac failure [see Warnings and Precautions (5.6)]

…

PATIENT INFORMATION

Additions and/or revisions underlined:

Before you take COMETRIQ, tell your healthcare provider about all of your medical conditions including if you:

have heart problems

…

What are the possible side effects of COMETRIQ?

…

heart problems. COMETRIQ can cause heart failure. Your healthcare provider may check your heart function before and during treatment with COMETRIQ. Tell your healthcare provider right away if you get any of the following signs and symptoms:

feeling like your heart is pounding, racing, or beating irregularly
swelling of your ankles or feet
feeling lightheaded
shortness of breath
tiredness

…

08/23/2023 (SUPPL-11)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 Hypertension and Hypertensive Crisis

Additions and/or revisions underlined:

COMETRIQ can cause hypertension, including hypertensive crisis. Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (modified JNC criteria) stage 1 or 2 hypertension was identified in 61% in COMETRIQ-treated patients compared with 30% of placebo-treated patients in the randomized trial [see Adverse Reactions (6.1)].

Do not initiate COMETRIQ in patients with uncontrolled hypertension. Monitor blood pressure regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy and for hypertensive crisis [see Dosage and Administration (2.2)].

5.12 Hypocalcemia

Newly added subsection

COMETRIQ can cause hypocalcemia. Based on the safety population [see Clinical Trial Experience (6.1)], hypocalcemia occurred in 52% of patients treated with COMETRIQ, including Grade 3 or 4 in 12% of patients.
Monitor blood calcium levels and replace calcium as necessary during treatment. Withhold and resume at a reduced dose upon recovery or discontinue COMETRIQ depending on severity [see Dosage and Administration (2.2)].

6 Adverse Reactions

Addition of the following to the bulleted line listing:

Hypocalcemia [see Warnings and Precautions (5.12)]

6.1 Clinical Trials Experience

Changes to table 2; please refer to label

6.2 Postmarketing Experience

Additions and/or revisions underlined:

The following adverse reactions have been identified during postapproval use of COMETRIQ. 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.
Hematology: A case of supratherapeutic international normalized ratio (INR) and epistaxis during concomitant use of warfarin
Musculoskeletal and Connective Tissue Disorders: Extremity pain
Vascular Disorders: Arterial (including aortic) aneurysms, dissections, and rupture

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Advise patients to read the FDA-approved patient labeling (Patient Information).

…

Hypocalcemia: Advise patients that COMETRIQ can cause low calcium levels and that their serum calcium levels should be monitored regularly during treatment. Advise patients to immediately contact their healthcare provider for signs or symptoms of hypocalcemia [see Warnings and Precautions (5.12)].

…

PATIENT INFORMATION

Additions and/or revisions underlined:

…

Before you take COMETRIQ, tell your healthcare provider about all of your medical conditions including if you:

have a recent history of coughing up blood or bleeding or any unusual bleeding
have an open or healing wound
have high blood pressure
have a low calcium level in your blood (hypocalcemia)
plan to have any surgery, a dental procedure, or have had a recent surgery. You should stop taking COMETRIQ at least 3 weeks before planned surgery. See “What are the possible side effects of COMETRIQ?”
have liver problems
are pregnant or plan to become pregnant. COMETRIQ can harm your unborn baby.
- If you are able to become pregnant, your healthcare provider will check your pregnancy status before you start treatment with COMETRIQ.
- Females who are able to become pregnant should use effective birth control (contraception) during treatment and for 4 months after the final dose of COMETRIQ.
- Talk to your healthcare provider about birth control methods that may be right for you.
- If you become pregnant or think you are pregnant, tell your healthcare provider right away.
are breastfeeding or plan to breastfeed. It is not known if COMETRIQ passes into your breast milk. Do not breastfeed during treatment and for 4 months after the final dose of COMETRIQ.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. COMETRIQ and certain other medicines may affect each other causing side effects.

…

What should I avoid while taking COMETRIQ?

Do not drink grapefruit juice, eat grapefruit or take supplements that contain grapefruit or St. John’s wort during treatment with COMETRIQ.

What are the possible side effects of COMETRIQ? COMETRIQ may cause serious side effects, including:

a tear in your stomach or intestinal wall (perforation) or an abnormal connection between 2 parts of your body (fistula) that may lead to death. Tell your healthcare provider right away if you get tenderness or pain in your stomach-area (abdomen) that is severe or that does not go away.

…

high blood pressure (hypertension). Hypertension is common with COMETRIQ and can be severe. Your healthcare provider will check your blood pressure before starting COMETRIQ and regularly during treatment with COMETRIQ. If needed, your healthcare provider may prescribe medicine to treat your high blood pressure. Tell your healthcare provider if you develop severe headaches, nose bleeds, tiredness or confusion, vision changes, chest pain, trouble breathing, irregular heartbeat, or blood in your urine.
severe jaw bone problems (osteonecrosis). Your healthcare provider should examine your mouth before you start and during treatment with COMETRIQ. Tell your dentist that you are taking COMETRIQ. It is important for you to practice good mouth care during treatment with COMETRIQ. Tell your healthcare provider right away if you develop any symptoms of jaw problems including: jaw pain, toothache, or sores on your gums.

…

decreased calcium level in your blood (hypocalcemia). COMETRIQ can cause you to have a decreased amount of calcium in your blood. Your healthcare provider will do blood tests to check you for this problem and give you calcium if needed. Tell your healthcare provider right away if you get any of the following signs or symptoms:

muscle stiffness or muscle spasms
sudden weight gain
numbness or tingling in your fingers, toes, or around
swelling of your arms, hands, legs, your mouth and ankles
seizures

…

The most common side effects of COMETRIQ include:

…

10/22/2020 (SUPPL-9)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions underlined)

…

Vascular Disorders: Arterial (including aortic) aneurysms, dissections, and rupture

01/31/2020 (SUPPL-8)

Approved Drug Label (PDF)

Boxed Warning

(Effective 2/1/2020, Box Warning in supplement 8 has been removed)

5 Warnings and Precautions

(Extensive changes; please refer to label)

6 Adverse Reactions

(Extensive changes; please refer to label)

8 Use in Specific Populations

Females and Males of Reproductive Potential

(Newly added information)

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating COMETRIQ

[see Use in Specific Populations (8.1)].

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

Patient Counseling Information

(Extensive changes; please refer to label)

PATIENT INFORMATION

(Extensive changes; please refer to label)

01/12/2018 (SUPPL-5)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Perforations and Fistulas

(additions underlined)

Gastrointestinal (GI) perforations and fistulas were reported in 3% and 1% of COMETRIQ- treated patients, respectively. All were serious and one GI fistula was fatal (< 1%). Non-GI fistulas including tracheal/esophageal were reported in 4% of COMETRIQ-treated patients. Two (1%) of these were fatal.

Monitor patients for symptoms of perforations and fistulas, including abscess. Discontinue COMETRIQ in patients who experience a perforation or a fistula.

6 Adverse Reactions

6.1 Clinical Trial Experience

(additions underlined)

…

Other clinically important adverse reactions (all grades) that were reported in clinical trials include: hepatitis cholestatic (<1%).

6.2 Post-Marketing Experience

(new subsection added)

Hematology: A case of supratherapeutic international normalized ratio (INR) and epistaxis during concomitant use of warfarin.

05/20/2016 (SUPPL-2)

Approved Drug Label (PDF)

5 Warnings and Precautions

Embryo-Fetal Toxicity

Based on data from animal studies and its mechanism of action, COMETRIQ can cause fetal harm when administered to a pregnant woman. Cabozantinib administration to pregnant animals during organogenesis resulted in embryolethality at exposures below those occurring clinically at the recommended dose, and in increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with COMETRIQ and for 4 months after the last dose.

7 Drug Interactions

Effect of CYP3A4 Inducers

with COMETRIQ…or increase the dosage of COMETRIQ if concomitant use with strong CYP3A4 inducers cannot be avoided..

Effect of CYP3A4 Inhibitors

while taking COMETRIQ…or reduce the dosage of COMETRIQ if concomitant use with strong CYP3A4 inhibitors cannot be avoided.
Avoid ingestion of foods (e.g., grapefruit, grapefruit juice) or nutritional supplements that are known to inhibit cytochrome P450 while taking COMETRIQ.

Effect of MRP2 Inhibitors

Concomitant administration of MRP2 inhibitors may increase the exposure to cabozantinib. Monitor patients for increased toxicity when MRP2 inhibitors (e.g., abacavir, adefovir, cidofovir, furosemide, lamivudine, nevirapine, ritonavir, probenecid, saquinavir, and tenofovir) are coadministered with COMETRIQ.

8 Use in Specific Populations

Hepatic Impairment

Increased exposure to cabozantinib has been observed in patients with mild to moderate hepatic impairment. Reduce the starting dose of COMETRIQ in patients with mild (Child-Pugh score (C-P) A) or moderate (C-P B) hepatic impairment. COMETRIQ is not recommended for use in patients with severe hepatic impairment.

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

MG - Before you take COMETRIQ, tell your healthcare provider about all of your medical conditions including if you:

are pregnant or plan to become pregnant. COMETRIQ can harm your unborn baby. If you are able to become pregnant, you should use effective birth control during treatment and for 4 months after the final dose of COMETRIQ. Talk to your healthcare provider about birth control methods that may be right for you. If you become pregnant or think you are pregnant, tell your healthcare provider right away.
are breastfeeding or plan to breastfeed. It is not known if COMETRIQ passes into your breast milk. Do not breastfeed during treatment and for 4 months after the final dose of COMETRIQ.

Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with COMETRIQ if you have certain side effects.

MG - The most common side effects of COMETRIQ are:

diarrhea
redness, swelling or pain in your mouth or throat, or mouth sores. Tell your healthcare provider if these symptoms prevent you from eating or drinking.
weight loss
decreased appetite
nausea
tiredness
hair color turning lighter
change in taste
pain in your abdomen
constipation
increased liver function blood tests
decreased calcium and phosphate blood levels
decreased white blood cell counts
decreased platelet counts
increased bilirubin blood levels

PCI - Important Administration Information

Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking COMETRIQ. Instruct patients that COMETRIQ capsules should not be opened or crushed and to take COMETRIQ capsules with a full glass (at least 8 ounces) of water.
Advise patients not to consume grapefruits or grapefruit juice while taking COMETRIQ.

PCI - Inform patients of the following:

Diarrhea: Inform patients of the need to contact their healthcare provider if severe diarrhea occurs during treatment with COMETRIQ.
Palmar-plantar erythrodysesthesia syndrome: Advise patients to contact their healthcare provider for progressive or intolerable rash.
Mucositis and oral pain: Advise patients to contact their healthcare provider if they experience sores in the mouth, oral pain, changes in taste, nausea or vomiting that are severe or prevents them from eating and drinking.
Weight loss: COMETRIQ often causes weight loss which may be significant in some cases. Advise patients to report significant weight loss.
Wound complications: Advise patients to contact their healthcare provider before any planned surgeries, including dental procedures.
Embryo-fetal toxicity: Advise females of reproductive potential of the potential risk to a fetus. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with COMETRIQ.
Females of reproductive potential: Advise patients of reproductive potential to use effective contraception during treatment with COMETRIQ and for at least four months after the final dose of COMETRIQ.
Lactation: Advise women not to breastfeed during treatment with COMETRIQ and for 4 months following the last dose.