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.

WELIREG (NDA-215383)

(BELZUTIFAN)

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

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05/14/2025 (SUPPL-12)

Approved Drug Label (PDF)

5 Warnings and Precautions

WARNINGS AND PRECAUTIONS

5.1 Anemia

Additions and/or revisions underlined:

. . .

Pheochromocytoma or Paraganglioma (PPGL)

In LITESPARK-015, anemia occurred in 96% of patients and 22% had Grade 3 events [see Adverse Reactions (6.1)]. Median time to onset of anemia was 29 days (range: 1 day to 22.1 months). Of the patients with anemia, 20% received transfusions only, 26% received ESAs only, and 6% received both transfusion and ESAs.

6 Adverse Reactions

6.1 Clinical Trials Experience

Extensive changes; please refer to label for complete information

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of WELIREG have been established in pediatric patients aged 12 years and older for the treatment of locally advanced, unresectable, or metastatic pheochromocytoma or paraganglioma. Use of WELIREG in pediatric patients aged 12 years and older is supported by evidence from an adequate and well-controlled study of WELIREG in adults with additional pharmacokinetic data demonstrating that belzutifan exposure is predicted to be within range of that observed in adults, and that the course of locally advanced, unresectable, or metastatic pheochromocytoma or paraganglioma is sufficiently similar in adults and pediatric patients to allow extrapolation of data in adults to pediatric patients [see Clinical Pharmacology (12.3), and Clinical Studies (14.3)].

The safety and effectiveness of WELIREG have not been established in pediatric patients younger than 12 years of age.

8.5 Geriatric Use

Additions and/or revisions underlined:

Of the 61 patients who received WELIREG for VHL in LITESPARK-004, 3.3% were ?65 years old [see Clinical Studies (14.1)] Clinical trials of WELIREG in patients with VHL did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently from younger patients.

. . .

Of the 72 patients who received WELIREG for PPGL in LITESPARK-015, 13% were ?65 years old and 4.2% were ?75 years old [see Clinical Studies (14.1)]. Clinical trials of WELIREG in patients with PPGL did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

8.6 Renal Impairment

Additions and/or revisions underlined:

No dosage modification of WELIREG is recommended in patients with renal impairment including end- stage renal disease. For patients with severe renal impairment (eGFR 15-29 mL/min estimated by MDRD), monitor for increased adverse reactions and modify the dosage as recommended [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

Additions and/or revisions underlined:

No dosage modification of WELIREG is recommended in patients with mild [total bilirubin less than or equal to upper limit of normal (ULN) and aspartate aminotransferase (AST) greater than ULN or total bilirubin greater than 1 to 1.5 x ULN and any AST] or moderate (total bilirubin within range of greater than 1.5 x ULN and less than or equal to 3 x ULN and any AST or Child-Pugh B) hepatic impairment. WELIREG has not been studied in patients with severe hepatic impairment (total bilirubin greater than 1.5 x ULN and any AST). For patients with moderate and severe hepatic impairment, monitor for increased adverse reactions and modify the dosage as recommended [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].

8.8 Dual UGT2B17 and CYP2C19 Poor Metabolizers

Additions and/or revisions underlined:

Patients who are dual UGT2B17 and CYP2C19 poor metabolizers have higher belzutifan exposures, which may increase the risk of adverse reactions of WELIREG. Monitor for increased adverse reactions in patients who are dual UGT2B17 and CYP2C19 poor metabolizers [see Warnings and Precautions (5), Adverse Reactions (6), Clinical Pharmacology (12.5)].

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

MEDICATION GUIDE

Additions and/or revisions underlined:

. . .

von Hippel-Lindau (VHL) disease in adults who need treatment for a type of kidney cancer called renal cell carcinoma (RCC), tumors in the brain and spinal cord called central nervous system hemangioblastomas (CNS), or a type of pancreatic cancer called pancreatic neuroendocrine tumors (pNET), that do not require surgery right away.
a type of kidney cancer called RCC with a clear cell component in adults that has spread (advanced RCC) following treatment with a programmed death-receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI) cancer medicines.

neuroendocrine tumors called pheochromocytoma or paraganglioma (PPGL) in adults and children 12 years of age and older that have spread to areas near the adrenal glands (locally advanced), or cannot be removed by surgery (unresectable), or that has spread to other parts of the body (metastatic).

It is not known if WELIREG is safe and effective in children younger than 12 years of age.

. . .

The most common side effects of WELIREG in adults with PPGL include:

tiredness
shortness of breath
muscle and joint pain
increased blood potassium levels
decreased white blood cells
headache
increased liver function tests
dizziness
increased blood calcium levels

nausea

. . .

04/15/2025 (SUPPL-11)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and or revisions underlined:

…

Advanced Renal Cell Carcinoma (RCC)

LITESPARK-005

The safety of WELIREG was evaluated in a randomized, active-controlled study (LITESPARK- 005) in 732 patients with advanced RCC with a clear cell component that has progressed after prior PD-1 or PD- L1 checkpoint inhibitor and VEGF receptor targeted therapies [see Clinical Studies (14.2)]. Patients received 120 mg WELIREG (n=372) or 10 mg everolimus (n=360) by oral administration once daily. The median duration of exposure to WELIREG was 7.6 months (range 0.1 to 28.5 months).

…

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

MEDICATION GUIDE

…

What is WELIREG?

WELIREG is a prescription medicine used to treat adults with:

von Hippel-Lindau (VHL) disease who need treatment for a type of kidney cancer called renal cell carcinoma (RCC), tumors in the brain and spinal cord called central nervous system hemangioblastomas (CNS), or a type of pancreatic cancer called pancreatic neuroendocrine tumors (pNET), that do not require surgery right away.
a type of kidney cancer called RCC with a clear cell component, that has spread (advanced RCC) following treatment with a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI) cancer medicines.
…

12/14/2023 (SUPPL-6)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Anemia

(Additions and/or revisions underlined)

WELIREG can cause severe anemia that can require blood transfusion.

Monitor for anemia before initiation of, and periodically throughout, treatment with WELIREG. Transfuse patients as clinically indicated. For patients with hemoglobin <8g/dL, withhold WELIREG until greater than or equal to 8g/dL, then resume at the same or reduced dose or permanently discontinue WELIREG, depending on the severity of anemia. For life threatening anemia or when urgent intervention is indicated, withhold WELIREG until hemoglobin greater than or equal to 8g/dL, then resume at a reduced dose or permanently discontinue WELIREG [see Dosage and Administration (2.2)].

von Hippel-Lindau (VHL) disease

In LITESPARK-004, decreased hemoglobin occurred in 93% of patients and 7% had Grade 3 events [see Adverse Reactions (6.1)]. Median time to onset of anemia was 31 days (range: 1 day to 8.4 months).

The safety of erythropoiesis stimulating agents (ESAs) for treatment of anemia in patients with VHL disease treated with WELIREG has not been established. Randomized controlled trials in patients with cancer receiving myelosuppressive chemotherapy with ESAs have shown that ESAs increased the risks of death and serious cardiovascular reactions, and decreased progression-free survival and/or overall survival. See the prescribing information for ESAs for more information.

Advanced Renal Cell Carcinoma (RCC)

In LITESPARK-005, decreased hemoglobin occurred in 88% of patients and 29% had Grade 3 events [see Adverse Reactions (6.1)]. Median time to onset of anemia was 29 days (range: 1 day to 16.6 months). Of the patients with anemia, 22% received transfusions only, 20% of patients received ESAs only and 12% received both transfusion and ESAs.

5.2 Hypoxia

(Additions and/or revisions underlined)

…

Advise patients to report signs and symptoms of hypoxia immediately to a healthcare provider.

von Hippel-Lindau (VHL) disease

In LITESPARK- 004, hypoxia occurred in 1.6% of patients [see Adverse Reactions (6.1)]. Advanced Renal Cell Carcinoma (RCC)

In LITESPARK- 005, hypoxia occurred in 15% of patients and 10% had Grade 3 events [see Adverse Reactions (6.1)]. Of the patients with hypoxia, 69% were treated with oxygen therapy. Median time to onset of hypoxia was 30.5 days (range: 1 day to 21.1 months).

6 Adverse Reactions

6.1 Clinical Trials Experience

(Extensive changes; please refer to label for complete information)

8 Use in Specific Populations

8.5 Geriatric Use

(Additions and/or revisions underlined)

Of the patients who received WELIREG in LITESPARK-004, 3.3% were ?65 years old [see Clinical Studies (14.1)] Clinical trials of WELIREG in patients with VHL did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently from younger patients.

Of the 372 patients who received WELIREG for advanced RCC in LITESPARK-005, 62% of patients younger than 65 years, 28% of patients were 65 to 74 years, and 10% were 75 years and over. No overall difference in efficacy was reported between patients who were ?65 years of age and younger patients. Dose interruptions occurred in 48% of patients greater than or equal to 65 years of age and in 34% of younger patients. Dose reductions occurred in 18% of patients greater than or equal to 65 years of age and in 10% of younger patients.