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.

BALVERSA (NDA-212018)

(ERDAFITINIB)

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

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10/17/2025 (SUPPL-11)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

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

Skeletal adverse reactions have occurred in pediatric patients treated with BALVERSA. In a study of BALVERSA that included pediatric patients ages 6 to <18 years with FGFR-positive advanced solid tumors, epiphysiolysis and bone fractures occurred.

In the postmarket setting and in literature reports, cases of slipped capital femoral epiphysis and accelerated linear growth in patients treated with BALVERSA have been reported.

Juvenile Animal Toxicity Data

In 4 and 13-week repeat-dose toxicology studies in rats and dogs, toxicities in bone and teeth were observed at an exposure less than the human exposure (AUC) at the maximum recommended human dose. Chondroid dysplasia/metaplasia were reported in multiple bones in both species, and tooth abnormalities included abnormal/irregular denting in rats and dogs and discoloration and degeneration of odontoblasts in rats.

01/19/2024 (SUPPL-7)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Ocular Disorders

(Additions and/or revisions underlined)

BALVERSA can cause ocular disorders, including central serous retinopathy/retinal pigment epithelial detachment (CSR/RPED) resulting in visual field defect.

In the pooled safety population [see Adverse Reactions (6)], CSR/RPED occurred in 22% of patients treated with BALVERSA, with a median time to first onset of 46 days. In 104 patients with CSR, 40% required dose interruptions and 56% required dose reductions; 2.9% of BALVERSA-treated patients required permanent discontinuation for CSR. Of the 24 patients who restarted BALVERSA after dose interruption with or without dose reduction, 67% had recurrence and/or worsening of CSR after restarting. CSR was ongoing in 41% of the 104 patients at the time of last evaluation.

Dry eye symptoms occurred in 26% of BALVERSA-treated patients. All patients should receive dry eye prophylaxis with ocular demulcents as needed.

Perform monthly ophthalmological examinations during the first 4 months of treatment and every 3 months afterwards, and urgently at any time for visual symptoms. Ophthalmological examination should include assessment of visual acuity, slit lamp examination, fundoscopy, and optical coherence tomography.

Withhold or permanently discontinue BALVERSA based on severity and/or ophthalmology exam findings [see Dosage and Administration (2.3)].

5.2 Hyperphosphatemia and Soft Tissue Mineralization

(Additions and/or revisions underlined)

In the pooled safety population [see Adverse Reactions (6)], increased phosphate occurred in 73% of BALVERSA-treated patients. The median onset time of increased phosphate was 16 days (range: 8-421) after initiating BALVERSA. Twenty-four percent of patients received phosphate binders during treatment with BALVERSA. Vascular calcification was observed in 0.2% of patients treated with BALVERSA.

Monitor for hyperphosphatemia throughout treatment. Restrict dietary phosphate intake (600-800 mg daily) and avoid concomitant use of agents that may increase serum phosphate levels.

If serum phosphate is above 7.0 mg/dL, consider adding an oral phosphate binder until serum phosphate level returns to <7.0 mg/dL. Withhold, dose reduce, or permanently discontinue BALVERSA based on duration and severity of hyperphosphatemia according to Table 2 [see Dosage and Administration (2.3)].

6 Adverse Reactions

6.1 Clinical Trials Experience

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

7 Drug Interactions

7.1 Effect of Other Drugs on BALVERSA

(Additions and/or revisions underlined)

Table 7: Drug Interactions that Affect BALVERSA

Moderate CYP2C9 or Strong CYP3A4 Inhibitors

Clinical Management

…

If co-administration of a moderate CYP2C9 or strong CYP3A4 inhibitor is unavoidable, monitor closely for adverse reactions and consider dose modifications accordingly [see Dosage and Administration (2.3)]. If the moderate CYP2C9 or strong CYP3A4 inhibitor is discontinued, resume the BALVERSA dose before dose modifications in the absence of drug-related toxicity.

Strong CYP3A4 Inducers

Clinical Impact

Co-administration of BALVERSA with strong CYP3A4 inducers decreased erdafitinib plasma concentrations significantly [see Clinical Pharmacology (12.3)].

Clinical Management

Avoid co-administration of strong CYP3A4 inducers with BALVERSA.

Moderate CYP3A4 Inducers

Clinical Impact

Co-administration of BALVERSA with moderate CYP3A4 inducers of decrease erdafitinib plasma concentrations [see Clinical Pharmacology (12.3)].
Decreased erdafitinib plasma concentrations may lead to decreased activity.

Clinical Management

If a moderate CYP3A4 inducer must be co-administered at the start of BALVERSA treatment, administer BALVERSA at a dose as recommended 9 mg daily.
When a moderate CYP3A4 inducer of is discontinued, continue BALVERSA at the same dose, in the absence of drug-related toxicity.

8 Use in Specific Populations

8.3 Females and Males of Reproductive Potential

(Additions and/or revisions underlined)

BALVERSA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating treatment with BALVERSA.

8.5 Geriatric Use

(Additions and/or revisions underlined)

Of the 479 patients treated with BALVERSA in clinical studies, 40% of patients were less than 65 years old, 40% of patients were 65 years to 74 years old, and 20% were 75 years old and over.

Patients 65 years of age and older treated with BALVERSA experienced a higher incidence of adverse reactions requiring treatment discontinuation than younger patients. In clinical trials, the incidence of treatment discontinuations of BALVERSA due to adverse reactions was 10% in patients younger than 65 years, 20% in patients ages 65-74 years, and 35% in patients 75 years or older.

No overall difference in efficacy was observed between these patients and younger patients [see Clinical Studies (14.1)].

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

…

Infertility

Advise females of reproductive potential that BALVERSA may impair fertility [see Use in Specific Populations (8.3)].

03/20/2023 (SUPPL-5)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Revision to Table 4; please refer to label for complete information

01/11/2023 (SUPPL-4)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

… The most common adverse reactions (ARs) including laboratory abnormalities (?20%) were phosphate increased, stomatitis, fatigue, creatinine increased, diarrhea, dry mouth, nail disorder, alanine aminotransferase increased …

Table 3: Adverse Reactions Reported in greater than or equal to 10% (Any Grade) or greater than or equal to 5% (Grade 3-4) of Patients

Skin and subcutaneous disorders

‘nail disorder’ replaces ‘onycholysis’

‘onychomadesis’ added to the nail disorder footnote c.

04/28/2022 (SUPPL-3)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Hyperphosphatemia and Soft Tissue Mineralization

Additions underlined

BALVERSA can cause hyperphosphatemia leading to soft tissue mineralization, cutaneous calcinosis, non-uremic calciphylaxis and vascular calcification. Increases in phosphate levels are a pharmacodynamic effect of BALVERSA [see Pharmacodynamics (12.2)]. Hyperphosphatemia was reported as adverse reaction in 76% of patients treated with BALVERSA. The median onset time for any grade event of hyperphosphatemia was 20 days (range: 8-116) after initiating BALVERSA. Thirty-two percent of patients received phosphate binders during treatment with BALVERSA. Cutaneous calcinosis, non-uremic calciphylaxis and vascular calcification have been observed in 0.3% of patients treated with BALVERSA.

Monitor for hyperphosphatemia throughout treatment. In all patients, restrict phosphate intake to 600- 800 mg daily. If serum phosphate is above 7.0 mg/dL, consider adding an oral phosphate binder until serum phosphate level returns to <5.5 mg/dL. Withhold, dose reduce, or permanently discontinue BALVERSA based on duration and severity of hyperphosphatemia according to Table 2 [see Dosage and Administration (2.3)].

8 Use in Specific Populations

8.6 Renal Impairment

New subsection added

No dose adjustment is recommended for patients with mild to moderate renal impairment [estimated glomerular filtration rate (eGFR) 30 to 89 mL/min/1.73 m²]. No data are available in patients with severe renal impairment [see Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

New subsection added

No dose adjustment is recommended for patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. Limited data are available in patients with severe (Child-Pugh C) hepatic impairment. [see Clinical Pharmacology (12.3)].

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

PATIENT COUNSELING INFORMATION

Additions underlined

…

Hyperphosphatemia and Soft Tissue Mineralization

Inform patients that BALVERSA may cause hyperphosphatemia and soft tissue mineralization. Advise patients to immediately inform their healthcare provider of painful skin lesions or any symptoms related to acute change in phosphate levels such as muscle cramps, numbness, or tingling around the mouth [see Warnings and Precautions (5.2)].

Advise patients that their healthcare provider will assess their serum phosphate level between 14 and 21 days of initiating treatment and will adjust the dose if needed [see Warnings and Precautions (5.2)]. Advise patients to restrict phosphate intake to 600-800 mg daily. During this initial phosphate-assessment period, advise patients to avoid concomitant use with agents that can alter serum phosphate levels. Advise patients that, after the initial phosphate assessment period, monthly phosphate level monitoring for hyperphosphatemia should be performed during treatment with BALVERSA [see Drug Interactions (7.1)].

…

PATIENT INFORMATION

Additions underlined

…

What are the possible side effects of BALVERSA?

BALVERSA may cause serious side effects, including:

…

High phosphate levels in the blood (hyperphosphatemia). Hyperphosphatemia is common with BALVERSA but can also be serious. High levels of phosphate in your blood may lead to build-up of minerals such as calcium in different tissues in your body. Your healthcare provider will check your blood phosphate level between 14 and 21 days after starting treatment with BALVERSA, and then monthly.

Your healthcare provider may prescribe changes in your diet or phosphate lowering therapy, or change or stop treatment with BALVERSA if needed.
Tell your healthcare provider right away if you develop painful skin lesions, any muscle cramps, or numbness or tingling around your mouth.

…