Drug Safety-related Labeling Changes (SrLC)
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Guide
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.
STIVARGA (NDA-203085)
(REGORAFENIB)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
02/03/2026 (SUPPL-18)
07/21/2020 (SUPPL-13)
02/13/2020 (SUPPL-11)
07/31/2019 (SUPPL-10)
04/27/2017 (SUPPL-7)
5 Warnings and Precautions
5.1 Hepatotoxicity(additions underlined)
Severe drug-induced liver injury with fatal outcome occurred in STIVARGA-treated patients in clinical trials. In most cases, liver dysfunction occurred within the first 2 months of therapy and was characterized by a hepatocellular pattern of injury.
In the CORRECT study, fatal hepatic failure occurred in 1.6% of patients in the regorafenib arm and in 0.4% of patients in the placebo arm. In the GRID study, fatal hepatic failure occurred in 0.8% of patients in the regorafenib arm. In the RESORCE study, there was no increase in the incidence of fatal hepatic failure as compared to placebo.
Obtain liver function tests (ALT, AST, and bilirubin) before initiation of STIVARGA and monitor at least every two weeks during the first 2 months of treatment. Thereafter, monitor monthly or more frequently as clinically indicated. Monitor liver function tests weekly in patients experiencing elevated liver function tests until improvement to less than 3 times the ULN or baseline.
Temporarily hold and then reduce or permanently discontinue STIVARGA depending on the severity and persistence of hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis.
(subsection added)
STIVARGA caused an increased risk of infections. The overall incidence of infection (Grades 1-5) was higher (32% vs. 17%) in 1142 STIVARGA-treated patients as compared to the control arm in randomized placebo-controlled trials.The incidence of grade 3 or greater infections in STIVARGA treated patients was 9%. The most common infections were urinary tract infections (5.7%), nasopharyngitis (4.0%), mucocutaneous and systemic fungal infections (3.3%) and pneumonia (2.6%). Fatal outcomes caused by infection occurred more often in patients treated with STIVARGA (1.0%) as compared to patients receiving placebo (0.3%); the most common fatal infections were respiratory (0.6% in STIVARGA-treated patients vs 0.2% in patients receiving placebo).
Withhold STIVARGA for Grade 3 or 4 infections, or worsening infection of any grade. Resume STIVARGA at the same dose following resolution of infection.
(subsection revised, additions underlined)
STIVAGA
caused an increased incidence of hemorrhage. The overall incidence (Grades 1-5)
was 18.2% in 1142 patients treated with STIVARGA and 9.5% in
patients receiving placebo in randomized, placebo-controlled trials. The
incidence of grade 3 or greater hemorrhage in patients treated with STIVARGA
was 3.0%. The incidence of fata hemorrhagic events was 0.7%, involving the central nervous
system or the respiratory, gastrointestinal,
or genitourinary tracts.
Permanently discontinue STIVARGA in patients with severe or life-threatening hemorrhage. Monitor INR levels more frequently in patients receiving warfarin.
(subsection revised, additions underlined)
In randomized, placebo-controlled trials, adverse skin reactions occurred in 71.9% of patients in the regorafenib arm and in 25.5% of patients in the placebo arm, including hand-foot skin reaction (HFSR) also known as palmar-plantar erythrodysesthesia syndrome (PPES), and severe rash requiring dose modification.
In the randomized, placebo-controlled trials, the overall incidence of HFSR was higher in 1142 STIVARGA-treated patients (53%) than in the placebo-treated patients (8%). Most cases of HFSR in STIVARGA-treated patients appeared during the first cycle of treatment. The incidences of Grade 3 HFSR (16% versus <1%), Grade 3 rash (3% versus <1%), serious adverse reactions of erythema multiforme (<0.1% vs. 0%) and Stevens-Johnson Syndrome (<0.1% vs. 0%) were also higher in STIVARGA-treated patients [see Adverse Reactions (6.1)]. Across all trials, a higher incidence of HFSR was observed in Asian patients treated with STIVARGA (all grades: 78.4% 72%; Grade 3: 18%).
Toxic epidermal necrolysis occurred in 0.02% of 4518 STIVARGA-treated patients across all clinical trials Of STIVARGA administered as a single agent.
Withhold STIVARGA, reduce the dose, or permanently discontinue STIVARGA depending on the severity and persistence of dermatologic toxicity [see Dosage and Administration (2.2)]. Institute supportive measures for symptomatic relief.
(additions underlined)
In randomized, placebo-controlled trials, hypertensive
crisis occurred in 0.2% of patients in the regorafenib arms and in none of the patients
in the placebo arms. STIVARGA caused an
increased incidence of hypertension (30% versus 8% in CORRECT, 59% versus
27% in GRID, and 31% versus 6% in RESORCE). The onset of hypertension occurred during the first cycle of treatment
in most patients who developed hypertension (67% in randomized, placebo-controlled
trials).
Do not initiate STIVARGA unless blood pressure is adequately controlled. Monitor blood pressure weekly for the first 6 weeks of treatment and then every cycle, or more frequently, as clinically indicated. Temporarily or permanently withhold STIVARGA for severe or uncontrolled hypertension
6 Adverse Reactions
6.1 Clinical Trials Experience(additions and revisions, please refer to label)
(additions underlined)
…
Infections
…
8 Use in Specific Populations
8.5 Geriatric Use(additions underlined)
Of the 1142 STIVARGA-treated patients enrolled in randomized, placebo-controlled trials, 40% were 65 years of age and over, while 10% were 75 and over. No overall differences in efficacy were observed between these patients and younger patients. There was an increased incidence of Grade 3 hypertension (18% versus 9%) in the placebo-controlled trials among STIVARGA-treated patients 65 years of age and older as compared to younger patients. In addition, one Grade 4 hypertension event has been reported in the 65 years and older age group and none in the younger age group.
(additions underlined)
No dose adjustment is recommended in patients with mild (total bilirubin ?ULN and AST >ULN, or total bilirubin >ULN to ?1.5 times ULN) or moderate (total bilirubin >1.5 to ?3 times ULN and any AST) hepatic impairment, Closely monitor patients with hepatic impairment for adverse reactions.
STIVARGA is not recommended for use in patients with severe hepatic impairment (total bilirubin >3x ULN) as STIVARGA has not been studied in this population.
(additions underlined)
No dose adjustment is recommended for patients with renal impairment. The pharmacokinetics of regorafenib have not been studied in patients who are on dialysis and there is no recommended dose for this patient population.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION(additions underlined)
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Hepatotoxicity
Advise patients that they will need to undergo monitoring for liver damage and to report immediately any signs or symptoms of severe liver damage to their healthcare provider.
Infections
Advise patients to contact their healthcare provider if they experience signs and symptoms of infection.
…
Gastrointestinal Perforation or Fistula
Advise patients to contact a healthcare provider immediately if they experience severe pains in their abdomen, persistent swelling of the abdomen, high fever, chills, nausea, vomiting, or dehydration.
Dermatologic Toxicity
Advise patients to contact their healthcare provider if they experience skin changes including HFSR, rash, pain, blisters, bleeding, or swelling.
…
Dosing Instructions
Advise patients to take STIVARGA after a low fat meal. Advise patients to take any missed dose on the same day, as soon as they remember, and that they must not take two doses on the same day to make up for a dose missed on the previous day.