Regorafenib side effects: what 11,542 FDA adverse event reports show
Drug class
Kinase inhibitor
Brand names
Stivarga
Who reports
11,542 reports · 90% serious · 2,363 with death outcome · 40% female
Used for
STIVARGA is a kinase inhibitor indicated for the treatment of adult patients with: • Metastatic colorectal cancer (CRC) who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if RAS wild-type, an anti-EGFR therapy.
What it is
STIVARGA (regorafenib) is a multikinase inhibitor with the chemical name 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide monohydrate.
Boxed warning
HEPATOTOXICITY • Severe and sometimes fatal hepatotoxicity has occurred in clinical trials [see Warnings and Precautions ( 5.1 )] . • Monitor hepatic function prior to and during treatment [see Warnings and Precautions ( 5.1 )].
Causality screen of the 40 strongest signals
What the badges mean
- Labeled adverse reaction The exact term appears in the label's warnings or adverse-reactions sections: a known, expected effect. The FAERS signal confirms the label rather than discovering anything.
- Labeled (related wording) The label describes this effect under different wording (e.g. 'neutropenia' for 'neutrophil count decreased'). Treated as known.
- Likely indication confounding The term appears in the label's indications: reports probably describe the disease being treated (or its progression), not a drug effect. Classic confounding by indication.
- Lab value / disease marker A laboratory result, investigation or disease-activity marker (antibody positive, CRP abnormal, swollen joint count) not described in the label. These usually mirror the monitored disease or testing protocol rather than a drug effect; not screened further.
- Not in label — unassessed Not found in the label text, not an artifact pattern. This is a genuine candidate for a formal causality assessment (Bradford Hill / WHO-UMC); it has NOT had one here.
Strongest disproportionality signals
Flagged terms (PRR ≥ 2, χ² ≥ 4, n ≥ 10), ranked by PRR; infinite PRRs (no comparator reports) excluded. The EBGM column is a second, shrinkage-based estimate (MGPS) with its 5th percentile EB05 and the BCPNN IC025; a pair flagged by PRR alone is marked PRR-only and should be read as fragile. The strata column recomputes the PRR on serious reports only and flags pairs whose reports are unusually skewed by sex or come mostly from consumers rather than clinicians. 969 further terms are in the interactive explorer. Reaction links open the term's cross-drug page.
| Reaction | Reports | PRR 95% CI · ROR · χ²/p | EBGM EB05 · IC025 | Label screen | Serious-only & strata | Trial cross-check |
|---|---|---|---|---|---|---|
| Gastrointestinal stromal cancer | 15 | 995.5 529.7–1,870.8ROR 996.7 · χ² 8,951 / p <1e-300 | 352.2 EB05 226.6 · IC025 +4.0 3/3 methods agree | Likely indication confounding term in indications; also in warnings | serious n=15 | not reported in cached trials |
| Colorectal cancer metastatic | 320 | 295.9 263.2–332.5ROR 304.3 · χ² 80,466 / p <1e-300 | 250.3 EB05 228.1 · IC025 +7.3 3/3 methods agree | Likely indication confounding term in indications; also in warnings | serious n=320 | NCT05328908: 1/358 (0.3%) on Regorafenib (serious AE) |
| Osteosarcoma metastatic | 11 | 234.6 125.2–439.8ROR 234.9 · χ² 2,061 / p <1e-300 | 153.1 EB05 91.2 · IC025 +3.4 3/3 methods agree | Not in label — unassessed | serious n=11 | not reported in cached trials |
| Colorectal cancer recurrent | 13 | 204.3 115.2–362.6ROR 204.6 · χ² 2,182 / p <1e-300 | 144.9 EB05 90.1 · IC025 +3.6 3/3 methods agree | Likely indication confounding shares a disease stem with the indications wording | serious n=13 | not reported in cached trials |
| Plantar erythema | 24 | 196.4 128.9–299.2ROR 196.8 · χ² 4,030 / p <1e-300 | 155.4 EB05 109.9 · IC025 +4.6 3/3 methods agree | Labeled (related wording) related wording | serious n=24 · ♀ 62% (drug 40%) | not reported in cached trials |
| Alpha 1 foetoprotein increased | 51 | 139.7 105.1–185.7ROR 140.3 · χ² 6,388 / p <1e-300 | 123.8 EB05 97.8 · IC025 +5.4 3/3 methods agree | Lab value / disease marker | serious n=51 · ♀ 15% (drug 40%) | not reported in cached trials |
| Colon cancer recurrent | 19 | 135.6 85.1–216.2ROR 135.9 · χ² 2,237 / p <1e-300 | 112.2 EB05 75.9 · IC025 +4.1 3/3 methods agree | Not in label — unassessed | serious n=19 | not reported in cached trials |
| Hepatocellular carcinoma | 487 | 123.9 113.2–135.5ROR 129.3 · χ² 55,426 / p <1e-300 | 115.4 EB05 107.1 · IC025 +6.5 3/3 methods agree | Likely indication confounding term in indications; also in warnings | serious PRR 73.9 · ♀ 19% (drug 40%) | not reported in cached trials |
| Rectal cancer metastatic | 22 | 123.2 80.0–189.7ROR 123.4 · χ² 2,382 / p <1e-300 | 105.0 EB05 73.1 · IC025 +4.3 3/3 methods agree | Likely indication confounding term in indications; also in warnings | serious n=22 | NCT05328908: 1/358 (0.3%) on Regorafenib (serious AE) |
| Palmar-plantar erythrodysaesthesia syndrome | 1,439 | 119.1 113.3–125.3ROR 136.0 · χ² 158,118 / p <1e-300 | 111.6 EB05 106.8 · IC025 +6.7 3/3 methods agree | Not in label — unassessed | serious PRR 86.5 | NCT05328908: 6/383 (1.6%) on Regorafenib |
| Gastrointestinal stromal tumour | 142 | 101.7 86.0–120.3ROR 102.9 · χ² 13,304 / p <1e-300 | 95.1 EB05 82.7 · IC025 +5.9 3/3 methods agree | Likely indication confounding term in indications; also in warnings | serious n=140 | not reported in cached trials |
| Carcinoembryonic antigen increased | 101 | 100.3 82.1–122.4ROR 101.1 · χ² 9,307 / p <1e-300 | 93.4 EB05 79.1 · IC025 +5.7 3/3 methods agree | Lab value / disease marker | serious n=99 | not reported in cached trials |
| Colon cancer metastatic | 78 | 92.7 73.9–116.4ROR 93.4 · χ² 6,644 / p <1e-300 | 86.4 EB05 71.5 · IC025 +5.5 3/3 methods agree | Not in label — unassessed | serious n=78 | NCT05328908: 1/383 (0.3%) on Regorafenib (serious AE) |
| Palmoplantar keratoderma | 27 | 70.7 48.2–103.9ROR 70.9 · χ² 1,719 / p <1e-300 | 65.1 EB05 47.0 · IC025 +4.3 3/3 methods agree | Not in label — unassessed | serious n=22 | not reported in cached trials |
| Food refusal | 31 | 69.3 48.4–99.1ROR 69.4 · χ² 1,943 / p <1e-300 | 64.2 EB05 47.4 · IC025 +4.4 3/3 methods agree | Not in label — unassessed | serious n=30 | not reported in cached trials |
| Rectal cancer | 98 | 59.7 48.8–72.9ROR 60.2 · χ² 5,417 / p <1e-300 | 57.2 EB05 48.3 · IC025 +5.2 3/3 methods agree | Likely indication confounding term in indications; also in warnings | serious n=98 | NCT05328908: 1/383 (0.3%) on Regorafenib (serious AE) |
| Tumour compression | 10 | 58.9 31.4–110.6ROR 59.0 · χ² 497 / p 2e-110 | 51.8 EB05 30.1 · IC025 +2.9 3/3 methods agree | Not in label — unassessed | serious n=10 | not reported in cached trials |
| Metastases to lung | 329 | 53.3 47.8–59.4ROR 54.8 · χ² 16,350 / p <1e-300 | 51.6 EB05 47.1 · IC025 +5.4 3/3 methods agree | Not in label — unassessed | serious PRR 33.3 | not reported in cached trials |
| Metastases to abdominal cavity | 14 | 52.9 31.1–90.0ROR 53.0 · χ² 643 / p 3e-142 | 48.3 EB05 30.6 · IC025 +3.3 3/3 methods agree | Labeled (related wording) related wording | serious n=14 | not reported in cached trials |
| Hyperkeratosis | 149 | 50.3 42.7–59.1ROR 50.9 · χ² 6,950 / p <1e-300 | 48.6 EB05 42.4 · IC025 +5.1 3/3 methods agree | Not in label — unassessed | serious n=136 | not reported in cached trials |
| Rectal adenocarcinoma | 16 | 49.9 30.4–82.1ROR 50.0 · χ² 700 / p 2e-154 | 46.1 EB05 30.1 · IC025 +3.5 3/3 methods agree | Not in label — unassessed | serious n=16 | not reported in cached trials |
| Tumour rupture | 14 | 47.2 27.7–80.1ROR 47.2 · χ² 572 / p 1e-126 | 43.5 EB05 27.5 · IC025 +3.3 3/3 methods agree | Labeled (related wording) related wording | serious n=14 | not reported in cached trials |
| Carbohydrate antigen 19-9 increased | 13 | 46.7 26.9–80.9ROR 46.7 · χ² 523 / p 5e-116 | 42.9 EB05 26.7 · IC025 +3.2 3/3 methods agree | Lab value / disease marker | serious n=13 | not reported in cached trials |
| Metastases to adrenals | 22 | 44.5 29.2–68.0ROR 44.6 · χ² 872 / p 7e-192 | 42.0 EB05 29.3 · IC025 +3.8 3/3 methods agree | Not in label — unassessed | serious n=22 | not reported in cached trials |
| Colon cancer | 344 | 42.8 38.5–47.6ROR 44.1 · χ² 13,693 / p <1e-300 | 41.8 EB05 38.2 · IC025 +5.1 3/3 methods agree | Not in label — unassessed | serious PRR 26.9 | NCT05328908: 1/383 (0.3%) on Regorafenib (serious AE) |
| Metastases to pelvis | 14 | 41.2 24.3–69.9ROR 41.2 · χ² 498 / p 1e-110 | 38.4 EB05 24.3 · IC025 +3.2 3/3 methods agree | Not in label — unassessed | serious n=14 | not reported in cached trials |
| Metastases to peritoneum | 54 | 40.0 30.6–52.4ROR 40.2 · χ² 1,972 / p <1e-300 | 38.7 EB05 30.8 · IC025 +4.4 3/3 methods agree | Not in label — unassessed | serious n=54 | not reported in cached trials |
| Retroperitoneal lymphadenopathy | 11 | 38.7 21.3–70.3ROR 38.8 · χ² 360 / p 2e-80 | 35.8 EB05 21.3 · IC025 +2.8 3/3 methods agree | Not in label — unassessed | serious n=11 | not reported in cached trials |
| Pulmonary cavitation | 16 | 34.3 20.9–56.2ROR 34.3 · χ² 475 / p 2e-105 | 32.5 EB05 21.2 · IC025 +3.2 3/3 methods agree | Not in label — unassessed | serious n=16 | not reported in cached trials |
| Angular cheilitis | 12 | 32.4 18.3–57.3ROR 32.4 · χ² 328 / p 1e-73 | 30.4 EB05 18.5 · IC025 +2.9 3/3 methods agree | Not in label — unassessed | serious n=12 | not reported in cached trials |
| Coma hepatic | 13 | 32.0 18.5–55.4ROR 32.1 · χ² 354 / p 3e-79 | 30.2 EB05 18.8 · IC025 +2.9 3/3 methods agree | Not in label — unassessed | serious n=13 | not reported in cached trials |
| Metastases to liver | 282 | 29.7 26.4–33.3ROR 30.4 · χ² 7,667 / p <1e-300 | 29.2 EB05 26.4 · IC025 +4.6 3/3 methods agree | Labeled (related wording) related wording | serious PRR 18.8 | not reported in cached trials |
| Tumour marker increased | 77 | 29.5 23.6–37.0ROR 29.7 · χ² 2,061 / p <1e-300 | 28.9 EB05 23.9 · IC025 +4.2 3/3 methods agree | Lab value / disease marker | serious n=75 | not reported in cached trials |
| Adenocarcinoma of colon | 29 | 28.5 19.8–41.2ROR 28.6 · χ² 732 / p 2e-161 | 27.7 EB05 20.2 · IC025 +3.6 3/3 methods agree | Not in label — unassessed | serious n=29 | not reported in cached trials |
| Intra-abdominal fluid collection | 27 | 28.1 19.2–41.1ROR 28.2 · χ² 669 / p 1e-147 | 27.2 EB05 19.6 · IC025 +3.6 3/3 methods agree | Not in label — unassessed | serious n=26 | not reported in cached trials |
| Dysphonia | 821 | 25.9 24.2–27.7ROR 27.8 · χ² 19,392 / p <1e-300 | 25.5 EB05 24.1 · IC025 +4.5 3/3 methods agree | Labeled adverse reaction exact term | serious PRR 27.8 | NCT05328908: 2/383 (0.5%) on Regorafenib |
| Tumour pain | 18 | 25.0 15.7–39.9ROR 25.1 · χ² 386 / p 3e-86 | 24.1 EB05 16.1 · IC025 +3.1 3/3 methods agree | Labeled (related wording) related wording | serious n=18 | NCT05328908: 1/383 (0.3%) on Regorafenib (serious AE) |
| Cancer pain | 32 | 22.9 16.2–32.5ROR 23.0 · χ² 641 / p 1e-141 | 22.4 EB05 16.6 · IC025 +3.5 3/3 methods agree | Labeled (related wording) related wording | serious n=31 | NCT05328908: 4/358 (1.1%) on Regorafenib (serious AE) |
| Tumour necrosis | 13 | 22.7 13.2–39.3ROR 22.8 · χ² 246 / p 1e-55 | 21.7 EB05 13.2 · IC025 +2.7 3/3 methods agree | Labeled (related wording) related wording | serious n=13 | not reported in cached trials |
| Palmar erythema | 14 | 22.4 13.2–38.0ROR 22.5 · χ² 262 / p 3e-59 | 21.5 EB05 13.4 · IC025 +2.8 3/3 methods agree | Labeled (related wording) related wording | serious n=14 | not reported in cached trials |
Trial evidence (ClinicalTrials.gov)
✓ Trial adverse-event data found on ClinicalTrials.gov
Largest completed trials with posted results that list Regorafenib as a study intervention. The right-hand column of the signal table shows whether each FAERS term was also recorded in these trials, with a real denominator (9 of 40 signal terms matched).
- NCT05328908 — A Study of Nivolumab-relatlimab Fixed-dose Combination Versus Regorafenib or TAS-102 in Participants With Late (N=769, PHASE3; 270 AE terms posted; arms: Arm A; Arm B)
- NCT01103323 — Patients With Metastatic Colorectal Cancer Treated With Regorafenib or Placebo After Failure of Standard Thera (N=760, PHASE3; 210 AE terms posted; arms: Regorafenib (BAY73-4506)+BSC; Placebo+BSC; Placebo - Regorafenib After Unblinding)
Caveats: trial populations, doses and follow-up differ from the reporting population; AE terms are sponsor-coded and matched here by wording; absence from a trial list means the term was not reported above the sponsor's frequency threshold, not that it cannot occur.
Most frequently reported reactions
By raw co-report count, regardless of disproportionality. Common terms here are often the illness itself or generic outcomes.
| Reaction | Reports | PRR 95% CI · ROR · χ²/p | EBGM EB05 · IC025 | Label screen | Serious-only & strata | Trial cross-check |
|---|---|---|---|---|---|---|
| Off label use (used outside approved label) | 2,073 | 4.3 4.2–4.5ROR 5.1 · χ² 5,558 / p <1e-300 | 4.3 EB05 4.2 · IC025 +2.0 3/3 methods agree | Reporting / coding artifact | serious PRR 4.9 | not reported in cached trials |
| Fatigue (tiredness) | 1,769 | 4.1 4.0–4.3ROR 4.7 · χ² 4,369 / p <1e-300 | 4.1 EB05 4.0 · IC025 +2.0 3/3 methods agree | Labeled adverse reaction exact term | serious PRR 4.7 | NCT05328908: 1/383 (0.3%) on Regorafenib (serious AE) |
| Palmar-plantar erythrodysaesthesia syndrome | 1,439 | 119.1 113.3–125.3ROR 136.0 · χ² 158,118 / p <1e-300 | 111.6 EB05 106.8 · IC025 +6.7 3/3 methods agree | Not in label — unassessed | serious PRR 86.5 | NCT05328908: 6/383 (1.6%) on Regorafenib |
| Diarrhoea (diarrhea) | 1,418 | 4.0 3.8–4.2ROR 4.4 · χ² 3,297 / p <1e-300 | 4.0 EB05 3.8 · IC025 +1.9 3/3 methods agree | Labeled adverse reaction exact term | serious PRR 4.2 | NCT05328908: 5/383 (1.3%) on Regorafenib (serious AE) |
| Decreased appetite (loss of appetite) | 1,091 | 8.6 8.1–9.1ROR 9.4 · χ² 7,360 / p <1e-300 | 8.5 EB05 8.1 · IC025 +3.0 3/3 methods agree | Labeled adverse reaction exact term | serious PRR 7.9 | NCT05328908: 3/383 (0.8%) on Regorafenib (serious AE) |
| Death | 1,001 | 2.1 2.0–2.2ROR 2.2 · χ² 610 / p 5e-135 | 2.1 EB05 2.0 · IC025 +1.0 3/3 methods agree | Outcome field, not a reaction boxed warning mentions mortality | serious PRR 1.3 | NCT05328908: 1/383 (0.3%) on Regorafenib (serious AE) |
| Asthenia (weakness) | 946 | 4.6 4.3–4.9ROR 4.9 · χ² 2,685 / p <1e-300 | 4.6 EB05 4.3 · IC025 +2.1 3/3 methods agree | Labeled adverse reaction exact term | serious PRR 4.0 | NCT05328908: 3/383 (0.8%) on Regorafenib (serious AE) |
| Dysphonia | 821 | 25.9 24.2–27.7ROR 27.8 · χ² 19,392 / p <1e-300 | 25.5 EB05 24.1 · IC025 +4.5 3/3 methods agree | Labeled adverse reaction exact term | serious PRR 27.8 | NCT05328908: 2/383 (0.5%) on Regorafenib |
| Nausea | 815 | 1.9 1.8–2.0ROR 1.9 · χ² 346 / p 1e-77 | 1.9 EB05 1.8 · IC025 +0.8 | Labeled adverse reaction exact term | serious PRR 2.2 | NCT05328908: 1/383 (0.3%) on Regorafenib (serious AE) |
| Pain in extremity | 774 | 4.8 4.5–5.1ROR 5.0 · χ² 2,332 / p <1e-300 | 4.8 EB05 4.5 · IC025 +2.1 3/3 methods agree | Not in label — unassessed | serious PRR 5.0 | NCT01103323: 2/500 (0.4%) on Regorafenib (serious AE) |
| Pyrexia (fever) | 752 | 4.0 3.7–4.2ROR 4.2 · χ² 1,680 / p <1e-300 | 3.9 EB05 3.7 · IC025 +1.9 3/3 methods agree | Labeled (related wording) related wording | serious PRR 3.1 | NCT05328908: 1/383 (0.3%) on Regorafenib (serious AE) |
| Hypertension (high blood pressure) | 695 | 6.0 5.6–6.4ROR 6.3 · χ² 2,891 / p <1e-300 | 5.9 EB05 5.6 · IC025 +2.4 3/3 methods agree | Labeled — boxed warning exact term | serious PRR 4.5 | NCT05328908: 8/383 (2.1%) on Regorafenib |
| Weight decreased (weight loss) | 636 | 4.1 3.8–4.5ROR 4.3 · χ² 1,533 / p <1e-300 | 4.1 EB05 3.9 · IC025 +1.9 3/3 methods agree | Labeled (related wording) related wording | serious PRR 3.8 | NCT05328908: 18/383 (4.7%) on Regorafenib |
| Vomiting | 570 | 2.2 2.0–2.4ROR 2.3 · χ² 385 / p 6e-86 | 2.2 EB05 2.1 · IC025 +1.0 3/3 methods agree | Labeled adverse reaction exact term | serious PRR 2.0 | NCT05328908: 7/383 (1.8%) on Regorafenib (serious AE) |
| Rash | 556 | 2.3 2.1–2.5ROR 2.4 · χ² 430 / p 9e-96 | 2.3 EB05 2.2 · IC025 +1.1 3/3 methods agree | Labeled adverse reaction exact term | serious PRR 3.0 | NCT05328908: 1/383 (0.3%) on Regorafenib (serious AE) |
Unlabeled candidate signals
These flagged terms were not found in the FDA label text and do not match an artifact pattern. They are the pairs that would merit a structured assessment (temporality, dose-response, biological plausibility, consistency across databases, trial or cohort evidence). The screen has not done that; string-matching misses label wording, and a strong PRR can still be stimulated reporting, co-medication, or the disease itself.
- Palmar-plantar erythrodysaesthesia syndrome — n=1,439, PRR 119.1 (also seen in trial arm)
- Colon cancer metastatic — n=78, PRR 92.7 (also seen in trial arm)
- Palmoplantar keratoderma — n=27, PRR 70.7
- Food refusal — n=31, PRR 69.3
- Metastases to lung — n=329, PRR 53.3
- Hyperkeratosis — n=149, PRR 50.3
- Metastases to adrenals — n=22, PRR 44.5
- Colon cancer — n=344, PRR 42.8 (also seen in trial arm)
- Metastases to peritoneum — n=54, PRR 40.0
- Adenocarcinoma of colon — n=29, PRR 28.5
Want to assess one of these properly? The runbook describes the Bradford Hill / trial-evidence workflow used on the assessment page, and handoff_top1000_signals.csv lists the strongest unassessed pairs across all drugs.
Common questions
What are the most reported side effects of Regorafenib?
In FDA FAERS, the most frequently co-reported reaction terms for Regorafenib are fatigue, palmar-plantar erythrodysaesthesia syndrome, diarrhoea, decreased appetite, asthenia, dysphonia. These are report counts, not rates: FAERS has no denominator, reporting is voluntary and uneven, and a term can be reported because of the illness being treated rather than the drug.
Does Regorafenib have an FDA boxed warning?
Yes. The current FDA label carries a boxed warning: HEPATOTOXICITY • Severe and sometimes fatal hepatotoxicity has occurred in clinical trials [see Warnings and Precautions ( 5.1 )] . • Monitor hepatic function prior to and during treatment [see Warnings and Precautions ( 5.1 )].
Do FAERS signals prove that Regorafenib causes these side effects?
No. A disproportionality signal (PRR, ROR) means a reaction is reported more often with this drug than with others in the database. That can reflect a real effect, but also the disease being treated, stimulated reporting after news or litigation, co-medications, or how reports are coded. Causality needs temporality, dose-response, biological plausibility, consistency across data sources and, ideally, trial or cohort evidence. This page screens each term against the FDA label and ClinicalTrials.gov results; it does not establish causation.
Sources & methods
- FDA label via openFDA (set ID 824f19c9-0546-4a8a-8d8f-c4055c04f7c7, effective 20260209; matched on
openfda.generic_name.exact:"REGORAFENIB") - Bayesian shrinkage measures computed offline over all 1,317,300 cached pairs: BCPNN information component (IC, with Norén closed-form IC025) and MGPS empirical-Bayes geometric mean (EBGM, EB05) with a two-component gamma prior fitted by maximum marginal likelihood (α₁=0.57, β₁=0.02, α₂=1.42, β₂=0.70, w=0.17); unstratified
- FAERS pair statistics from the OpenPV build of 2026-09-14 (openFDA
count=aggregation, fieldpatient.drug.openfda.generic_name.exact, 1,009 reaction terms, min 3 co-reports); PRR/ROR with 95% CI, chi-square with Yates correction - Serious-only and stratified counts (serious:1, patient.patientsex, primarysource.qualification) from openFDA count queries; serious-only PRR uses the drug serious report total and the term global serious total (N_serious=11,882,979); strata shown only when n ≥ 20
- Seriousness and sex counts from openFDA
count=serious,patient.patientsex,seriousnessdeath - ClinicalTrials.gov API v2 (query
REGORAFENIB, results-bearing studies sorted by enrollment)
Page generated 2026-10-08. Label and PubChem text are retrieved automatically and may lag the current label; always check the current prescribing information. OpenPV is a beta research tool of the Open Source Medicine Foundation.