Summary: labeled contraindications, warnings, and adverse reactions

The prescribing information lists no contraindications and three warnings and precautions: ocular toxicity, hyperphosphatemia and soft tissue mineralization, and embryo-fetal toxicity. Among 385 participants in the REFOCUS safety population (232 with cholangiocarcinoma and 153 with other solid tumors), retinal pigment epithelial detachment occurred in 31% (grade 3 in 1.8%), with a median time to onset of 57 days, blurred vision in 18%, dry eye in 38%, corneal toxicity or keratitis in 11%, and hyperphosphatemia in 21%, with a median time to onset of 15 days and one dose interruption (0.3%). Ophthalmological examination including optical coherence tomography of the macula is required before treatment, every 2 months for the first 13 months, and every 4 months thereafter. Among the 116 participants with cholangiocarcinoma, serious adverse reactions occurred in 32% and one participant died of hemorrhage; the most frequent adverse reactions were nail toxicity (89%, grade 3 or 4 in 12%), palmar-plantar erythrodysesthesia syndrome (82%, grade 3 or 4 in 33%), stomatitis (80%, grade 3 or 4 in 12%), and alopecia (66%). Treatment-related adverse events led to dose reduction in 75.9%, dose interruption in 82.8%, and discontinuation in 4.3% of participants in the ASCO Gastrointestinal Cancers Symposium 2026 report, and the prescribing information reports permanent discontinuation for an adverse reaction in 5%, dosage interruption in 88%, and dose reduction in 81%. The FDA required a postmarketing randomized trial to characterize severe stomatitis, palmar-plantar erythrodysesthesia syndrome, retinal pigment epithelial detachment, and nail toxicities at 70 mg once daily compared with a lower dosage.

Contraindications and boxed warning

“Contraindications: None.” (opens the source at this quote in a new tab)

“The prescribing information includes warnings and precautions for ocular toxicity, hyperphosphatemia and soft tissue mineralization, and embryo-fetal toxicity.” (opens the source at this quote in a new tab)

Ocular toxicity: retinal pigment epithelial detachment

“LYRFIGTU can cause RPED, which may cause symptoms such as blurred vision.” (opens the prescribing information at this quote)
“The median time to onset of RPED was 57 days (range 4 to 221).” (opens the prescribing information at this quote)
“Perform a comprehensive ophthalmological examination, including OCT of the macula, prior to initiation of therapy, every 2 months for the first 13 months, and every 4 months thereafter. For onset of visual symptoms, obtain ophthalmologic evaluation urgently, with follow-up every 3 weeks until resolution or discontinuation of LYRFIGTU.” (opens the prescribing information at this quote)

“Among 385 patients who received LYRFIGTU, RPED occurred in 31% of patients, including Grade 3 events in 1.8%. The median time to first onset was 57 days. RPED led to dose interruption in 15% of patients and dose reduction in 10%.” (opens the source at this quote in a new tab)

Ocular toxicity: blurred vision, dry eye, and corneal toxicity

“Among 385 patients who received LYRFIGTU, blurred vision occurred in 18% of patients with Grade 3 events in 1.3% of patients.” (opens the source at this quote in a new tab)
“Dry eye occurred in 38% of patients. Treat patients with ocular demulcents as needed.” (opens the source at this quote in a new tab)
“Among 385 patients who received LYRFIGTU, corneal toxicity/keratitis occurred in 11% of patients. Treat patients with ocular demulcents as needed.” (opens the source at this quote in a new tab)

Hyperphosphatemia and soft tissue mineralization

“LYRFIGTU can cause hyperphosphatemia leading to soft tissue mineralization, calcinosis, nonuremic calciphylaxis, and vascular calcification.” (opens the prescribing information at this quote)
“The median time to onset of hyperphosphatemia was 15 days (range 6-194).” (opens the prescribing information at this quote)
“Monitor patients for hyperphosphatemia throughout treatment.” (opens the prescribing information at this quote)

“Hyperphosphatemia occurred in 21% of patients. The median time to onset was 15 days. Hyperphosphatemia led to dose interruption in one (0.3%) patient and no permanent discontinuation.” (opens the source at this quote in a new tab)

Embryo-fetal toxicity

“Based on findings from animal studies and its mechanism of action, LYRFIGTU can cause fetal harm or loss of pregnancy when administered to a pregnant woman.” (opens the prescribing information at this quote)
“Advise females of reproductive potential to use effective contraception during treatment with LYRFIGTU and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with LYRFIGTU and for 3 months after the last dose” (opens the prescribing information at this quote)

Safety population in the prescribing information

“The safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to LYRFIGTU 70 mg orally once daily in 385 patients with multiple advanced solid tumors evaluated in REFOCUS including 232 patients with cholangiocarcinoma and 153 patients with other advanced solid tumors.” (opens the prescribing information at this quote)

Serious adverse reactions, fatal events, and discontinuations in cholangiocarcinoma

“Serious adverse reactions occurred in 32% of patients. Serious adverse reactions reported in ≥2% of patients were infection (6%), pneumonia (3.4%), fatigue (2.6%), and hemorrhage (2.6%). A fatal adverse reaction of hemorrhage occurred in one patient.” (opens the source at this quote in a new tab)

“Adverse reactions requiring permanent discontinuation of LYRFIGTU included palmar-plantar erythrodysesthesia syndrome (3 patients), stomatitis, anaphylactic reaction, and infection (1 patient each).” (opens the prescribing information at this quote)

“Most common Grade ≥3 treatment-related adverse events (TRAEs) were palmar-plantar erythrodysesthesia (32.8%) and stomatitis (12.1%). TRAEs led to dose reduction, dose interruption, and treatment discontinuation were observed in 75.9%, 82.8%, and 4.3%, respectively.” (opens the source at this quote in a new tab)

Permanent discontinuation, dosage interruption, and dose reduction for adverse reactions in cholangiocarcinoma

“Permanent discontinuation due to an adverse reaction occurred in 5% of patients who received LYRFIGTU.” (opens the prescribing information at this quote)
“Dosage interruptions due to an adverse reaction occurred in 88% of patients who received LYRFIGTU 70 mg once daily. Adverse reactions requiring dose interruption in ≥5% of patients included palmar-plantar erythrodysesthesia syndrome, nail toxicity, stomatitis, retinal pigment epithelial detachment, rash, infection, fatigue, blurred vision, corneal toxicity, blood bilirubin increased, alanine transferase increased, and pyrexia.” (opens the prescribing information at this quote)
“Dose reductions due to an adverse reaction occurred in 81% of patients who received LYRFIGTU. Adverse reactions requiring dose reductions in ≥2% of patients included palmar-plantar erythrodysesthesia syndrome, nail toxicity, stomatitis, retinal pigment epithelial detachment, rash, blurred vision, alanine aminotransferase increased, fatigue, aspartate aminotransferase increased, corneal toxicity and hyponatremia.” (opens the prescribing information at this quote)

Adverse reactions in 15% or more of participants with cholangiocarcinoma (N=116)

Adverse reaction	All grades (%)	Grade 3 or 4 (%)
Nail toxicity	“89”	“12”
Palmar-plantar erythrodysaesthesia syndrome	“82”	“33”
Stomatitis	“80”	“12”
Alopecia	“66”	“0”
Dry eye	“53”	“0”
Dry mouth	“50”	“0”
Fatigue	“43”	“3.4”
Dysgeusia	“39”	“0.9”
Retinal pigment epithelial detachment	“38”	“1.7”
Constipation	“37”	“0.9”
Dry skin	“37”	“0”
Infection	“34”	“8”
Rash	“34”	“5”
Abdominal pain	“28”	“3.4”
Blurred vision	“22”	“0.9”
Diarrhea	“22”	“0.9”
Hemorrhage	“22”	“2.6”
Nausea	“21”	“1.7”
Decreased appetite	“20”	“0”

Laboratory abnormalities worsening from baseline in participants with cholangiocarcinoma

Laboratory abnormality	All grades (%)	Grade 3 or 4 (%)
Phosphate increased	“75”	“0”
Alanine aminotransferase increased	“53”	“7”
Creatinine increased	“52”	“0.9”
Sodium decreased	“49”	“20”
Hemoglobin decreased	“49”	“8”
Lymphocytes decreased	“47”	“7”
Blood bilirubin increased	“45”	“5”
Aspartate aminotransferase increased	“42”	“5”
Platelets decreased	“39”	“3.4”
Glucose increased	“37”	“5”

Postmarketing required trial on severe dermatologic, mucosal, ocular, and nail toxicities

“known serious risks of severe stomatitis, palmar-plantar erythrodysesthesia syndrome, retinal pigment epithelial detachment, and nail toxicities; and to assess a signal of a serious risk of increased drug toxicity when lirafugratinib is used concomitantly with sensitive P-gp and BCRP substrates.” (opens the source at this quote in a new tab)

Lirafugratinib (Lyrfigtu)

Contraindications/Warnings/Precautions/Adverse effects

Warnings and precautions