HYRNUO
Clinical safety rating: caution
Comprehensive clinical and safety monograph for HYRNUO (HYRNUO).
(E)-2-(((2-(6,7-dimethoxyquinazolin-4-ylamino)phenyl)thio)methyl)-4-methyl-2H-pyrazolo[1,5-a]pyrazin-3(5H)-one is a selective inhibitor of fibroblast growth factor receptor (FGFR) 1, 2, 3, and 4. It binds to the ATP-binding site of FGFR kinases, blocking downstream signaling pathways, including RAS-MAPK-ERK and PI3K-AKT, thereby inhibiting tumor cell proliferation and angiogenesis.
| Metabolism | Primarily metabolized by CYP2C9 and CYP3A4; minor contributions from CYP2C19 and CYP2D6. Forms active metabolites M1 (desmethyl) and M2 (N-oxide). |
| Excretion | Renal excretion of unchanged drug accounts for approximately 60% of elimination; biliary/fecal excretion accounts for 30% (including metabolites), with the remainder eliminated via minor metabolic pathways. |
| Half-life | Terminal elimination half-life is 12-15 hours in adults with normal renal function, supporting twice-daily dosing. |
| Protein binding | 98% bound primarily to albumin. |
| Volume of Distribution | 0.3-0.4 L/kg, indicating distribution into total body water with limited tissue binding. |
| Bioavailability | Oral: 85% (fasting); 60% with high-fat meal (reduced absorption). |
| Onset of Action | Oral: 30-60 minutes; intravenous: 5-10 minutes. |
| Duration of Action | 12-24 hours depending on dose and renal function; may be prolonged in renal impairment. |
100 mg orally once daily
| Dosage form | TABLET |
| Renal impairment | GFR ≥60 mL/min: No adjustment. GFR 30-59: 50 mg once daily. GFR <30: Not recommended. |
| Liver impairment | Child-Pugh A: No adjustment. Child-Pugh B: 50 mg once daily. Child-Pugh C: Not recommended. |
| Pediatric use | Not established for patients under 18 years. |
| Geriatric use | No specific dose adjustment; monitor renal function and consider age-related decline. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for HYRNUO (HYRNUO).
| Breastfeeding | No data available on excretion into breast milk or effects on the breastfed infant. M/P ratio unknown. Due to potential for serious adverse reactions, breastfeeding is not recommended during treatment and for at least 2 weeks after the last dose. |
| Teratogenic Risk | HYRNUO is contraindicated in pregnancy due to demonstrated teratogenicity in animal studies and limited human data. First trimester exposure is associated with major congenital malformations including neural tube defects and cardiovascular anomalies. Second and third trimester exposure may cause fetal growth restriction and oligohydramnios. |
■ FDA Black Box Warning
None
| Serious Effects |
["Concurrent use with strong CYP2C9 or CYP3A4 inducers","Pregnancy and lactation"]
| Precautions | ["Retinal pigment epithelial detachment (RPED) and other visual disturbances: conduct ophthalmic examinations prior to and during treatment","Hyperphosphatemia: monitor serum phosphate levels and manage with phosphate-lowering therapy or dose modification","Non-healing corneal ulcers: requires ophthalmologic evaluation","Embryo-fetal toxicity: can cause fetal harm; advise effective contraception"] |
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| Fetal Monitoring | Monitor for fetal growth restriction via serial ultrasound. Assess amniotic fluid volume. In neonates, monitor for signs of toxicity (e.g., respiratory depression, hypotonia). |
| Fertility Effects | HYRNUO may impair fertility in females based on animal studies showing disruption of estrous cycles and reduced ovarian function. Reversal of effects after discontinuation has not been established. In males, no data available. |