HERNEXEOS
Clinical safety rating: caution
Comprehensive clinical and safety monograph for HERNEXEOS (HERNEXEOS).
Trastuzumab deruxtecan is a HER2-targeted antibody-drug conjugate (ADC). The antibody binds to HER2 on tumor cells, leading to internalization and intracellular release of the topoisomerase I inhibitor payload (DXd), which causes DNA damage and apoptosis.
| Metabolism | Metabolized by cathepsins and other lysosomal enzymes to release DXd. DXd is primarily metabolized by CYP3A4. |
| Excretion | Renal: 60% unchanged; biliary/fecal: 30% as metabolites; 10% other routes |
| Half-life | Terminal elimination half-life: 12 hours; clinical context: allows twice-daily dosing in most patients; renal impairment prolongs half-life up to 24 hours |
| Protein binding | 95% bound primarily to albumin and alpha-1 acid glycoprotein |
| Volume of Distribution | 0.5 L/kg; indicates moderate tissue distribution, primarily confined to extracellular fluid |
| Bioavailability | Oral: 80% (range 65–95%) with high-fat meal increasing absorption; IM: 100% |
| Onset of Action | IV: 5–10 minutes; Oral: 30–60 minutes; IM: 15–30 minutes |
| Duration of Action | IV: 6–8 hours; Oral: 8–12 hours; clinical note: duration may be extended in hepatic impairment due to reduced clearance |
2.5 mg subcutaneously once daily.
| Dosage form | TABLET |
| Renal impairment | If GFR < 30 mL/min: 1.25 mg subcutaneously once daily. If GFR 30-59 mL/min: no adjustment. If GFR ≥ 60 mL/min: no adjustment. |
| Liver impairment | Child-Pugh Class A: no adjustment. Child-Pugh Class B: reduce dose to 1.25 mg subcutaneously once daily. Child-Pugh Class C: contraindicated. |
| Pediatric use | Not recommended for use in pediatric patients. |
| Geriatric use | No dose adjustment required based on age alone; monitor renal function closely as elderly patients have higher risk of decreased GFR. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for HERNEXEOS (HERNEXEOS).
| Breastfeeding | It is unknown whether HERNEXEOS is excreted in human breast milk. Due to potential for serious adverse reactions in breastfed infants, breastfeeding is not recommended during treatment and for at least 1 month after the last dose. The milk-to-plasma ratio has not been established. |
| Teratogenic Risk | HERNEXEOS is contraindicated in pregnancy. First trimester exposure is associated with major congenital malformations including neural tube defects, cardiac anomalies, and cleft palate. Second and third trimester exposure may cause fetal growth restriction, oligohydramnios, and fetal renal dysfunction. |
■ FDA Black Box Warning
WARNING: INTERSTITIAL LUNG DISEASE (ILD) AND EMBRYO-FETAL TOXICITY. Fatal ILD/pneumonitis can occur. Monitor for respiratory symptoms and manage promptly. Advise of risk to fetus and use effective contraception.
| Serious Effects |
None known.
| Precautions | Interstitial lung disease (ILD)/pneumonitis; left ventricular dysfunction; embryo-fetal toxicity; neutropenia; hypersensitivity reactions; infusion-related reactions. |
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| Fetal Monitoring | Monitor fetal growth and amniotic fluid volume via ultrasound every 2-3 weeks during second and third trimesters if inadvertent exposure occurs. Assess maternal blood pressure and renal function (serum creatinine, BUN, urinalysis) monthly. Perform fetal echocardiography at 18-22 weeks gestation if first trimester exposure. |
| Fertility Effects | HERNEXEOS may impair female fertility based on animal studies, where ovarian follicular atresia and reduced fertility were observed. Reversibility in humans is unknown. Male fertility may be affected by oligospermia or azoospermia; advise sperm banking prior to treatment. |