NERATINIB MALEATE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for NERATINIB MALEATE (NERATINIB MALEATE).
Irreversible inhibitor of human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR) tyrosine kinases, leading to inhibition of downstream signaling pathways and tumor cell proliferation.
| Metabolism | Primarily metabolized by CYP3A4; also a substrate of P-glycoprotein (P-gp). |
| Excretion | Primarily fecal (approximately 97% of the administered dose recovered in feces as unchanged drug and metabolites); renal excretion is minimal (approximately 1% of the dose recovered in urine). |
| Half-life | Terminal half-life is approximately 7–17 hours (mean 12 hours); this supports twice-daily dosing. Steady-state is achieved within 7 days. |
| Protein binding | Highly protein bound (≥99%) primarily to albumin and α1-acid glycoprotein. |
| Volume of Distribution | Apparent volume of distribution (Vd/F) is approximately 6433 L (≈92 L/kg for a 70 kg adult), indicating extensive tissue distribution. |
| Bioavailability | Oral bioavailability is approximately 48% (range 24–79%) under fasting conditions; administration with food increases exposure (Cmax by 1.7-fold, AUC by 2.2-fold) and is recommended to be taken with food. |
| Onset of Action | Oral: Time to steady-state concentration is 7 days; time to tumor response is variable (weeks to months). |
| Duration of Action | Duration of clinical effect is continuous with daily dosing; efficacy is maintained until disease progression or unacceptable toxicity. |
240 mg (6 tablets of 40 mg) orally once daily with food, continuously until disease progression or unacceptable toxicity.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (CrCl ≥30 mL/min). Severe renal impairment (CrCl <30 mL/min) or end-stage renal disease: no specific recommendation; use with caution. |
| Liver impairment | Child-Pugh Class A: 240 mg once daily. Child-Pugh Class B: reduce to 120 mg once daily. Child-Pugh Class C: not recommended. |
| Pediatric use | Safety and efficacy in pediatric patients (<18 years) have not been established; no specific dosing recommendations. |
| Geriatric use | No specific dose adjustment required for elderly patients (≥65 years) based on age alone. Monitor for increased adverse reactions (e.g., diarrhea, hepatotoxicity) due to potential age-related changes in organ function. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for NERATINIB MALEATE (NERATINIB MALEATE).
| Breastfeeding | Not recommended during breastfeeding. No human data on M/P ratio; however, neratinib is highly protein-bound and excreted in rat milk. Potential for serious adverse reactions in breastfed infants (e.g., diarrhea, hepatotoxicity). Discontinue nursing or drug based on maternal need. |
| Teratogenic Risk | First trimester: Embryotoxic and teratogenic in animal studies, causing fetal malformations (e.g., skeletal abnormalities) and reduced fetal weight. Second/third trimester: Risk of oligohydramnios and fetal renal impairment due to inhibition of EGFR/HER2 pathways; may cause fetal growth restriction and potential neonatal respiratory distress. |
■ FDA Black Box Warning
None
| Serious Effects |
["None known"]
| Precautions | ["Hepatotoxicity: Elevations in liver enzymes and bilirubin; monitor liver function tests.","Diarrhea: Severe and potentially dehydrating; manage with antidiarrheals and fluid replacement.","Left ventricular dysfunction: Assess left ventricular ejection fraction (LVEF) before and during treatment.","Embryo-fetal toxicity: Can cause fetal harm; advise effective contraception."] |
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| Fetal Monitoring | Monitor maternal liver function tests (AST, ALT, bilirubin) every 1-2 weeks during pregnancy; assess renal function and electrolytes. Fetal ultrasound for growth, amniotic fluid volume, and anatomy (especially renal and skeletal) every 4-6 weeks. Neonatal monitoring for electrolyte disturbances and diarrhea. |
| Fertility Effects | In animal studies, neratinib caused impaired fertility in females (reduced ovarian weights, disrupted estrous cycles) and males (decreased sperm motility and count). Human fertility implications unknown; advise pre-treatment fertility preservation counseling. |