LAPATINIB DITOSYLATE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for LAPATINIB DITOSYLATE (LAPATINIB DITOSYLATE).
Reversible tyrosine kinase inhibitor that inhibits ErbB-1 (EGFR) and ErbB-2 (HER2) by binding to the ATP-binding pocket, preventing receptor autophosphorylation and downstream signaling.
| Metabolism | Primarily metabolized by CYP3A4 and to a lesser extent by CYP2C8 and CYP2C19; forms several inactive metabolites. |
| Excretion | Fecal (approximately 87% as metabolites, with 3% as parent drug); renal (approximately 3% as metabolites). |
| Half-life | Terminal elimination half-life is 14–24 hours; after repeated dosing, effective half-life is ~24 hours clinically. |
| Protein binding | >99% bound to albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | 2200–3500 L (approximately 31–50 L/kg), indicating extensive tissue distribution. |
| Bioavailability | Not determined (oral tablet); absorption is variable and incomplete (peak plasma concentrations at 4–6 hours). |
| Onset of Action | Not applicable for immediate clinical effect; requires daily dosing for weeks to achieve therapeutic response. |
| Duration of Action | Duration of action corresponds to dosing interval (once daily); pharmacodynamic effects persist for 24 hours based on trough levels. |
Lapatinib ditosylate 1250 mg orally once daily on days 1-21 continuously, plus capecitabine 2000 mg/m2 orally once daily in 2 divided doses on days 1-14 of a 21-day cycle. Alternatively, 1500 mg orally once daily with letrozole 2.5 mg orally once daily continuously.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (CrCl ≥30 mL/min). Insufficient data for severe renal impairment (CrCl <30 mL/min) or hemodialysis; use with caution. |
| Liver impairment | Child-Pugh Class A: No dose adjustment. Child-Pugh Class B: Reduce dose to 750 mg orally once daily. Child-Pugh Class C: Reduce dose to oral once daily (exact dose not established; consider 500 mg orally once daily and escalate as tolerated). |
| Pediatric use | Safety and efficacy not established in pediatric patients; no standard dosing available. |
| Geriatric use | No specific dose adjustment required; but elderly patients may have decreased hepatic and renal function, monitor closely for adverse effects such as diarrhea and hepatotoxicity. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for LAPATINIB DITOSYLATE (LAPATINIB DITOSYLATE).
| Breastfeeding | No human data on M/P ratio. Lapatinib is present in rat milk. Due to potential for severe adverse reactions in breastfed infants, advise women not to breastfeed during treatment and for at least 1 week after last dose. |
| Teratogenic Risk | Pregnancy Category D. First trimester: Risk of oligohydramnios, fetal renal impairment, and developmental toxicity based on animal studies and human case reports. Second and third trimesters: Oligohydramnios, fetal growth restriction, and potential for irreversible fetal renal dysfunction. Avoid use in pregnancy unless benefit outweighs risk. |
■ FDA Black Box Warning
Hepatotoxicity has been observed in clinical trials and postmarketing experience; monitoring of liver function tests is recommended.
| Serious Effects |
["Hypersensitivity to lapatinib or any component of the formulation"]
| Precautions | ["Hepatotoxicity: Monitor liver function tests before and during therapy","Decreased left ventricular ejection fraction: Assess LVEF before and during therapy","Interstitial lung disease: Monitor for pulmonary symptoms","Severe diarrhea: Manage with antidiarrheals and hydration","QT prolongation: Caution in patients with risk factors"] |
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| Fetal Monitoring | Monitor maternal renal function, blood pressure, and fetal ultrasound for amniotic fluid volume and fetal growth every 2-4 weeks during pregnancy. Assess for signs of oligohydramnios. Monitor infant for renal dysfunction postpartum. |
| Fertility Effects | May impair fertility in females based on animal studies showing ovarian dysfunction and altered estrous cycles. No data in males. Reversibility unknown. |