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. |
| Molecular Weight | 943.5 |
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 | Avoid use in first trimester; animal studies have shown teratogenicity and adverse effects on embryofetal development. Human data are limited but caution is warranted. |
| 2nd trimester | Avoid use in second trimester; may cause fetal harm based on animal data and mechanism of action (EGFR/ErbB2 inhibition). |
| 3rd trimester | Avoid use in third trimester; potential for oligohydramnios and fetal renal impairment due to EGFR inhibition in fetal kidney development. |
Clinical note
Comprehensive clinical and safety monograph for LAPATINIB DITOSYLATE (LAPATINIB DITOSYLATE).
| Placental transfer | Lapatinib crosses the placenta in animal studies and is expected to cross the human placenta based on its molecular weight and lipophilicity. Human data are limited; however, placental transfer is likely. |
| Breastfeeding | Lapatinib is excreted in human milk at low concentrations; however, due to the potential for serious adverse reactions in nursing infants, breastfeeding is not recommended during treatment and for at least 1 week after the last dose. |
■ FDA Black Box Warning
Hepatotoxicity has been observed in clinical trials and postmarketing experience; monitoring of liver function tests is recommended.
| Serious Effects |
Severe hepatic impairment (Child-Pugh class C)Known hypersensitivity to lapatinib or any component of the formulationConcomitant use with strong CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin) if dose adjustment not feasible
| 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 |
| Food/Dietary | Lapatinib absorption is significantly increased by food, especially high-fat meals, which can lead to unpredictable systemic exposure and toxicity. Take on an empty stomach, at least 1 hour before or 1 hour after food. Grapefruit and grapefruit juice inhibit CYP3A4 and may increase lapatinib levels; avoid concurrent use. |
Loading safety data…
| Lactation Rating | L5 (Avoid) or 'Avoid' |
| 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. |
| 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. |
| Clinical Pearls | Lapatinib ditosylate is a dual tyrosine kinase inhibitor (EGFR/HER2) used in HER2-positive metastatic breast cancer. It should be taken at least 1 hour before or 1 hour after a meal to ensure consistent absorption. Concomitant use with strong CYP3A4 inhibitors (e.g., ketoconazole) increases lapatinib exposure, requiring dose reduction to 500 mg daily; strong inducers (e.g., rifampin) decrease exposure, requiring cautious dose escalation. Monitor left ventricular ejection fraction (LVEF) due to risk of cardiac dysfunction, and be alert for hepatotoxicity (check LFTs at baseline and periodically). Lapatinib can cause severe diarrhea; manage with antidiarrheals and hydration. Avoid use with drugs that prolong QT interval. |
| Patient Advice | Take lapatinib on an empty stomach, at least 1 hour before or 1 hour after a meal. · Swallow tablets whole; do not crush or chew. · Avoid grapefruit and grapefruit juice during treatment. · Report symptoms of heart problems: shortness of breath, swelling of ankles/legs, rapid heartbeat. · Notify your doctor if you experience severe or persistent diarrhea, nausea, vomiting, or abdominal pain. · Use effective contraception during treatment and for at least 1 week after stopping. · Do not breastfeed while taking lapatinib and for at least 1 week after the last dose. · Have regular blood tests to monitor liver function and heart function. |