TYKERB
Clinical safety rating: caution
Comprehensive clinical and safety monograph for TYKERB (TYKERB).
Tykerb (lapatinib) is a reversible tyrosine kinase inhibitor that selectively inhibits the intracellular tyrosine kinase domains of epidermal growth factor receptor (EGFR/ErbB1) and human epidermal growth factor receptor 2 (HER2/ErbB2). It prevents receptor autophosphorylation and downstream signaling pathways, including MAPK and PI3K/Akt, leading to inhibition of tumor cell proliferation and angiogenesis.
| Metabolism | Lapatinib is extensively metabolized primarily by CYP3A4 and to a lesser extent by CYP3A5. It is also a substrate of P-glycoprotein (P-gp). |
| Excretion | Primarily hepatic metabolism (CYP3A4), with fecal excretion of metabolites (~92%) and renal excretion of unchanged drug (<2%) |
| Half-life | Terminal elimination half-life is approximately 24 hours following continuous daily dosing, supporting once-daily administration |
| Protein binding | >99% bound primarily to albumin and alpha-1 acid glycoprotein |
| Volume of Distribution | Volume of distribution is approximately 2.0 L/kg, indicating extensive tissue distribution |
| Bioavailability | Oral bioavailability is not well defined (estimated ~2-10% due to extensive first-pass metabolism), but therapeutic plasma concentrations are achieved with 1250 mg daily |
| Onset of Action | Oral: Clinical effect (tumor response) typically observed after 2-4 weeks of continuous therapy |
| Duration of Action | Therapeutic effect persists with continuous daily dosing; dosing interruptions may reduce efficacy; duration limited by toxicity or disease progression |
| Molecular Weight | 943.5 Da |
| Action Class | Tyrosine kinase inhibitors |
| Brand Substitutes | Lapahope 250mg Tablet, Herduo Tablet, Bretolap Tablet, Libset Tablet |
Oral, 1250 mg (5 tablets of 250 mg) once daily continuously in combination with capecitabine (2000 mg/m2/day orally in 2 divided doses for 14 days every 21 days) for treatment of advanced HER2-positive breast cancer. For use in combination with letrozole: 1500 mg (6 tablets) once daily continuously with letrozole 2.5 mg once daily.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment is recommended for mild to moderate renal impairment (CrCl >= 30 mL/min). Insufficient data for severe renal impairment (CrCl < 30 mL/min) or dialysis; use with caution. |
| Liver impairment | Child-Pugh Class A: No dose adjustment. Child-Pugh Class B: Dose reduction to 1000 mg (4 tablets) once daily. Child-Pugh Class C: Not recommended due to lack of data. |
| Pediatric use | Safety and effectiveness in pediatric patients have not been established; no recommended pediatric dosing. |
| Geriatric use | No specific dose adjustment required; clinical studies included similar exposure in elderly vs younger adults. Monitor renal and hepatic function. |
| 1st trimester | Avoid. Animal studies show embryotoxicity and fetotoxicity at exposures lower than human therapeutic levels. Human data limited; risk of fetal harm cannot be excluded. |
| 2nd trimester | Avoid. Potential for oligohydramnios, fetal renal impairment, and fetal loss due to inhibition of EGFR (ErbB1) and HER2 (ErbB2) signaling, which are critical for fetal development. |
| 3rd trimester | Avoid. Continued risk of fetal renal impairment and oligohydramnios. Should not be used in pregnancy unless benefit outweighs risk. |
Clinical note
Comprehensive clinical and safety monograph for TYKERB (TYKERB).
| Placental transfer | Lapatinib crosses the placenta in animal models, with fetal concentrations approximately 1-10% of maternal plasma levels. Human data not available, but likely due to molecular weight. |
| Breastfeeding | Excreted into human breast milk in animal studies. No human data available. Due to potential for serious adverse reactions in nursing infants, women should not breastfeed during treatment and for at least 3 weeks after the last dose. |
■ FDA Black Box Warning
Hepatotoxicity: Lapatinib has been associated with severe and fatal hepatotoxicity. Monitor liver function tests before and during treatment. Discontinue if severe changes in liver function occur. Not recommended in patients with severe hepatic impairment.
| Serious Effects |
Hypersensitivity to lapatinib or any excipientPregnancy (unless benefit clearly outweighs risk)
| Precautions | Hepatotoxicity: Monitor LFTs periodically; discontinue if severe hepatotoxicity., Decreased left ventricular ejection fraction (LVEF): Assess LVEF before and during treatment; withhold or discontinue if significant decline., Diarrhea: Severe diarrhea may occur; manage with antidiarrheals and intravenous fluids., Interstitial lung disease/pneumonitis: Monitor for pulmonary symptoms; discontinue if confirmed., QT prolongation: Monitor electrolytes and ECG; avoid in patients with hypokalemia, hypomagnesemia, or on QT-prolonging drugs., Fetal harm: Can cause fetal harm; advise contraception. |
| Food/Dietary | TYKERB should be taken on an empty stomach (at least 1 hour before or 1 hour after a meal). Avoid grapefruit and grapefruit juice as they inhibit CYP3A4 and may increase lapatinib levels. High-fat meals significantly increase lapatinib absorption and should be avoided. |
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| Lactation Rating | L5 (Contraindicated) |
| Teratogenic Risk | Pregnancy Category D. There is positive evidence of human fetal risk. Based on its mechanism of action (EGFR/HER2 inhibitor) and animal studies showing embryotoxicity and teratogenicity, TYKERB (lapatinib) should not be used during pregnancy. If used, first trimester exposure carries highest risk of major malformations; second and third trimester exposure may cause fetal growth restriction and oligohydramnios. |
| Fetal Monitoring | Monitor liver function tests (ALT, AST, bilirubin) monthly. Assess cardiac function (LVEF) at baseline and periodically during therapy. In pregnancy, perform fetal ultrasound for growth and amniotic fluid volume. Monitor maternal blood pressure and renal function. |
| Fertility Effects | May impair fertility. In animal studies, lapatinib caused testicular degeneration and reduced spermatogenesis. Effects on human fertility are unknown; however, based on animal data, both male and female fertility may be compromised. Advise patients about fertility preservation options before treatment. |
| Clinical Pearls | TYKERB (lapatinib) is a dual tyrosine kinase inhibitor of EGFR and HER2. It is used in combination with capecitabine for HER2-positive metastatic breast cancer after prior anthracycline, taxane, and trastuzumab therapy. Monitor left ventricular ejection fraction (LVEF) before and during treatment due to risk of cardiomyopathy. Hepatotoxicity requires baseline and periodic liver function tests. Diarrhea is common; manage with loperamide and hydration. Avoid strong CYP3A4 inhibitors and inducers; adjust dose accordingly. QT prolongation possible; monitor electrolytes and ECG if risk factors present. |
| Patient Advice | Take TYKERB on an empty stomach, at least 1 hour before or 1 hour after a meal. · Do not crush or split tablets; swallow whole with water. · Avoid grapefruit and grapefruit juice during treatment. · Report any signs of heart problems: shortness of breath, swelling, rapid weight gain. · Report any signs of liver issues: yellow skin/eyes, dark urine, abdominal pain. · Use effective non-hormonal contraception during and for 2 weeks after treatment. · Do not breastfeed while taking TYKERB and for 2 weeks after last dose. · Take missed dose if remembered within 12 hours; otherwise skip and resume next day. |