Usage
Lapatinib is prescribed for the treatment of advanced or metastatic breast cancer that overexpresses human epidermal growth factor receptor 2 (HER2). It is used in patients who have already received prior therapy, including an anthracycline, a taxane, and trastuzumab. Lapatinib is also used in combination with letrozole for postmenopausal women with hormone receptor-positive and HER2-positive metastatic breast cancer.
It is classified as a kinase inhibitor, specifically a tyrosine kinase inhibitor.
Lapatinib works by blocking the intracellular tyrosine kinase domains of both epidermal growth factor receptor (EGFR) and HER2. This inhibits downstream signaling pathways involved in cell growth and proliferation, ultimately leading to decreased tumor growth.
Alternate Names
The International Nonproprietary Name (INN) is lapatinib. It is marketed under the brand name Tykerb (US) and Tyverb (Europe).
How It Works
Pharmacodynamics: Lapatinib reversibly and selectively inhibits the intracellular tyrosine kinase domains of EGFR (HER1) and HER2 (ErbB2) receptors, which play a crucial role in signal transduction pathways regulating cell growth and proliferation. By blocking these receptors, lapatinib disrupts downstream signaling cascades, leading to inhibition of tumor cell growth and proliferation, and potentially inducing apoptosis (programmed cell death) in tumor cells.
Pharmacokinetics: Lapatinib is well absorbed orally, reaching peak plasma concentrations within 4 to 5 hours. Food intake can delay and reduce absorption. Lapatinib is extensively metabolized, primarily by CYP3A4 and CYP3A5, with minor contributions from CYP2C19 and CYP2C8. It is highly protein-bound (>99%). Lapatinib’s half-life is approximately 24 hours, reaching steady-state plasma concentrations within 6-7 days of daily dosing. The primary route of elimination is via feces, with a small amount (<2%) excreted unchanged in urine.
Dosage
Standard Dosage
Adults:
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With Capecitabine: 1250 mg (5 tablets) orally once daily continuously on days 1-21 of a repeating 21-day cycle, in combination with capecitabine 2000 mg/m²/day (in two divided doses approximately 12 hours apart) on days 1-14 of the same 21-day cycle.
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With Letrozole: 1500 mg (6 tablets) orally once daily continuously, in combination with letrozole 2.5 mg orally once daily.
Children:
The safety and efficacy of lapatinib in children have not been established.
Special Cases:
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Elderly Patients: No dosage adjustment is generally required, although closer monitoring is recommended due to potential increased sensitivity to side effects.
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Patients with Renal Impairment: No dose adjustment is typically necessary as renal elimination is minimal.
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Patients with Hepatic Dysfunction:
- Mild to moderate impairment (Child-Pugh A or B): No dosage adjustment necessary.
- Severe impairment (Child-Pugh C): Dose reduction should be considered; 750 mg/day with capecitabine, and 1000 mg/day with letrozole.
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Patients with Comorbid Conditions: Close monitoring and dose adjustment might be necessary for patients with cardiac conditions, particularly those with risk factors for QT prolongation.
Clinical Use Cases
Lapatinib’s clinical use is specifically for advanced or metastatic breast cancer, not for the scenarios listed (Intubation, Surgical Procedures, Mechanical Ventilation, Intensive Care Unit (ICU) Use, Emergency Situations).
Dosage Adjustments
Dosage adjustments may be necessary for patients with severe hepatic impairment, experiencing certain side effects (e.g., diarrhea, cardiac toxicity), or taking medications that interact with lapatinib’s metabolism (CYP3A4 inhibitors or inducers).
Side Effects
Common Side Effects
Diarrhea, palmar-plantar erythrodysesthesia (hand-foot syndrome), nausea, rash, vomiting, fatigue, dry skin, and difficulty sleeping.
Rare but Serious Side Effects
Decreased left ventricular ejection fraction (LVEF), hepatotoxicity, interstitial lung disease/pneumonitis, QT prolongation, severe diarrhea, and hypersensitivity reactions.
Long-Term Effects
Potential long-term effects are not fully characterized but may include cardiac dysfunction and pulmonary complications.
Adverse Drug Reactions (ADR)
Severe diarrhea requiring hospitalization, hepatotoxicity indicated by abnormal liver function tests, and cardiac events, such as decreased LVEF or QT prolongation, are significant ADRs requiring immediate intervention.
Contraindications
Known severe hypersensitivity (e.g., anaphylaxis) to lapatinib or its components.
Drug Interactions
Lapatinib is primarily metabolized by CYP3A4 and is also a substrate and inhibitor of CYP2C8 and several transport proteins (P-glycoprotein, BCRP, and OATP1B1).
- CYP3A4 inhibitors: Concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir) can increase lapatinib exposure and should be avoided or require dose reduction. Grapefruit juice should be avoided.
- CYP3A4 inducers: Strong CYP3A4 inducers (e.g., rifampin, phenytoin, carbamazepine, St. John’s Wort) can decrease lapatinib exposure and should be avoided or require dose titration.
- QT prolonging drugs: Use with caution with drugs known to prolong the QT interval.
Pregnancy and Breastfeeding
Lapatinib is classified as Pregnancy Category D. It can cause fetal harm. Effective contraception is required during treatment and for at least one week after the last dose for both female and male patients. Breastfeeding is not recommended during treatment and for at least one week after the last dose.
Drug Profile Summary
- Mechanism of Action: Reversible and selective inhibitor of EGFR/HER2 tyrosine kinases.
- Side Effects: Diarrhea, hand-foot syndrome, nausea, rash, vomiting, fatigue; rarely LVEF decrease, hepatotoxicity, pneumonitis, QT prolongation.
- Contraindications: Hypersensitivity to lapatinib.
- Drug Interactions: CYP3A4 inhibitors and inducers, QT prolonging drugs.
- Pregnancy & Breastfeeding: Contraindicated in pregnancy; not recommended while breastfeeding.
- Dosage: 1250 mg/day with capecitabine, 1500 mg/day with letrozole. Adjustments needed for hepatic impairment and drug interactions.
- Monitoring Parameters: LVEF, liver function tests, electrolytes (potassium, magnesium), ECG for QT interval.
Popular Combinations
- Lapatinib + Capecitabine
- Lapatinib + Letrozole (in postmenopausal women)
- Lapatinib + Trastuzumab (investigational)
Precautions
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General Precautions: Assess LVEF before and during treatment. Monitor liver function regularly. Correct electrolyte imbalances before starting therapy. Monitor for signs of pulmonary toxicity.
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Specific Populations: Avoid in pregnancy. Do not breastfeed while taking lapatinib. Use with caution in elderly patients.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Lapatinib?
A: 1250 mg once daily with capecitabine, or 1500 mg once daily with letrozole. Dosage adjustments are necessary for patients with severe hepatic impairment and concomitant use of strong CYP3A4 inhibitors or inducers.
Q2: What is the mechanism of action of Lapatinib?
A: Lapatinib reversibly inhibits the tyrosine kinase activity of EGFR and HER2, thereby disrupting downstream signaling and leading to reduced tumor cell growth.
Q3: What are the most common side effects of Lapatinib?
A: Diarrhea, hand-foot syndrome, nausea, vomiting, rash, and fatigue.
A: Decreased left ventricular ejection fraction (LVEF), hepatotoxicity, interstitial lung disease/pneumonitis, and severe diarrhea.
Q5: What are the contraindications for using Lapatinib?
A: Known hypersensitivity to lapatinib or any of its components.
Q6: What are the key drug interactions to be aware of with Lapatinib?
A: Strong CYP3A4 inhibitors and inducers can significantly alter lapatinib exposure. Concomitant use of QT-prolonging drugs requires caution.
Q7: Can Lapatinib be used during pregnancy or breastfeeding?
A: Lapatinib is contraindicated during pregnancy and should not be used while breastfeeding.
Q8: What are the important monitoring parameters for patients on Lapatinib?
A: Left ventricular ejection fraction (LVEF), liver function tests, electrolytes (potassium and magnesium), and ECG for QT interval should be monitored.
Q9: How should Lapatinib be administered?
A: Lapatinib tablets should be swallowed whole, once daily, at least one hour before or one hour after a meal. Do not crush or split the tablets.
Q10: What should be done if a dose of Lapatinib is missed?
A: Do not double the next dose. Resume with the next scheduled daily dose.
