lapatinib

High Alert

Advanced or metastatic breast cancer with tumor overexpression of the human epidermal receptor type 2 (HER2) and past therapy with an anthracycline, a taxane, and trastuzumab (in combination with capecitabine).
Hormone-receptor positive metastatic breast cancer that overexpresses HER2 in postmenopausal women for whom hormonal therapy is indicated (in combination with letrozole).

Action ⬆ ⬇

Acts as an inhibitor of intracellular tyrosine kinase, affecting epidermal growth factor (EGFR, ErbB1) and HER2 (ErbB2). Inhibits the growth of ErbB-driven tumors. Effect is additive with capecitabine.

Therapeutic effects:

Decreased/slowed spread of metastatic breast cancer.

Pharmacokinetics ⬆ ⬇

Absorption: Incompletely and variably absorbed following oral administration; levels ↑ by food.

Distribution: Unknown.

Protein Binding: >99%.

Metabolism/Excretion: Extensively metabolized by the liver via the CYP3A4 and CYP3A5 isoenzymes; <2% excreted by kidneys.

Half-Life: 24 hr.

Time/Action Profile ⬆ ⬇

(plasma concentrations)

ROUTE	ONSET	PEAK	DURATION
PO	unknown	4 hr	24 hr

Contraind./Precautions ⬆ ⬇

Contraindicated in:

Hypersensitivity;
↓left ventricular ejection fraction (LVEF) (Grade ≥2);
OB: Pregnancy;
Lactation: Lactation.

Use Cautiously in:

Severe hepatic impairment (dose ↓ recommended);
Known QTc interval prolongation or coexisting risk factors for QTc interval prolongation including hypokalemia, hypomagnesemia, concurrent antiarrhythmics, or medications that are known to prolong the QTc interval;
Rep: Women of reproductive potential and men with female partners of reproductive potential;
Pedi: Safety and effectiveness not established in children;
Geri: Older adults may be more sensitive to effects.

Adv. Reactions/Side Effects ⬆ ⬇

CV: ↓LVEF, QT interval prolongation

Derm: palmar-plantar erythrodysesthesia, rash, dry skin, ERYTHEMA MULTIFORM (EM), nail disorders, STEVENS-JOHNSON SYNDROME (SJS), TOXIC EPIDERMAL NECROLYSIS (TEN)

GI: nausea, vomiting, ↑liver enzymes, DIARRHEA, dyspepsia, HEPATOTOXICITY, stomatitis

Hemat: neutropenia

MS: pain

Neuro: fatigue, insomnia

Resp: dyspnea, INTERSTITIAL LUNG DISEASE (ILD)

Interactions ⬆ ⬇

Drug-drug:

May ↑ effects of midazolam, paclitaxel, and digoxin.
Strong CYP3A4 inhibitors, including ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, nelfinavir, ritonavir, and voriconazole, may ↑ levels and risk of toxicity; avoid concurrent use; if concurrent use unavoidable, ↓ lapatinib dose.
Strong CYP3A4 inducers, including dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, and phenobarbital, may ↓ levels and effectiveness; avoid concurrent use; if concurrent use unavoidable, ↑ lapatinib dose.

Drug-Natural Products:

St. John's wort may ↓ levels and effectiveness; avoid concurrent use; if concurrent use unavoidable, ↑ lapatinib dose.

Drug-Food:

Grapefruit juice may ↑ levels and risk of toxicity; avoid concurrent use.

Route/Dosage ⬆ ⬇

HER2-Positive Metastatic Breast Cancer (Past Therapy with an Anthracycline, a Taxane and Trastuzumab)

PO (Adults ): 1250 mg once daily on Days 1–21 of 21-day cycle; continue until disease progression or unacceptable toxicity; Concurrent use of strong CYP3A4 inhibitors: 500 mg once daily on Days 1–21 of 21-day cycle; continue until disease progression or unacceptable toxicity; Concurrent use of strong CYP3A4 inducers: Gradually titrate dose from 1250 mg once daily up to 4500 mg once daily as tolerated; administer dose on Days 1–21 of 21-day cycle and continue until disease progression or unacceptable toxicity.

Hepatic Impairment

PO (Adults ): Severe hepatic impairment: 750 mg once daily on Days 1–21 of 21-day cycle; continue until disease progression or unacceptable toxicity.

Hormone Receptor-Positive, HER2-Positive Metastatic Breast Cancer (Hormone Therapy Indicated)

PO (Adults ): 1500 mg once daily on Days 1–21 of 21-day cycle; continue until disease progression or unacceptable toxicity; Concurrent use of strong CYP3A4 inhibitors: 500 mg once daily on Days 1–21 of 21-day cycle; continue until disease progression or unacceptable toxicity; Concurrent use of strong CYP3A4 inducers: Gradually titrate dose from 1500 mg once daily up to 5500 mg once daily as tolerated; administer dose on Days 1–21 of 21-day cycle and continue until disease progression or unacceptable toxicity.

Hepatic Impairment

PO (Adults ): Severe hepatic impairment: 1000 mg once daily on Days 1–21 of 21-day cycle; continue until disease progression or unacceptable toxicity.

Availability ⬆ ⬇

(Generic available)

Tablets: 250 mg

Assessment ⬆ ⬇

Evaluate LVEF before and periodically during therapy. If LVEF ↓ to Grade ≥2, discontinue therapy. If asymptomatic and LVEF returns to normal after 2 wk, resume therapy at ↓ dose of 1000 mg/day (with capecitabine) or 1250 mg/day (with letrozole).
Monitor for diarrhea; usually occurs within first 6 days of therapy and lasts 4–5 days. If Grade 3 or Grades 1–2 diarrhea with complicating factors occurs, hold therapy until Grade ≤1; may resume at ↓ dose from 1500 mg/day to 1250 mg/day or from 1250 mg/day to 1000 mg/day. If Grade 4 diarrhea occurs, permanently discontinue lapatinib.
Monitor ECG during therapy to assess QTc interval in patients who have or may develop QTc interval prolongation (hypokalemia, hypomagnesemia, congenital long QT syndrome, antiarrhythmics, cumulative high-dose anthracyclines).
Monitor respiratory status. If Grade ≥3 ILD or pneumonitis occurs, discontinue lapatinib.
Monitor for signs and symptoms of skin reactions (progressive rash, blisters, mucosal lesions). If EM, SJS, or TEN suspected, discontinue lapatinib.

Lab Test Considerations:

Verify negative pregnancy test before starting therapy.
Monitor liver enzymes before starting therapy, every 4–6 wk during therapy, and then as clinically indicated. If severe hepatic toxicity occurs during therapy, permanently discontinue lapatinib. Hepatotoxicity may occur days to several months after initiation of treatment.
- Monitor serum potassium and magnesium before starting and periodically during therapy.

Implementation ⬆ ⬇

Correct hypokalemia and hypomagnesemia before starting therapy.
PO: Administer ≥1 hr before or 1 hr after a meal. Do not divide daily dose.

Patient/Family Teaching ⬆ ⬇

Explain purpose and side effects of medication. Advise patient to read Patient Information before starting therapy. If a dose is missed, take as soon remembered that day. If a day is missed, omit; do not double doses.
Advise patient to avoid drinking grapefruit juice or eating grapefruit during therapy.
Advise patient to notify health care provider if symptoms of ↓ LVEF (shortness of breath, palpitations, fatigue) or rash occur.
Advise patient to notify health care provider of all Rx or OTC medications, vitamins, or herbal products being taken and to consult health care provider before taking other medications, especially St. John's wort.
Advise patient that lapatinib may cause diarrhea, which may become severe. Instruct patient in how to prevent and manage diarrhea and to notify health care provider if severe.
Rep: May cause fetal harm. Advise women of reproductive potential and men with female partners of reproductive potential to use effective contraception during therapy and for 1 wk after last dose and to avoid breastfeeding for 1 wk after last dose. Advise patient to notify health care provider if pregnancy is planned or suspected.

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Pronunciation ⬇

Classifications ⬆ ⬇

Indications ⬆ ⬇