lapatinib

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

Distribution: Unknown.

Protein Binding: >99%.

Metabolism/Excretion: Extensively metabolized by, mostly by CYP3A4 and CYP3A5 enzyme systems; <2% excreted by kidneys.

Half-life: 24 hr.

Contraind./Precautions ⬆ ⬇

Contraindicated in:

Hypersensitivity
↓left ventricular ejection fraction (Grade 2 or greater)
OB: Pregnancy (may cause fetal harm)
Lactation: Lactation.

Use Cautiously in:

Concurrent use of CYP3A4 inhibitors including ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, and voriconazole should be avoided (if necessary, ↓ lapatinib dose)
Concurrent use of CYP3A4 inducers including dexamathasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John's wort should be avoided (if necessary, ↑ lapatinib dose
Severe hepatic impairment (dose ↓ recommended for Child-Pugh Class C)
Known QTc interval prolongation or co-existing 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: ↓left ventricular ejection fraction, QT interval prolongation.

Derm: ERYTHEMA MULTIFORM, STEVENS-JOHNSON SYNDROME, TOXIC EPIDERMAL NECROLYSIS, palmar-plantar erythrodysesthesia, rash, dry skin, nail disorders.

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

Hemat: neutropenia.

MS: back pain, extremity pain.

Neuro: fatigue, insomnia.

Resp: dyspnea, interstitial lung disease, pneumonitis.

Interactions ⬆ ⬇

Drug-Drug:

Lapatinib inhibits CYP3A4, CYP28, and P-glycoprotein; concurrent use of drugs which are substrates for these enzymes should be undertaken with caution.
May ↑ effects of midazolam, paclitaxel, and digoxin.
Strong CYP3A4 inhibitors, including ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, 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:

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

Drug-Food:

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

Route/Dosage ⬆ ⬇

HER2–Positive Metastatic Breast Cancer

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

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.

Implementation ⬆ ⬇

Correct hypokalemia and hypomagnesemia prior to therapy.
PO: Administer tablets once daily at least 1 hr before or 1 hr after a meal for 21 days. Do not divide daily dose.

US Brand Names ⬆ ⬇

Classifications ⬆ ⬇

Therapeutic Classification: antineoplastics

Pharmacologic Classification: enzyme inhibitors, kinase inhibitors

Availability ⬆ ⬇

(Generic available)

Tablets: 250 mg;

Time/Action Profile ⬆ ⬇

(blood levels)

ROUTE	ONSET	PEAK	DURATION
PO	unknown	4 hr	24 hr

Assessment ⬆ ⬇

Evaluate left ventricular ejection fraction (LVEF) prior to therapy to determine if within institution's normal limits. Continue to monitor periodically during therapy to ensure it does not fall below limits. If LVEF decreases to Grade 2 or greater discontinue therapy. If returns to normal and patient is asymptomatic after 2 wk, may restart therapy at a reduced 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. Treat with antidiarrheals (loperamide) after first loose stool. If diarrhea is severe, treat with oral or intravenous fluids, antibiotics (fluoroquinolones) especially if diarrhea persists >24 hrs or accompanied by fever; may require interruption or discontinuation of therapy. If accompanied by moderate to severe abdominal cramping, nausea or vomiting, decreased performance status, fever, sepsis, neutropenia, frank bleeding, or dehydration, interrupt therapy and reintroduce at lower dose (from 1,250 mg/day to 1,000 mg/day or from 1,500 mg/day to 1,250 mg/day) when diarrhea <Grade 1. If Grade 4 diarrhea occurs, discontinue therapy.
Monitor ECG prior to and periodically during therapy to monitor QT. Monitor patients who have or may develop prolongation of QTc (hypokalemia, hypomagnesemia, congenital long QT syndrome, patients taking antiarrhythmics or other medication with known risk for QT prolongation/torsades de pointes, and cumulative high-dose anthracycline therapy) during therapy.
Monitor for respiratory status for symptoms of interstitial lung disease and pneumonitis (dyspnea, cough); may require discontinuation of therapy.
Monitor for signs and symptoms of skin reactions (progressive skin rash often with blisters or mucosal lesions). Discontinue lapatinib if erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis are suspected.

Lab Test Considerations:

Verify negative pregnancy test before starting therapy.Monitor liver function tests prior to initiation and every 4–6 wk during therapy and as clinically indicated. Discontinue and do not restart lapatinib if patients experience severe changes in liver function tests.
- Monitor serum potassium and magnesium prior to and periodically during therapy. Correct hypokalemia or hypomagnesemia before starting therapy.

Patient/Family Teaching ⬆ ⬇

Instruct patient to take lapatinib as directed and to review the Patient Information Sheet prior to therapy and with each refill for new information. If a dose is missed take as soon remembered that day. If a day is missed, skip the dose; do not double doses. Caution patient not to share this medication with others, even with same condition; may be harmful.
Advise patient to avoid drinking grapefruit juice or eating grapefruit during therapy.
Advise patient to report signs or decreased LVEF (shortness of breath, palpitations, fatigue) and skin rash to health care professional promptly.
Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care professional before taking any new 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 professional if severe.
Rep: May cause fetal harm. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during and for 1 wk after last dose and to avoid breastfeeding for 1 wk after last dose. Advise patient to notify healthcare professional if pregnancy is planned or suspected.

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Pronunciation ⬇

Indications ⬆ ⬇

Action ⬆ ⬇

Pharmacokinetics ⬆ ⬇