lapatinib

Action

Lapatinib is a 4-anilinoquinazoline kinase inhibitor of the intracellular tyrosine kinase domains of both Epidermal Growth Factor Receptor (EGFR [ErbB1]) and of Human Epidermal Receptor Type 2 (HER2 [ErbB2]) receptors (estimated K_i^app values of 3nM and 13nM, respectively) with a dissociation half-life of ≥300 minutes. Lapatinib inhibits ErbB-driven tumor cell growth in vitro and in various animal models.

Availability

Tablets: 250 mg

Indications and dosages

➣ Advanced or metastatic breast cancer in patients whose tumors over-express HER2 and who have received prior therapy, including an anthracycline, a taxane, and trastuzumab

Adults: 1,250 mg P.O. daily on days 1 to 21 continuously in combination with capecitabine on days 1 to 14 in repeating 21-day cycle

➣ Postmenopausal women with hormone receptor-positive metastatic breast cancer that overexpresses HER2 receptor, for whom hormonal therapy is indicated

Adults: 1,500 mg P.O. daily continuously in combination with letrozole

Dosage adjustment

• Severe hepatic impairment

• Cardiac toxicity

• Grade 2 or greater NCI CTCAE toxicity

• Concurrent use of strong CYP3A4 inducers/inhibitors

Contraindications

• Hypersensitivity to drug or its components

Precautions

Use cautiously in:

• severe hepatic impairment (Child-Pugh Class C)

• decreased left ventricular ejection fraction (LVEF), patients who have or may develop prolongation of QT interval (including patients with hypokalemia, hypomagnesemia, congenital long QT syndrome; patients taking antiarrhythmics or other products leading to QT-interval prolongation; and cumulative high-dose anthracycline therapy)

• Grade 2 or greater NCI CTCAE toxicity

• interstitial lung disease and pneumonitis, diarrhea

• strong CYP3A4 inducers including St. John's wort, strong CYP3A4 inhibitors (avoid use)

• concurrent use of CYP3A4, CYP2C8, and P-glycoprotein (PgP) substrates

• grapefruit, grapefruit products (avoid use)

• pregnant or breastfeeding patients

• children (safety and efficacy not established).

Administration

• Administer at least 1 hour before or 1 hour after a meal, but give capecitabine with food or within 30 minutes after food. Don't give with grapefruit or grapefruit juice. Don't divide daily doses.

• Correct hypokalemia or hypomagnesemia before lapatinib administration.

• Assess serum digoxin concentration before starting drug. If digoxin serum concentration is greater than 1.2 ng/ml, reduce digoxin dosage as prescribed.

• Evaluate LVEF before starting lapatinib treatment to ensure patient has baseline LVEF within institution's normal limits. Be aware that drug should be discontinued in patients with decreased LVEF that is Grade 2 or greater NCI CTCAE toxicity and in patients with LVEF that drops below institution's lower limit of normal. Lapatinib in combination with capecitabine may be restarted at reduced dosage of 1,000 mg/day and in combination with letrozole may be restarted at reduced dosage of 1,250 mg/day after minimum of 2 weeks if LVEF recovers to normal and patient is asymptomatic.

☞ Obtain liver function test results (transaminases, bilirubin, and ALP) before starting treatment. Consider reducing dosage in patients with severe hepatic impairment from 1,250 mg/day to 750 mg/day (HER2-positive metastatic breast cancer indication) or from 1,500 mg/day to 1,000 mg/day (hormone receptor-positive, HER2-positive breast cancer indication) to adjust area under the curve (AUC) to normal range. In patients who develop severe hepatotoxicity during therapy, discontinue drug and don't restart.

☞ Discontinue drug in patients who experience pulmonary signs and symptoms indicative of interstitial lung disease/pneumonitis that are Grade 3 or greater (NCI CTCAE).

• If patient must receive a strong CYP3A4 inhibitor concurrently, consider reducing lapatinib dosage to 500 mg/day. This dosage is predicted to adjust lapatinib AUC to the range observed without inhibitors. If the strong inhibitor is discontinued, a washout period of approximately 1 week should be allowed before lapatinib dosage is adjusted upward to indicated dosage.

• If patient must receive a strong CYP3A4 inducer concurrently, consider titrating lapatanib dosage gradually from 1,250 mg/day up to 4,500 mg/day (HER2-positive metastatic breast cancer indication) or from 1,500 mg/day up to 5,500 mg/day (hormone receptor-positive, HER2-positive breast cancer indication) based on tolerability. This dosage is predicted to adjust lapatinib AUC to the range observed without inducers. If the strong inducer is discontinued, lapatinib dosage should be reduced to indicated dosage.

• Be aware that severe diarrhea may require administration of oral or I.V. electrolytes and fluids and interruption or discontinuation of therapy.

Adverse reactions

CNS: headache, fatigue, insomnia, asthenia

CV: prolonged QT interval

EENT: epistaxis

GI: nausea, vomiting, diarrhea, anorexia, dyspepsia, stomatitis

Hepatic: hepatotoxicity

Musculoskeletal: extremity pain, back pain

Respiratory: dyspnea, interstitial lung disease, pneumonitis

Skin: rash, dry skin, alopecia, pruritus, nail disorder, palmar-plantar erythrodysesthesia

Other: mucosal inflammation

Interactions

Drug-drug. CYP3A4 substrates (midazolam), CYP2C8 and PgP substrates (paclitaxel), PgP substrates (digoxin): increased exposure of these drugs

Strong CYP3A4 inducers (such as carbamazepine, dexamethasone, phenobarbital, phenytoin, rifabutin, rifampin, rifapentin): decreased lapatinib systemic exposure

Strong CYP3A4 inhibitors (such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole): increased lapatinib systemic exposure and half-life

Drug-diagnostic tests. ALT, AST, total bilirubin: increased levels

Hemoglobin, neutrophils, platelets: decreased levels

Drug-food. Any food: increased lapatinib systemic exposure

Grapefruit: increased lapatinib plasma concentration

High-fat meal: increased AUC value

Drug-herbs. St. John's Wort: decreased lapatinib systemic exposure

Patient monitoring

• Monitor CBC with differential and hepatic function tests closely.

• Monitor serum digoxin concentration throughout coadministration with lapatinib.

☞ Continue to monitor patient for prolonged QT interval, interstitial lung disease, and pneumonitis.

Patient teaching

• Tell patient to take lapatinib at least 1 hour before or 1 hour after a meal but if capecitabine is also prescribed to take capecitabine with food or within 30 minutes after food. Advise patient not to take lapatinib with grapefruit or grapefruit juice or divide daily doses.

☞ Instruct patient to immediately report tiredness, dizziness, shortness of breath, pounding or racing heartbeats, itching, yellowing of skin or eyes, dark urine, right upper abdominal pain or discomfort, or red, painful hands and feet.

• Teach patient how to prevent and manage diarrhea, which may be severe; instruct patient to inform prescriber of changes in bowel pattern or severe diarrhea.

• Instruct patient to tell prescriber about all drugs he's taking, because some drugs have potential for serious drug interactions and shouldn't be taken with lapatinib.

• Advise patient not to use St. John's wort or other herbal supplements without consulting prescriber.

• Advise female patient of childbearing age to avoid becoming pregnant during therapy.

• Advise breastfeeding patient that she should decide whether to discontinue breastfeeding or discontinue drug, taking into account importance of drug for her treatment.

• As appropriate, review all other significant and life-threatening adverse reactions and interactions, especially those related to the drugs, tests, foods, and herbs mentioned above.