Lapatinib

Pronunciation: la-PA-ti-nib
Class: Tyrosine kinase inhibitor

Trade Names

Tykerb
- Tablets 250 mg

Pharmacology

Inhibits both epidermal growth factor receptor and human epidermal growth receptor 2–driven tumor cell growth in vitro and in animal models.

Slideshow: Flashback: FDA Drug Approvals 2013

Pharmacokinetics

Absorption

Oral absorption is incomplete and variable. C max occurs approximately 4 h after administration, and steady state is reached in 6 to 7 days. Following a dose of 1,250 mg daily, the C max was 2.43 mcg/mL. The AUC is 2-fold higher with divided daily doses compared with single-dose administration. When taken with a low- or high-fat meal, AUC is increased 3- and 4-fold, respectively.

Distribution

Binding to albumin and alpha-1 acid glycoprotein is more than 99%.

Metabolism

Primarily metabolized by CYP3A4 and CYP3A5, with minor metabolism by CYP2C19 and CYP2C8.

Elimination

The half-life is 24 h with repeated dosing. Elimination is primarily via CYP3A4/5 metabolism, with negligible (less than 2%) renal excretion. Fecal elimination accounts for approximately 27%.

Special Populations

Renal Function Impairment

Because less than 2% of an administered dose is eliminated by the kidneys, renal impairment is unlikely to affect the pharmacokinetics.

Hepatic Function Impairment

AUC increased after a single dose by approximately 14% and 63% in patients with moderate and severe hepatic impairment, respectively. Use with caution and consider dose reduction in patients with severe hepatic impairment.

Elderly

Studies of the effects of age on the pharmacokinetics have not been performed.

Children

Studies of the effects of age on the pharmacokinetics have not been performed.

Gender

Studies of the effects of gender on the pharmacokinetics have not been performed.

Race

Studies of the effects of race on the pharmacokinetics have not been performed.

Indications and Usage

In combination with capecitabine for the treatment of advanced or metastatic breast cancer in patients whose tumors overexpress human epidermal growth factor receptor type 2 (HER2), and who have received prior therapy, including an anthracycline, a taxane, and trastuzumab; in combination with letrozole for the treatment of postmenopausal women with hormone receptor-positive metastatic breast cancer that overexpresses HER2 for whom hormonal therapy is indicated.

Contraindications

Standard considerations.

Dosage and Administration

HER2-positive metastatic breast cancer
Adults

PO 1,250 mg once daily on days 1 to 21 continuously with capecitabine 2,000 mg/m 2 /day on days 1 to 14 in a repeating 21-day cycle. Discontinuation or interruption of dosing may be considered if the patient develops at least grade 2 National Cancer Institute Common Terminology Criteria for Adverse Events. Restart treatment at 1,250 mg/day when toxicity improves to grade 1 or less. If toxicity recurs, restart at 1,000 mg/day.

Hormone receptor–positive, HER2-positive metastatic breast cancer
Adults

PO 1,500 mg once daily continuously in combination with letrozole 2.5 mg once daily. Discontinuation or interruption of dosing may be considered if patient develops toxicity or grade 2 or higher. Restart treatment at 1,250 mg/day.

Cardiac Events
Adults

PO Discontinue in patients with a decreased left ventricular ejection fraction (LVEF) that is grade 2 or more, and in patients with an LVEF that drops below the lower limit of normal. Restart at a reduced dosage of 1,000 mg/day (HER2-positive metastatic breast cancer) or 1,250 mg/day (hormone receptor–positive, HER2-positive breast cancer) after a minimum of 2 wk if LVEF recovers to normal and the patient is asymptomatic.

Coadministration With a Strong CYP3A4 Inducer
Adults

PO Consider gradually increasing dosage from 1,250 to 4,500 mg/day (HER2-positive metastatic breast cancer) or from 1,500 to 5,500 mg/day (hormone receptor–positive, HER2-positive breast cancer) based on tolerability. When the inducer is discontinued, reduce the dose to the indicated dose.

Coadministration With a Strong CYP3A4 Inhibitor
Adults

PO Consider dosage reduction to 500 mg/day. When the inhibitor is discontinued, allow 1 wk before adjusting dose upward to the indicated dose.

Hepatic Function Impairment
Adults

PO In patients with severe hepatic function impairment, consider dosage reduction to 750 mg/day (HER2-positive metastatic breast cancer) or to 1,000 mg/day (hormone receptor–positive, HER2-positive breast cancer).

General Advice

  • Lapatinib should be taken once daily at least 1 h before or after a meal.
  • The dose of lapatinib should be once daily; dividing the dose is not recommended.

Storage/Stability

Store at 59° to 86°F.

Drug Interactions

Antiarrhythmic agents or other drugs that prolong the QTc interval

Because lapatinib may prolong the QTc interval, use with caution in patients receiving medications that produce QT prolongation.

CYP3A4 inducers (eg, carbamazepine, dexamethasone, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, St. John's wort)

Lapatinib plasma concentrations may be reduced, decreasing efficacy. A lapatinib dose increase may be needed. Once the inducer is discontinued, immediately reduce lapatinib to the labeled dose.

CYP3A4 inhibitors (eg, atazanavir, clarithromycin, grapefruit juice, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole)

Lapatinib plasma concentrations may be elevated, increasing the risk of toxicity. Lapatinib dose reduction may be needed. Once the inhibitor is discontinued, wait 1 wk, then titrate lapatinib up to the labeled dose.

Modafinil, nevirapine

Lapatinib plasma concentrations and efficacy may be decreased. An increase in the lapatinib dose may be needed. Monitor the patient and adjust the lapatinib dose as indicated.

P-glycoprotein inhibitors (eg, quinidine)

Lapatinib plasma concentrations may be elevated, increasing the risk of toxicity. If coadministration cannot be avoided, carefully monitor patients during concomitant therapy and adjust lapatinib dose as needed.

P-glycoprotein substrates (eg, amiodarone, cyclosporine, digoxin)

Because lapatinib inhibits P-glycoprotein (P-gp), increased concentrations of drugs that are substrates for P-gp may occur. Use with caution. Carefully monitor patients during concomitant therapy and adjust dose of P-gp substrate as needed.

Paclitaxel

Paclitaxel exposure may be increased. Monitor the patient and adjust the paclitaxel dose as needed.

Adverse Reactions

The following adverse reactions were reported with combined use of lapatinib and capecitabine or lapatinib and letrozole.

Cardiovascular

Decreased LVEF (more than 57%).

CNS

Fatigue (20%); headache (14%); asthenia (12%); insomnia (10%).

Dermatologic

Palmar-plantar erythrodysesthesia (53%); rash (44%); dry skin (13%); pruritis (12%); nail disorder (11%).

GI

Diarrhea (65%); nausea (44%); vomiting (26%); stomatitis (14%); anorexia, dyspepsia (11%).

Lab Tests

Abnormal hemoglobin (56%); abnormal AST (53%); abnormal ALT (46%); abnormal total bilirubin (45%); abnormal neutrophils (22%); abnormal platelets (18%).

Musculoskeletal

Pain in extremities (12%); back pain (11%).

Respiratory

Dyspnea (12%); epistaxis (11%); interstitial lung disease, pneumonitis.

Miscellaneous

Mucosal inflammation (15%).

Precautions

Warnings

Hepatotoxicity, severe and life-threatening, has occurred. The cause of death is uncertain.


Monitor

Monitor for pulmonary symptoms indicative of interstitial lung disease or pneumonitis; evaluate LVEF throughout use; monitor LFTs before initiation of treatment, every 4 to 6 wk during treatment, and as clinically indicated thereafter.


Pregnancy

Category D .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

No differences in safety and efficacy have been observed between subjects 65 yr of age and older compared with younger subjects.

Renal Function

Because less than 2% of an administered dose is eliminated by the kidneys, renal impairment is not likely to affect the pharmacokinetics.

Hepatic Function

Lapatinib dose reduction may be needed in patients with severe hepatic impairment.

CV effects

LVEF may be reduced, with the majority occurring within the first 9 wk of treatment. Use with caution.

Diarrhea

Diarrhea, including severe diarrhea, has been reported. Management with antidiarrheal agents is important. Severe cases may require oral or IV electrolytes and fluids, as well as withholding or discontinuing therapy.

Interstitial lung disease

Interstitial lung disease and pneumonitis have been reported. Discontinue therapy in patients experiencing pulmonary symptoms that are grade 3 or higher.

QT prolongation

QT prolongation has been measured by automated machine-read evaluation of ECG. Administer with caution in patients who have or may develop prolongation of the QTC interval, including patients taking antiarrhythmic drugs.

Overdosage

Symptoms

Toxicity may be increased; grade 3 diarrhea and vomiting have been reported.

Patient Information

  • Advise patient to read the patient information before using product the first time and with each refill.
  • Instruct patient to inform health care provider if fatigue, palpitations, severe diarrhea, or shortness of breath occurs.
  • Instruct patient to take lapatinib at least 1 h before or after a meal.
  • Advise patients who have heart or liver problems to inform health care provider of their medical condition.
  • Advise patient not to eat or drink grapefruit products while taking lapatinib.
  • Instruct patients to take the dose of lapatinib once daily and not divide the daily dose.

Copyright © 2009 Wolters Kluwer Health.

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