Lapatinib (Monograph)

Brand name: Tykerb
Drug class: Antineoplastic Agents
- Kinase Inhibitors
- Receptor Tyrosine Kinase Inhibitors
- Tyrosine Kinase Inhibitors
- HER2 Dimerization Inhibitors
- Epidermal Growth Factor Receptor Inhibitors
- EGFR Inhibitors
- EGF Receptor Inhibitors
Chemical name: N-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furanyl]-4-quinazolinamine bis(4-methylbenzenesulfonate) monohydrate
Molecular formula: C₂₉H₂₆ClFN₄O₄S•(S₇H₈O₃S)₂ • H₂O
CAS number: 388082-78-8

Medically reviewed by Drugs.com on Oct 4, 2024. Written by ASHP.

Warning

Potentially severe or fatal hepatotoxicity observed. Causality of the deaths uncertain.

Introduction

Antineoplastic agent; inhibitor of HER1 and HER2 tyrosine kinases.

Uses for Lapatinib

Breast Cancer

In combination with letrozole for treatment of hormone receptor-positive metastatic breast cancer that overexpresses the human epidermal receptor type 2 (HER2) protein in postmenopausal women who are candidates for hormonal therapy. In patients with hormone receptor-positive, HER2-positive breast cancer, guidelines generally recommend HER2-targeted therapy plus chemotherapy, endocrine therapy plus trastuzumab or lapatinib (in selected cases), or endocrine therapy alone (in selected cases).

In combination with capecitabine for treatment of advanced or metastatic breast cancer in patients whose tumors overexpress HER2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab. In clinical practice guidelines, lapatinib in combination with trastuzumab or lapatinib in combination with capecitabine is recommended among several potential third-line treatment options in patients with advanced, HER2-positive breast cancer who have trialed 2 previous anti-HER2 regimens.

Lapatinib Dosage and Administration

General

Pretreatment Screening

Measure liver function tests, including serum concentrations of transaminases, bilirubin, and alkaline phosphatase, prior to initiation of lapatinib.
Monitor serum electrolytes and correct hypokalemia or hypomagnesemia prior to treatment with lapatinib.
Evaluate left ventricular ejection fraction (LVEF) prior to initiation of lapatinib.
Perform pregnancy testing in females of reproductive potential prior to starting lapatinib.

Patient Monitoring

Monitor liver function tests, including serum concentrations of transaminases, bilirubin, and alkaline phosphatase, every 4–6 weeks during therapy, and as clinically indicated.
Monitor for pulmonary symptoms of interstitial lung disease or pneumonitis during treatment with lapatinib.
Evaluate LVEF during treatment with lapatinib to ensure that it does not fall below the institution’s normal limits.

Administration

Oral Administration

Administer orally, at least 1 hour before or 1 hour after meals.

Do not divide daily dose.

If dose is missed, do not double the next dose.

Dosage

Available as lapatinib ditosylate monohydrate; dosage expressed in terms of lapatinib.

Adults

Breast Cancer

Hormone Receptor-Positive, HER2-Positive Metastatic Breast Cancer

Oral

Lapatinib/letrozole: Lapatinib 1.5 g once daily, given continuously in combination with letrozole 2.5 mg once daily. In clinical trial evaluating this regimen, treatment was continued until disease progression occurred or patient withdrew from study.

Previously Treated HER2-Positive Advanced or Metastatic Breast Cancer

Oral

Lapatinib/capecitabine: Lapatinib 1.25 g once daily on days 1–21 in combination with capecitabine 2 g/m² daily on days 1–14 of each 21-day cycle. Continue treatment until disease progression or unacceptable toxicity occurs.

Dosage Modification for Toxicity

Oral

Adverse effects may require temporary interruption and/or dosage reduction or permanent discontinuance. Adjust dosage based on individual safety and tolerability. If dosage reduction is required, the dosage of lapatinib should be reduced as described in Table 1.

Table 1: Recommended Dosage Reduction for Lapatinib Toxicity1
Adverse Reaction	Recommended Dosage Reduction of Lapatinib when Used in Combination with Letrozole for Hormone Receptor-positive, HER2-positive Metastatic Breast Cancer	Recommended Dosage Reduction of Lapatinib when Used in Combination with Capecitabine for HER2-positive, Advanced or Metastatic Breast Cancer
Cardiac events	1.25 g once daily	1 g once daily
Diarrhea	1.25 g once daily in patients previously receiving 1.5 g once daily 1 g once daily in patients previously receiving 1.25 g once daily	1.25 g once daily in patients previously receiving 1.5 g once daily 1 g once daily in patients previously receiving 1.25 g once daily
Other toxicity	1.25 g once daily	1 g once daily

Table 2 indicates the recommended dosage modification (i.e., temporary interruption of therapy, dosage reduction, discontinuance of therapy) for adverse effects according to severity.

Severity is defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE)

Complicating features include moderate to severe abdominal cramping, nausea or vomiting of grade ≥2, decreased performance status, sepsis, fever, neutropenia, frank bleeding, or dehydration

Table 2. Dosage Modification for Lapatinib Toxicity. 1
Adverse Reaction and Severity	Modification
Cardiac Events
Grade ≥2 decreased LVEF or LVEF that decreases below institution’s lower limit of normal (LLN)	Discontinue lapatinib; may restart at a reduced dosage (see Table 1) after ≥2 weeks if LVEF returns to normal and the patient is asymptomatic
Diarrhea
Grade 3 or Grade 1–2 with complicating features	Withhold therapy; may restart at a reduced dosage (see Table 1) once diarrhea resolves to ≤grade 1
Grade 4	Permanently discontinue lapatinib
Interstitial Lung Disease/Pneumonitis
Grade ≥3	Discontinue lapatinib
Other Toxicity
Grade ≥2	Consider interruption or discontinuance of lapatinib May restart at the standard dosage of 1.25 or 1.5 g once daily when the toxicity improves to grade ≤1; If the toxicity recurs, restart lapatinib at a reduced dosage (see Table 1)

Dosage Modification for CYP3A4 Interactions

Oral

Lapatinib/letrozole: When used concomitantly with a potent CYP3A4 inhibitor, manufacturer recommends lapatinib 500 mg once daily. When used concomitantly with a potent CYP3A4 inducer, manufacturer recommends gradually titrating lapatinib dosage from 1.5 g once daily up to 5.5 g once daily, based on tolerability.

Lapatinib/capecitabine: When used concomitantly with a potent CYP3A4 inhibitor, manufacturer recommends lapatinib 500 mg once daily. When used concomitantly with a potent CYP3A4 inducer, manufacturer recommends gradually titrating lapatinib dosage from 1.25 g once daily up to 4.5 g once daily, based on tolerability.

Special Populations

Hepatic Impairment

Breast Cancer

Lapatinib/Letrozole for Hormone Receptor-Positive, HER2-Positive Metastatic Breast Cancer

Oral

Severe impairment (Child-Pugh class C): Reduce lapatinib dosage; manufacturer suggests 1 g once daily; however, no clinical data available.

Lapatinib/Capecitabine for Previously Treated HER2-Positive Advanced or Metastatic Breast Cancer

Oral

Severe impairment (Child-Pugh class C): Reduce lapatinib dosage; manufacturer suggests 750 mg once daily; however, no clinical data available.

Renal Impairment

No specific dosage recommendations at this time.

Geriatric Patients

No specific dosage recommendations at this time.

Cautions for Lapatinib

Contraindications

Known hypersensitivity (e.g., anaphylaxis) to lapatinib or any ingredient in the formulation.

Warnings/Precautions

Warnings

Hepatic Toxicity

Possible severe or fatal hepatotoxicity (ALT or AST >3 times ULN, total bilirubin >2 times ULN). Causality of reported deaths uncertain.

Monitor liver function tests (i.e., transaminases, bilirubin, and alkaline phosphatase) before initiation of therapy, every 4–6 weeks during therapy, and as clinically indicated. Hepatotoxicity may occur days to several months after initiation of treatment. If severe changes in liver function occur, permanently discontinue lapatinib.

Pharmacogenomics of Lapatinib-induced Hepatotoxicity

Patients with human leukocyte antigen alleles DQA1*02:01 and DRB1*07:01 may have higher risk of hepatotoxicity reactions compared to non-carriers.

Other Warnings and Precautions

Decreased LVEF

May cause decreased LVEF. Usually occurs within first 12 weeks of therapy. Use caution if administered to patients with conditions that could impair LVEF. Evaluate LVEF prior to the initiation of therapy and periodically during treatment.

Discontinue in patients with decreased LVEF of NCI-CTCAE grade 2 or greater and in patients whose LVEF drops below the lower limit of normal.

Diarrhea

Diarrhea, including severe diarrhea and deaths, reported.

Instruct patients to report changes in bowel habits immediately and treat diarrhea promptly with antidiarrheal agents at first unformed stool. Management may include oral or IV electrolytes and fluids, administration of antibiotics, and interruption or discontinuance of therapy.

Interstitial Lung Disease/Pneumonitis

May cause interstitial lung disease and pneumonitis. Monitor for pulmonary symptoms.

QT Prolongation

QT interval prolongation reported.

Administer cautiously to patients who have or may develop prolongation of the corrected QT (QT_c) interval (e.g., patients with hypokalemia, hypomagnesemia, or congenital long QT syndrome; those receiving concomitant drugs that may prolong the QT_c interval, or are associated with torsades de pointes; those with cumulative high-dose anthracycline therapy).

Correct hypokalemia and hypomagnesemia prior to therapy.

Severe Cutaneous Reactions

Severe cutaneous reactions (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis) reported; discontinue if suspected.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; fetal anomalies, abortion, and death of offspring within days after birth demonstrated in animals. (See Pregnancy under Cautions.)

Specific Populations

Pregnancy

May cause fetal harm. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Avoid pregnancy during therapy. Perform pregnancy test prior to initiation of therapy.

If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.

Lactation

Not known whether lapatinib is distributed into milk. Effects on nursing infants and milk production also unknown. Discontinue nursing during therapy and for ≥1 week after drug discontinuance.

Females and Males of Reproductive Potential

The effect of lapatinib on human fertility is not known.

May cause fetal harm. Advise females of childbearing potential to use effective contraceptive methods while receiving lapatinib and for at least 1 week after discontinuance of the drug. In addition, advise males with such female partners to use effective methods of contraception while receiving lapatinib and for 1 week after discontinuance of the drug.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.

Hepatic Impairment

Use with caution in patients with severe preexisting hepatic impairment (Child-Pugh class C); possible greater systemic exposure to the drug. Consider dosage reduction.

Renal Impairment

Not studied in patients with renal impairment or undergoing hemodialysis.

Common Adverse Effects

Adverse effects reported in ≥20% when used with capecitabine: diarrhea, palmar-plantar erythrodysesthesia, nausea, vomiting, rash, fatigue.

Adverse effects reported in ≥20% when used with letrozole: diarrhea, rash, nausea, fatigue.

Drug Interactions

Metabolized by CYP3A4. Inhibits CYP3A4, CYP2C8, and P-glycoprotein (P-gp). Does not substantially inhibit CYP isoenzymes 1A2, 2C9, 2C19, and 2D6 or UGT enzymes in vitro.

Substrate and inhibitor of efflux transporter P-gp (ABCB1).

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP3A4 inhibitors: Substantial increase in lapatinib concentrations. Avoid concomitant use; if concomitant use cannot be avoided, consider reducing lapatinib dosage. Manufacturer recommends lapatinib 500 mg once daily. Dosage recommendation based on pharmacokinetic considerations; no clinical data available. If the potent inhibitor is discontinued, allow 1 week to elapse before increasing lapatinib dosage to usual recommended dosage.

Potent CYP3A4 inducers: Substantial decrease in lapatinib concentrations. Avoid concomitant use; if concomitant use cannot be avoided, consider gradual increase in lapatinib dosage. Manufacturer recommends gradually increasing lapatinib dosage, based on tolerability, from 1.5 g once daily up to 5.5 g once daily (when used in combination with letrozole) or from 1.25 g once daily up to 4.5 g once daily (when used in combination with capecitabine). Dosage recommendations based on pharmacokinetic considerations; no clinical data available. If the potent inducer is discontinued, reduce lapatinib dosage to usual recommended dosage.

Drugs Metabolized by Hepatic Microsomal Enzymes

CYP3A4 or CYP2C8 substrates: Increased exposure to the CYP substrate is likely. Use concomitantly with caution. Consider reducing dosage of CYP3A4 or CYP2C8 substrates with a narrow therapeutic index.

Drugs That Are Substrates or Inhibitors of P-glycoprotein Transport System

P-gp inhibitors: Increased lapatinib concentrations are likely. Use concomitantly with caution.

P-gp substrates: Increased exposure to the P-gp substrate is likely. Use concomitantly with caution. Consider reducing dosage of P-gp substrates with a narrow therapeutic index.

Drugs That Prolong QT Interval

Potential pharmacologic interactions (additive effect on QT interval prolongation). Use caution if concomitantly administered.

Drugs Affecting Gastric Acidity

Potential for decreased solubility of lapatinib when administered with drugs that increase gastric pH.

Specific Drugs and Foods

Drug or Food	Interaction	Comments
Anticonvulsants (carbamazepine, phenobarbital, phenytoin)	Decreased AUC of lapatinib (documented for carbamazepine)	Avoid concomitant use If must use concomitantly, consider gradually titrating lapatinib dosage up to 5.5 g daily (as lapatinib/letrozole regimen) or 4.5 g daily (as lapatinib/capecitabine regimen) as tolerated If anticonvulsant is discontinued, reduce lapatinib to the usual recommended dosage
Antifungals, azoles (itraconazole, ketoconazole, voriconazole)	Increased AUC and half-life of lapatinib (documented for ketoconazole)	Avoid concomitant use If must use concomitantly, consider reducing lapatinib dosage to 500 mg daily If antifungal is discontinued, wait approximately 1 week before increasing lapatinib to the usual recommended dosage
Antimycobacterials (rifabutin, rifampin, rifapentine)	Possible decreased AUC of lapatinib	Avoid concomitant use If must use concomitantly, consider gradually titrating lapatinib dosage up to 5.5 g daily (as lapatinib/letrozole regimen) or 4.5 g daily (as lapatinib/capecitabine regimen) as tolerated If antimycobacterial is discontinued, reduce lapatinib to the usual recommended dosage
Dexamethasone	Possible decreased AUC of lapatinib	Avoid concomitant use If must use concomitantly, consider gradually titrating lapatinib dosage up to 5.5 g daily (as lapatinib/letrozole regimen) or 4.5 g daily (as lapatinib/capecitabine regimen) as tolerated If dexamethasone is discontinued, reduce lapatinib to the usual recommended dosage
Digoxin	Increased digoxin AUC	Monitor digoxin concentration before and throughout concomitant use; if concentration >1.2 ng/mL, reduce digoxin dosage by 50%
Esomeprazole	No clinically important pharmacokinetic interactions
Grapefruit	Possible increased lapatinib plasma concentrations	Avoid concomitant use
HIV protease inhibitors (atazanavir, indinavir, nelfinavir, ritonavir, saquinavir)	Possible increased AUC and half-life of lapatinib	Avoid concomitant use If must use concomitantly, consider reducing lapatinib dosage to 500 mg daily If HIV protease inhibitor is discontinued, wait approximately 1 week before increasing lapatinib to the usual recommended dosage
Macrolides (clarithromycin, telithromycin)	Possible increased AUC and half-life of lapatinib	Avoid concomitant use If must use concomitantly, consider reducing lapatinib dosage to 500 mg daily If macrolide is discontinued, wait approximately 1 week before increasing lapatinib to the usual recommended dosage
Midazolam	Increased midazolam AUC; effect is larger with oral than IV midazolam	Use with caution; consider midazolam dosage reduction
Nefazodone	Possible increased AUC and half-life of lapatinib	Avoid concomitant use If must use concomitantly, consider reducing lapatinib dosage to 500 mg daily If nefazodone is discontinued, wait approximately 1 week before increasing lapatinib to the usual recommended dosage
Paclitaxel	Increased paclitaxel AUC
St. John’s wort (Hypericum perforatum)	Possible decreased AUC of lapatinib	Avoid concomitant use If must use concomitantly, consider gradually titrating lapatinib dosage up to 5.5 g daily (as lapatinib/letrozole regimen) or 4.5 g daily (as lapatinib/capecitabine regimen) as tolerated If St. John’s wort is discontinued, reduce lapatinib to the usual recommended dosage

Lapatinib Pharmacokinetics

Absorption

Bioavailability

Absorption from GI tract is variable and incomplete.

Dividing the daily dosage results in approximately twofold greater systemic exposure.

Food

Administration with a low-fat or high-fat meal increases systemic exposure by threefold or fourfold, respectively.

Distribution

Extent

Not known whether distributed into human milk.

Plasma Protein Binding

>99% (albumin and α-1 acid glycoprotein).

Elimination

Metabolism

Metabolized principally by CYP3A4 and CYP3A5 to oxidated metabolites.

Elimination Route

Median of 27% (range; 3–67%) of an oral dose eliminated unchanged in feces; renal excretion negligible (<2%).

Half-life

Single-dose terminal half-life: 14.2 hours.

Effective multiple-dose half-life: 24 hours.

Special Populations

Moderate or severe hepatic impairment increases AUC by 14 or 63%, respectively.

Renal impairment is unlikely to affect pharmacokinetics since renal elimination is negligible (<2%).

Stability

Storage

Oral

Tablets

20–25°C (excursions permitted between 15–30°C).

Actions

Inhibits human epidermal growth factor receptor (HER1/EGFR/ERBB1) and epidermal growth factor receptor type 2 (HER2/ERBB2) tyrosine kinases.
Inhibits ERBB-driven tumor cell growth in vitro and in animal models.
Exhibits additive antineoplastic activity with fluorouracil (the active metabolite of capecitabine) in vitro.
Retains substantial antineoplastic activity in vitro against breast cancer cell lines selected for long-term growth in trastuzumab-containing medium, suggesting a lack of cross-resistance between lapatinib and trastuzumab.
Combined use of endocrine (antiestrogen) therapy (e.g., letrozole) and an EGFR/HER2 inhibitor (e.g., lapatinib) in women with hormone receptor-positive, HER2-overexpressing breast cancer may delay or prevent emergence of endocrine resistance resulting from increased EGFR and HER2 signaling.

Advice to Patients

Inform patients about the importance of taking the total daily dose of lapatinib as a single dose; dividing the total daily dose is not recommended.
Advise patients to take lapatinib at least 1 hour before or at least 1 hour after food.
Inform patients to not eat or drink grapefruit products while taking lapatinib.
If a dose of lapatinib is missed, inform patients to take the next dose at the regularly scheduled time; do not double the dose.
Inform patients of symptoms of decreased left ventricular ejection fraction (e.g., shortness of breath, palpitations, fatigue) and advise them to inform their clinician if such symptoms occur during treatment with lapatinib.
Advise patients that periodic laboratory testing will be performed while taking lapatinib.
Inform patients of symptoms of liver dysfunction (e.g., itching, yellow eyes or skin, dark urine, pain or discomfort in the right upper area of the abdomen) and advise them to immediately contact their clinician if such symptoms occur.
Risk of severe diarrhea with lapatinib use; advise patients about appropriate countermeasures to prevent and/or manage diarrhea and advise them to inform their clinician if a change in bowel pattern or severe diarrhea occurs while taking lapatinib.
Advise patients to report pulmonary signs or symptoms indicative of interstitial lung disease or pneumonitis.
Advise patients to report severe cutaneous reactions to their clinician if they develop these symptoms while taking lapatinib.
Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses.
Inform female patients of the risk to a fetus. Advise females to inform their clinician if they are or plan to become pregnant or plan to breast-feed.
Advise females of reproductive potential to use effective contraception during treatment with lapatinib and for at least 1 week after discontinuance of therapy. Advise males who are partners of such females to use effective contraception during treatment with lapatinib and for 1 week after discontinuance of therapy.
Advise females to avoid breast-feeding while receiving the drug and for at least 1 week after discontinuance of therapy.
Advise patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.