Advanced Breast Cancer: Learn about treatment options.

Tykerb

Generic Name: Lapatinib Ditosylate
Class: Antineoplastic Agents
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

Warning(s)

  • Potentially severe or fatal hepatotoxicity observed.1 Causality of the deaths uncertain.1 (See Hepatic Toxicity under Cautions.)

Introduction

Antineoplastic agent; inhibitor of HER1 and HER2 tyrosine kinases.1 2 3

Uses for Tykerb

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.1 5 8 Combined therapy with lapatinib and an aromatase inhibitor has not been compared with trastuzumab-containing chemotherapy for treatment of metastatic breast cancer.1

Slideshow: 2013 Drug News Round-Up: Top 20 Stories

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.1 2

Tykerb Dosage and Administration

Administration

Oral Administration

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

Do not divide daily dose.1 (See Bioavailability under Pharmacokinetics.)

If dose is missed, do not double the next dose.1

Dosage

Available as lapatinib ditosylate monohydrate; dosage expressed in terms of lapatinib.1

Adults

Breast Cancer
Hormone Receptor-Positive, HER2-overexpressing Metastatic Breast Cancer
Oral

Lapatinib/letrozole: Lapatinib 1.5 g once daily, given continuously in combination with letrozole 2.5 mg once daily.1 In clinical trial evaluating this regimen, treatment was continued until disease progression occurred or patient withdrew from study.5 8

Previously Treated HER2-overexpressing 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.1 Continue treatment until disease progression or unacceptable toxicity occurs.1

Dosage Modification for CYP3A4 Interactions
Oral

Lapatinib/letrozole: When used concomitantly with a potent CYP3A4 inhibitor, manufacturer recommends lapatinib 500 mg once daily.1 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.1 (See Interactions.)

Lapatinib/capecitabine: When used concomitantly with a potent CYP3A4 inhibitor, manufacturer recommends lapatinib 500 mg once daily.1 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.1 (See Interactions.)

Dosage Modification for Decreased Left Ventricular Ejection Fraction (LVEF)
Oral

Discontinue if decreased LVEF of grade 2 or greater (as defined by National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE]) or if LVEF drops below the lower limit of normal.1

Lapatinib/letrozole: May restart at reduced lapatinib dosage of 1.25 g once daily after a minimum of 2 weeks if LVEF returns to normal and patient is asymptomatic.1 (See Decreased LVEF under Cautions.)

Lapatinib/capecitabine: May restart at reduced lapatinib dosage of 1 g once daily after a minimum of 2 weeks if LVEF returns to normal and patient is asymptomatic.1 (See Decreased LVEF under Cautions.)

Dosage Modification for Other Toxicity
Oral

Consider interruption or discontinuance of therapy if toxicity (other than decreased LVEF) of NCI grade 2 or greater occurs.1

Lapatinib/letrozole: Once toxicity improves to grade 1 or less, may restart at reduced lapatinib dosage of 1.25 g daily; if toxicity recurs, restart at same dosage (1.25 g daily).1

Lapatinib/capecitabine: Once toxicity improves to grade 1 or less, may restart at lapatinib dosage of 1.25 g daily.1 If toxicity recurs, restart at lower dosage (1 g daily).1

Discontinuance for Hepatic Toxicity
Oral

If severe liver function changes occur, permanently discontinue lapatinib; do not reinitiate in these patients.1 (See Hepatic Toxicity and also see Hepatic Impairment under Cautions.)

Discontinuance for GI Toxicity
Oral

If severe diarrhea occurs, may need to interrupt or discontinue lapatinib therapy.1

Discontinuance for Pulmonary Toxicity
Oral

If grade 3 or higher (NCI-CTCAE) pulmonary symptoms suggestive of interstitial lung disease or pneumonitis develop, discontinue lapatinib.1 (See Interstitial Lung Disease/Pneumonitis under Cautions.)

Special Populations

Hepatic Impairment

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

Severe impairment (Child-Pugh class C): Reduce lapatinib dosage; manufacturer suggests 1 g once daily; however, no clinical data available.1 (See Discontinuance for Hepatic Toxicity under Dosage and Administration and see Hepatic Toxicity under Cautions.)

Lapatinib/Capecitabine for Previously Treated HER2-overexpressing 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.1 (See Discontinuance for Hepatic Toxicity under Dosage and Administration and see Hepatic Toxicity under Cautions.)

Renal Impairment

No specific dosage recommendations at this time.1 (See Special Populations under Pharmacokinetics.)

Geriatric Patients

No specific dosage recommendations at this time.1 (See Geriatric Use under Cautions.)

Cautions for Tykerb

Contraindications

Known hypersensitivity (e.g., anaphylaxis) to lapatinib or any ingredient in the formulation.1

Warnings/Precautions

Warnings

Decreased LVEF

May rarely cause decreased LVEF; generally reversible and nonprogressive.1 4 Usually occurs within first 12 weeks of therapy.1 Use caution if administered to patients with conditions that could impair LVEF.1 Evaluate LVEF prior to the initiation of therapy and periodically during treatment.1

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.1 (See Dosage Modification for Decreased Left Ventricular Ejection Fraction [LVEF] under Dosage and Administration.)

Hepatic Toxicity

Possible severe or fatal hepatotoxicity (ALT or AST >3 times ULN, total bilirubin >2 times ULN).1 Causality of reported deaths uncertain.1

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.1 Hepatotoxicity may occur days to several months after initiation of treatment.1 (See Discontinuance for Hepatic Toxicity under Dosage and Administration.)

Diarrhea

Diarrhea, including severe diarrhea, reported.1 4 Manage proactively with antidiarrheal agents.1 4 Management may include oral or IV electrolytes and fluids, and interruption or discontinuance of therapy.1 4

Interstitial Lung Disease/Pneumonitis

May cause interstitial lung disease and pneumonitis.1 Monitor for pulmonary symptoms.1 (See Discontinuance for Pulmonary Toxicity under Dosage and Administration.)

Prolongation of QT Interval

QT interval prolongation reported.1

Administer cautiously to patients who have or may develop prolongation of the corrected QT (QTc) interval (e.g., patients with hypokalemia, hypomagnesemia, or congenital long QT syndrome, those receiving concomitant drugs that may prolong the QTc interval).1 (See Drugs that Prolong QT Interval under Interactions.)

Correct hypokalemia and hypomagnesemia prior to therapy.1 Consider ECG and electrolyte monitoring.1

Hematologic Effects

Possible hematologic abnormalities including neutropenia, thrombocytopenia, and hemoglobinemia.1

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; fetal anomalies, abortion, and death of offspring within days after birth demonstrated in animals.1 Avoid pregnancy during therapy.1 If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.1

Specific Populations

Pregnancy

Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether lapatinib is distributed into milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established.1

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.1

Hepatic Impairment

Use with caution in patients with severe preexisting hepatic impairment (Child-Pugh class C); possible greater systemic exposure to the drug.1 Consider dosage reduction.1 (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Not studied in patients with renal impairment or undergoing hemodialysis.1 (See Special Populations under Pharmacokinetics.)

Common Adverse Effects

When used with either letrozole or capecitabine: Diarrhea,1 5 nausea,1 5 vomiting,1 5 rash,1 5 dry skin,1 5 fatigue,1 5 liver function test (AST, ALT, total bilirubin) abnormalities.1

Also commonly reported with lapatinib and letrozole: Anorexia,1 5 alopecia,1 5 pruritus,1 5 nail disorder,1 5 asthenia,1 5 headache,1 5 epistaxis.1 5

Also commonly reported with lapatinib and capecitabine: Stomatitis,1 dyspepsia,1 palmar-plantar erythrodysesthesia (hand-foot syndrome),1 mucosal inflammation,1 pain,1 dyspnea,1 insomnia,1 hematologic (hemoglobin, platelets, neutrophils) abnormalities.1

Interactions for Tykerb

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

Substrate and inhibitor of efflux transporter P-gp (ABCB1).1

Drugs Affecting Hepatic Microsomal Enzymes

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

Potent CYP3A4 inducers: Substantial decrease in lapatinib concentrations.1 Avoid concomitant use; if concomitant use cannot be avoided, consider gradual increase in lapatinib dosage.1 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).1 Dosage recommendations based on pharmacokinetic considerations; no clinical data available.1 If the potent inducer is discontinued, reduce lapatinib dosage to usual recommended dosage.1

Drugs Metabolized by Hepatic Microsomal Enzymes

CYP3A4 or CYP2C8 substrates: Increased exposure to the CYP substrate is likely.1 Use concomitantly with caution.1 Consider reducing dosage of CYP3A4 or CYP2C8 substrates with a narrow therapeutic index.1

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

P-gp inhibitors: Increased lapatinib concentrations are likely.1 Use concomitantly with caution.1

P-gp substrates: Increased exposure to the P-gp substrate is likely.1 Use concomitantly with caution.1 Consider reducing dosage of P-gp substrates with a narrow therapeutic index.1

Drugs That Prolong QT Interval

Potential pharmacologic interactions (additive effect on QT interval prolongation).1 Use caution if concomitantly administered.1 (See Prolongation of QT Interval under Cautions.)

Specific Drugs and Foods

Drug or Food

Interaction

Comments

Anticonvulsants (carbamazepine, phenobarbital, phenytoin)

Decreased AUC of lapatinib (documented for carbamazepine)1

Avoid concomitant use1

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 tolerated1

If anticonvulsant is discontinued, reduce lapatinib to the usual recommended dosage1

Antifungals, azoles (itraconazole, ketoconazole, voriconazole)

Increased AUC and half-life of lapatinib (documented for ketoconazole)1

Avoid concomitant use1

If must use concomitantly, consider reducing lapatinib dosage to 500 mg daily1

If antifungal is discontinued, wait approximately 1 week before increasing lapatinib to the usual recommended dosage1

Antimycobacterials (rifabutin, rifampin, rifapentine)

Possible decreased AUC of lapatinib1

Avoid concomitant use1

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 tolerated1

If antimycobacterial is discontinued, reduce lapatinib to the usual recommended dosage1

Capecitabine

Pharmacokinetic interactions unlikely9

Dexamethasone

Possible decreased AUC of lapatinib1

Avoid concomitant use1

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 tolerated1

If dexamethasone is discontinued, reduce lapatinib to the usual recommended dosage1

Digoxin

Increased digoxin AUC1

Monitor digoxin concentration before and throughout concomitant use; if concentration >1.2 ng/mL, reduce digoxin dosage by 50%1

Grapefruit

Possible increased lapatinib plasma concentrations1

Avoid concomitant use1

HIV protease inhibitors (atazanavir, indinavir, nelfinavir, ritonavir, saquinavir)

Possible increased AUC and half-life of lapatinib1

Avoid concomitant use1

If must use concomitantly, consider reducing lapatinib dosage to 500 mg daily1

If HIV protease inhibitor is discontinued, wait approximately 1 week before increasing lapatinib to the usual recommended dosage1

Macrolides (clarithromycin, telithromycin)

Possible increased AUC and half-life of lapatinib1

Avoid concomitant use1

If must use concomitantly, consider reducing lapatinib dosage to 500 mg daily1

If macrolide is discontinued, wait approximately 1 week before increasing lapatinib to the usual recommended dosage1

Midazolam

Increased midazolam AUC; effect is larger with oral than IV midazolam1

Use with caution; consider midazolam dosage reduction1

Nefazodone

Possible increased AUC and half-life of lapatinib1

Avoid concomitant use1

If must use concomitantly, consider reducing lapatinib dosage to 500 mg daily1

If nefazodone is discontinued, wait approximately 1 week before increasing lapatinib to the usual recommended dosage1

Paclitaxel

Increased paclitaxel AUC1

St. John’s wort (Hypericum perforatum)

Possible decreased AUC of lapatinib1

Avoid concomitant use1

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 tolerated1

If St. John’s wort is discontinued, reduce lapatinib to the usual recommended dosage1

Tykerb Pharmacokinetics

Absorption

Bioavailability

Absorption from GI tract is variable and incomplete.1

Dividing the daily dosage results in approximately twofold greater systemic exposure.1 (See Oral Administration under Dosage and Administration.)

Food

Administration with a meal increases systemic exposure by threefold to fourfold.1

Distribution

Extent

Not known whether distributed into human milk.1

Plasma Protein Binding

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

Elimination

Metabolism

Metabolized principally by CYP3A4 and CYP3A5 to oxidated metabolites.1

Elimination Route

Median of 27% (range; 3–67%) of an oral dose eliminated unchanged in feces; renal excretion negligible (<2%). 1

Half-life

Single-dose terminal half-life: 14.2 hours.1

Effective multiple-dose half-life: 24 hours.1

Special Populations

Moderate or severe hepatic impairment increases AUC by 14 or 63%, respectively.1 (See Hepatic Impairment under Dosage and Administration and also under Cautions.)

Renal impairment is unlikely to affect pharmacokinetics since renal elimination is negligible (<2%).1

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).1

Actions

  • Inhibits human epidermal growth factor receptor (HER1/EGFR/ERBB1) and epidermal growth factor receptor type 2 (HER2/ERBB2) tyrosine kinases.1

  • Inhibits ERBB-driven tumor cell growth in vitro and in animal models.1

  • Exhibits additive antineoplastic activity with fluorouracil (the active metabolite of capecitabine) in vitro.1

  • 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.1

  • 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.5 6 8

Advice to Patients

  • Importance of taking total daily dose as a single dose; dividing the total daily dose is not recommended.1

  • Importance of taking lapatinib at least 1 hour before or at least 1 hour after food.1

  • Importance of not eating or drinking grapefruit products while taking lapatinib.1

  • If a dose of lapatinib is missed, importance of taking the next dose at the regularly scheduled time; do not double the dose.1

  • Inform patients of symptoms of decreased left ventricular ejection fraction (e.g., shortness of breath, palpitations, fatigue); advise patients to immediately contact their clinician if such symptoms occur.1

  • 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); advise patients to immediately contact their clinician if such symptoms occur.1

  • Risk of severe diarrhea with lapatinib use; importance of advising patient about appropriate countermeasures to prevent and/or manage diarrhea; advise patients to inform clinician if severe diarrhea occurs.1

  • Advise patients to inform clinician if a persistent cough occurs.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed; necessity for clinicians to advise women to avoid pregnancy during therapy.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

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

Lapatinib Ditosylate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

250 mg (of lapatinib)

Tykerb

GlaxoSmithKline

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions November 12, 2012. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. GlaxoSmithKline. Tykerb (lapatinib) prescribing information. Research Triangle Park, NC; 2011 Aug.

2. Geyer CE, Forster J, Lindquist D et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006; 355:2733-43. [PubMed 17192538]

3. Muss HB. Targeted therapy for metastatic breast cancer. N Engl J Med. 2006; 355:2783-5. Editorial. [PubMed 17192546]

4. GlaxoSmithKline, Research Triangle Park, NC: Personal communication.

5. Johnston S, Pippen J, Pivot X et al. Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol. 2009; 27:5538-46. [PubMed 19786658]

6. Massarweh S, Schiff R. Resistance to endocrine therapy in breast cancer: exploiting estrogen receptor/growth factor signaling crosstalk. Endocr Relat Cancer. 2006; 13 Suppl 1:S15-24. [PubMed 17259554]

7. Cameron D, Casey M, Oliva C et al. Lapatinib plus capecitabine in women with HER-2-positive advanced breast cancer: final survival analysis of a phase III randomized trial. Oncologist. 2010; 15:924-34. [PubMed 20736298]

8. Schwartzberg LS, Schwarzberg LS, Franco SX et al. Lapatinib plus letrozole as first-line therapy for HER-2+ hormone receptor-positive metastatic breast cancer. Oncologist. 2010; 15:122-9. [PubMed 20156908]

9. GlaxoSmithKline. Tykerb (lapatinib) prescribing information. Research Triangle Park, NC; 2008 Jul.

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