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
Brands: Tykerb

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  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 Lapatinib Ditosylate

Breast Cancer

In combination with capecitabine, for treatment of advanced or metastatic breast cancer in patients whose tumors overexpress the human epidermal receptor type 2 (HER2) protein and who have received prior therapy including an anthracycline, a taxane, and trastuzumab.¹

Effects of combination regimen on overall survival not yet established.^{1 4}

Lapatinib Ditosylate 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

Oral

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

When used concomitantly with a strong CYP3A4 inhibitor, manufacturer recommends 500 mg once daily.¹ (See Interactions.)

When used concomitantly with a strong CYP3A4 inducer, manufacturer recommends gradually titrating dose from 1.25 g to 4.5 g once daily, based on tolerability.¹ (See Interactions.)

Dosage Modification for Toxicity

Decreased Left Ventricular Ejection Fraction

Discontinue if decreased left ventricular ejection fraction (LVEF) grade 2 or greater (as defined by the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE]) or if LVEF drops below the lower limit of normal.¹ May restart at 1 g daily after a minimum of 2 weeks if LVEF returns to normal and patient is asymptomatic.¹ (See Decreased LVEF under Cautions.)

Consider interruption or discontinuance of therapy if toxicity of NCI ≥ grade 2 occurs (other than decreased LVEF); once toxicity improves to ≤ grade 1, may restart at a dosage of 1.25 g daily.¹ If toxicity recurs, restart at a lower dosage (1 g daily).¹

Hepatic Toxicity

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.)

Pulmonary Toxicity

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

Severe impairment (Child-Pugh Class C): reduce dosage; manufacturer suggests 750 mg daily; however, no clinical data available.¹ (See Hepatic Toxicity under Dosage and Administration and also under Cautions.)

Renal Impairment

No specific population dosage recommendations at this time.¹ (See Renal Impairment under Pharmacokinetics.)

Geriatric Patients

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

Cautions for Lapatinib Ditosylate

Warnings/Precautions

Warnings

Decreased LVEF

May rarely cause decreased LVEF; generally reversible and nonprogressive.^{1 4} Usually occurs within first 9 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 and in patients with an LVEF that drops below the lower limit of normal.¹ (See Dosage Modification for Toxicity under Dosage and Administration.)

Hepatic Toxicity

Possible severe or fatal hepatotoxicity (ALT or AST >3 times ULN, total bilirubin >1.5 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 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 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 (QT_c) interval (e.g., patients with hypokalemia, hypomagnesemia, or congenital long QT syndrome, those receiving concomitant medications that may prolong the QT_c interval).¹ (See Drugs that Prolong QT Interval under Interactions.)

Correct hypokalemia and hypomagnesemia prior to therapy; obtain an ECG with QT measurement at baseline and during treatment.¹

Hematologic Effects

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

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; no adequate and well-controlled studies in humans.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 capecitabine: diarrhea, nausea, vomiting, stomatitis, dyspepsia, hand-foot syndrome, rash, dry skin, mucosal inflammation, pain, dyspnea, fatigue, insomnia.¹

Interactions for Lapatinib Ditosylate

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

Substrate and inhibitor of efflux transporter Pgp (ABCB1).¹

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions likely with drugs that are inhibitors, inducers, or substrates of CYP3A4; possible alteration in metabolism of lapatinib and/or other drug.¹ Consider dosage adjustment.¹ (See Specific Drugs under Interactions.)

Pharmacokinetic interactions likely with drugs that are substrates of CYP2C8; possible increased concentrations of substrate drug.¹ Consider reducing dose of CYP2C8 substrates with a narrow therapeutic index.¹

Drugs that are Substrates of or Inhibitors of P-glycoprotein Transport System

Pharmacokinetic interactions likely with drugs that are inhibitors or substrates of Pgp; possible increased concentrations of the substrate drug and/or lapatinib.¹ Use concomitantly with caution.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 4.5 g daily 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 4.5 g daily as tolerated1 If antimycobacterial is discontinued, reduce lapatinib to the usual recommended dosage1
Capecitabine	Pharmacokinetic interactions unlikely1
Dexamethasone	Possible decreased AUC of lapatinib1	Avoid concomitant use1 If must use concomitantly, consider gradually titrating lapatinib dosage up to 4.5 g daily as tolerated1 If dexamethasone is discontinued, reduce lapatinib to the usual recommended dosage1
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
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
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 4.5 g daily as tolerated1 If St. John’s wort is discontinued, reduce lapatinib to the usual recommended dosage1

Lapatinib Ditosylate 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 Administration under Dosage and Administration.)

Food

Food increases extent of absorption.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

Hepatic Impairment

Increased AUC of 14 and 63% in moderate or severe hepatic impairment respectively.¹ (See Hepatic Impairment under Special Populations in Dosage and Administration and also Hepatic Impairment under Cautions.)

Renal Impairment

Renal impairment is unlikely to affect pharmacokinetics since <2% of drug and its metabolites are eliminated by kidneys.¹

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).¹

ActionsActions

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

  
  


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

  
  


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

  
  


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  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

  
  

Advice to Patients

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  Importance of taking daily dose only one time per day.¹

  
  


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

  
  


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

  
  


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  Importance of not doubling the next dose if a dose is missed; if remembered that day, take dose as soon as possible, otherwise skip missed dose.¹

  
  


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  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

  
  


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  Inform patients of symptoms of liver problems (e.g., itching, yellow eyes or skin, dark urine, pain or discomfort in the right upper area of the belly); advise patients to immediately contact their clinician if such symptoms occur.¹

  
  


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  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

  
  


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

  
  


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  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

  
  


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  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

  
  


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  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

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions January 2010. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

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

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.

More Lapatinib Ditosylate resources

• Lapatinib Ditosylate Side Effects (in more detail)
• Lapatinib Ditosylate Dosage
• Lapatinib Ditosylate Use in Pregnancy & Breastfeeding
• Lapatinib Ditosylate Drug Interactions
• Lapatinib Ditosylate Support Group
• 1 Review for Lapatinib Ditosylate - Add your own review/rating

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