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
Introduction
Antineoplastic agent; inhibitor of HER1 and HER2 tyrosine kinases.1 2 3
Uses for Tykerb
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
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
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 Tykerb
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 (QTc) interval (e.g., patients with hypokalemia, hypomagnesemia, or congenital long QT syndrome, those receiving concomitant medications that may prolong the QTc 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 Tykerb
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
|
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 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
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
Advice to Patients
Importance of taking daily dose only one time per day.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
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
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 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
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
|
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 Tykerb resources
- Tykerb Side Effects (in more detail)
- Tykerb Dosage
- Tykerb Use in Pregnancy & Breastfeeding
- Tykerb Drug Interactions
- Tykerb Support Group
- 1 Review for Tykerb - Add your own review/rating
- Tykerb Prescribing Information (FDA)
- Tykerb Consumer Overview
- Tykerb Advanced Consumer (Micromedex) - Includes Dosage Information
- Tykerb MedFacts Consumer Leaflet (Wolters Kluwer)
- Lapatinib Professional Patient Advice (Wolters Kluwer)
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