Tykerb

lapatinib

Tykerb

Pharmacologic class: 4-Anilinoquina-zoline kinase inhibitor

Therapeutic class: Antineoplastic

Pregnancy risk category D

Action

Lapatinib is a 4-anilinoquinazoline kinase inhibitor of the intracellular tyrosine kinase domains of both Epidermal Growth Factor Receptor (EGFR [ErbB1]) and of Human Epidermal Receptor Type 2 (HER2 [ErbB2]) receptors (estimated Kiapp values of 3nM and 13nM, respectively) with a dissociation half-life of ≥300 minutes. Lapatinib inhibits ErbB-driven tumor cell growth in vitro and in various animal models.

Availability

Tablets: 250 mg

Indications and dosages

Advanced or metastatic breast cancer in patients whose tumors over-express HER2 and who have received prior therapy, including an anthracycline, a taxane, and trastuzumab

Adults: 1,250 mg P.O. daily on days 1 to 21 continuously in combination with capecitabine on days 1 to 14 in repeating 21-day cycle

Postmenopausal women with hormone receptor-positive metastatic breast cancer that overexpresses HER2 receptor, for whom hormonal therapy is indicated

Adults: 1,500 mg P.O. daily continuously in combination with letrozole

Dosage adjustment

• Severe hepatic impairment
• Cardiac toxicity
• Grade 2 or greater NCI CTCAE toxicity
• Concurrent use of strong CYP3A4 inducers/inhibitors

Contraindications

• Hypersensitivity to drug or its components

Precautions

Use cautiously in:
• severe hepatic impairment (Child-Pugh Class C)
• decreased left ventricular ejection fraction (LVEF), patients who have or may develop prolongation of QT interval (including patients with hypokalemia, hypomagnesemia, congenital long QT syndrome; patients taking antiarrhythmics or other products leading to QT-interval prolongation; and cumulative high-dose anthracycline therapy)
• Grade 2 or greater NCI CTCAE toxicity
• interstitial lung disease and pneumonitis, diarrhea
• strong CYP3A4 inducers including St. John's wort, strong CYP3A4 inhibitors (avoid use)
• concurrent use of CYP3A4, CYP2C8, and P-glycoprotein (PgP) substrates
• grapefruit, grapefruit products (avoid use)
• pregnant or breastfeeding patients
• children (safety and efficacy not established).

Administration

• Administer at least 1 hour before or 1 hour after a meal, but give capecitabine with food or within 30 minutes after food. Don't give with grapefruit or grapefruit juice. Don't divide daily doses.
• Correct hypokalemia or hypomagnesemia before lapatinib administration.
• Assess serum digoxin concentration before starting drug. If digoxin serum concentration is greater than 1.2 ng/ml, reduce digoxin dosage as prescribed.
• Evaluate LVEF before starting lapatinib treatment to ensure patient has baseline LVEF within institution's normal limits. Be aware that drug should be discontinued in patients with decreased LVEF that is Grade 2 or greater NCI CTCAE toxicity and in patients with LVEF that drops below institution's lower limit of normal. Lapatinib in combination with capecitabine may be restarted at reduced dosage of 1,000 mg/day and in combination with letrozole may be restarted at reduced dosage of 1,250 mg/day after minimum of 2 weeks if LVEF recovers to normal and patient is asymptomatic.

Obtain liver function test results (transaminases, bilirubin, and ALP) before starting treatment. Consider reducing dosage in patients with severe hepatic impairment from 1,250 mg/day to 750 mg/day (HER2-positive metastatic breast cancer indication) or from 1,500 mg/day to 1,000 mg/day (hormone receptor-positive, HER2-positive breast cancer indication) to adjust area under the curve (AUC) to normal range. In patients who develop severe hepatotoxicity during therapy, discontinue drug and don't restart.

Discontinue drug in patients who experience pulmonary signs and symptoms indicative of interstitial lung disease/pneumonitis that are Grade 3 or greater (NCI CTCAE).
• If patient must receive a strong CYP3A4 inhibitor concurrently, consider reducing lapatinib dosage to 500 mg/day. This dosage is predicted to adjust lapatinib AUC to the range observed without inhibitors. If the strong inhibitor is discontinued, a washout period of approximately 1 week should be allowed before lapatinib dosage is adjusted upward to indicated dosage.
• If patient must receive a strong CYP3A4 inducer concurrently, consider titrating lapatanib dosage gradually from 1,250 mg/day up to 4,500 mg/day (HER2-positive metastatic breast cancer indication) or from 1,500 mg/day up to 5,500 mg/day (hormone receptor-positive, HER2-positive breast cancer indication) based on tolerability. This dosage is predicted to adjust lapatinib AUC to the range observed without inducers. If the strong inducer is discontinued, lapatinib dosage should be reduced to indicated dosage.
• Be aware that severe diarrhea may require administration of oral or I.V. electrolytes and fluids and interruption or discontinuation of therapy.

Adverse reactions

CNS: headache, fatigue, insomnia, asthenia

CV: prolonged QT interval

EENT: epistaxis

GI: nausea, vomiting, diarrhea, anorexia, dyspepsia, stomatitis

Hepatic: hepatotoxicity

Musculoskeletal: extremity pain, back pain

Respiratory: dyspnea, interstitial lung disease, pneumonitis

Skin: rash, dry skin, alopecia, pruritus, nail disorder, palmar-plantar erythrodysesthesia

Other: mucosal inflammation

Interactions

Drug-drug.CYP3A4 substrates (midazolam), CYP2C8 and PgP substrates (paclitaxel), PgP substrates (digoxin): increased exposure of these drugs

Strong CYP3A4 inducers (such as carbamazepine, dexamethasone, phenobarbital, phenytoin, rifabutin, rifampin, rifapentin): decreased lapatinib systemic exposure

Strong CYP3A4 inhibitors (such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole): increased lapatinib systemic exposure and half-life

Drug-diagnostic tests.ALT, AST, total bilirubin: increased levels

Hemoglobin, neutrophils, platelets: decreased levels

Drug-food.Any food: increased lapatinib systemic exposure

Grapefruit: increased lapatinib plasma concentration

High-fat meal: increased AUC value

Drug-herbs.St. John's Wort: decreased lapatinib systemic exposure

Patient monitoring

• Monitor CBC with differential and hepatic function tests closely.
• Monitor serum digoxin concentration throughout coadministration with lapatinib.

Continue to monitor patient for prolonged QT interval, interstitial lung disease, and pneumonitis.

Patient teaching

• Tell patient to take lapatinib at least 1 hour before or 1 hour after a meal but if capecitabine is also prescribed to take capecitabine with food or within 30 minutes after food. Advise patient not to take lapatinib with grapefruit or grapefruit juice or divide daily doses.

Instruct patient to immediately report tiredness, dizziness, shortness of breath, pounding or racing heartbeats, itching, yellowing of skin or eyes, dark urine, right upper abdominal pain or discomfort, or red, painful hands and feet.
• Teach patient how to prevent and manage diarrhea, which may be severe; instruct patient to inform prescriber of changes in bowel pattern or severe diarrhea.
• Instruct patient to tell prescriber about all drugs he's taking, because some drugs have potential for serious drug interactions and shouldn't be taken with lapatinib.
• Advise patient not to use St. John's wort or other herbal supplements without consulting prescriber.
• Advise female patient of childbearing age to avoid becoming pregnant during therapy.
• Advise breastfeeding patient that she should decide whether to discontinue breastfeeding or discontinue drug, taking into account importance of drug for her treatment.
• As appropriate, review all other significant and life-threatening adverse reactions and interactions, especially those related to the drugs, tests, foods, and herbs mentioned above.

lapatinib

(la-pat-i-nib) ,

Tykerb

(trade name)

Classification

Therapeutic: antineoplastics
Pharmacologic: enzyme inhibitors
Pregnancy Category: D

Indications

genetic implication Advanced or metastatic breast cancer with tumor overexpression of the Human Epidermal Receptor Type 2 (HER2) and past therapy with an anthracycline, a taxane and trastuzumab (used in combination with capecitabine).genetic implication Postmenopausal women with hormone-receptor positive metastatic breast cancer that overexpresses HER2 for whom hormonal therapy is indicated (used in combination with letrozole).

Action

genetic implication Acts as an inhibitor of intracellular tyrosine kinase affecting Epidermal Growth Factor (EGFR, ErbB1) and HER2 (ErbB2). Inhibits the growth of ErbB-driven tumors. Effect is additive with capecitabine.

Therapeutic effects

Decreased/slowed spread of metastatic breast cancer.

Pharmacokinetics

Absorption: Incompletely and variably absorbed following oral administration; blood levels ↑ by food.
Distribution: Unknown.
Protein Binding: >99%.
Metabolism and Excretion: Extensively metabolized by, mostly by CYP3A4 and CYP3A5 enzyme systems; <2% excreted by kidneys.
Half-life: 24 hr.

Time/action profile (blood levels)

ROUTEONSETPEAKDURATION
POunknown4 hr24 hr

Contraindications/Precautions

Contraindicated in: Hypersensitivity;↓ left ventricular ejection fraction (Grade 2 or greater); Obstetric / Lactation: Pregnancy or lactation.
Use Cautiously in: Concurrent use of CYP3A4 inhibitors including ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritoanvir, saquinavir, telithromycin, and voriconazole should be avoided (if necessary, ↓ lapatinib dose);Concurrent use of CYP3A4 inducers including dexamathasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, and St. John's wort should be avoided (if necassary, ↑ lapatinib dose;Severe hepatic impairment (dose ↓ recommended for Child-Pugh Class C);Known QTc interval prolongation or co-existing risk factors for QTc interval prolongation including hypokalemia, hypomagnesemia, concurrent antiarrhythmics or medications that are known to prolong the QTc interval; Geriatric: May be more sensitive to effects; Pediatric: Safety not established.

Adverse Reactions/Side Effects

Central nervous system

  • fatigue (most frequent)
  • insomnia

Respiratory

  • dyspnea
  • interstitial lung disease
  • pneumonitis

Cardiovascular

  • ↓ left ventricular ejection fraction
  • QT interval prolongation

Gastrointestinal

  • diarrhea (life-threatening)
  • hepatotoxicity (life-threatening)
  • nausea (most frequent)
  • vomiting (most frequent)
  • dyspepsia
  • ↑ liver enzymes
  • stomatitis

Dermatologic

  • palmar-plantar erythrodysesthesia (most frequent)
  • rash (most frequent)
  • dry skin
  • nail disorders

Hematologic

  • neutropenia

Musculoskeletal

  • back pain
  • extremity pain

Interactions

Drug-Drug interaction

Lapatinib inhibits CYP3A4, CYP28 and P-glycoprotein; concurrent use of drugs, which are substrates for these enzyme should be undertaken with caution.May ↑ effects of midazolam, paclitaxel, and digoxin.Concurrent use of strong CYP3A4 inhibitors including ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole may ↑ blood levels and the risk of toxicity. Concurrent use should be avoided, but if necessary, dose of lapatinib should be ↓.Concurrent use of strong CYP3A4 inducers including dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, and phenobarbital may ↓ blood levels and effectiveness. Concurrent use should be avoided, but if necessary, dose of lapatinib should be ↑.Concurrent use of St. John's wort may ↓ blood levels and effectiveness. Concurrent use should be avoided, but if necessary dose of lapatinib should be ↑and should be avoided.Concurrent grapefruit juice may ↑ blood levels and the risk of toxicity and should be avoided.

Route/Dosage

Oral (Adults) HER2 positive metastatic breast cancer—1250 mg once daily for 21 days; Hormone receptor positive, HER2 positive metastatic breast cancer—1500 mg once daily; Concurrent use of strong CYP3A4 inhibitor—↓ dose to 500 mg once daily; Concurrent use of strong CYP3A4 inducer—HER2 positive metastatic breast cancer: Gradually titrate dose from 1250 mg once daily up to 4500 mg once daily as tolerated; Hormone receptor positive, HER2 positive metastatic breast cancer: Gradually titrate dose from 1500 mg once daily up to 5500 mg once daily as tolerated.

Hepatic Impairment

Oral (Adults) Severe hepatic impairment—HER2 positive metastatic breast cancer: 750 mg/day; Hormone receptor positive, HER2 positive metastatic breast cancer: 1000 mg/day.

Availability

Tablets: 250 mg

Nursing implications

Nursing assessment

  • Evaluate left ventricular ejection fraction (LVEF) prior to therapy to determine if within institution's normal limits. Continue to monitor periodically during therapy to ensure it does not fall below limits. If LVEF decreases to Grade 2 or greater discontinue therapy. If returns to normal and patient is asymptomatic after 2 wk, may restart therapy at a reduced dose of 1000 mg/day (with cabcitabine) or 1250 mg/day (with letrazole).
  • Monitor for diarrhea; usually occurs within first 6 days of therapy and lasts 4–5 days. Treat with antidiarrheals (loperamide) after first loose stool. If diarrhea is severe, treat with oral or intravenous fluids, antibiotics (fluoroquinolones) especially if diarrhea persists >24 hrs or accompanied by fever; may require interruption or discontinuation of therapy. If accompanied by moderate to severe abdominal cramping, nausea or vomiting, decreased performance status, fever, sepsis, neutropenia, frank bleeding, or dehydration, interrupt therapy and reintroduce at lower dose (from 1,250 mg/day to 1,000 mg/day or from 1,500 mg/day to 1,250 mg/day) when diarrhea <Grade 1. If Grade 4 diarrhea occurs, discontinue therapy.
  • Monitor ECG prior to and periodically during therapy to monitor QT.
  • Monitor for respiratory status for symptoms of interstitial lung disease and pneumonitis (dyspnea, cough); may require discontinuation of therapy.
  • Lab Test Considerations: Monitor liver function tests prior to initiation and every 4–6 wk during therapy and as clinically indicated. Discontinue and do not restart lapatinib if patients experience severe changes in liver function tests.
    • Monitor serum potassium and magnesium prior to and periodically during therapy.

Potential Nursing Diagnoses

Diarrhea (Adverse Reactions)

Implementation

  • Correct hypokalemia and hypomagnesemia prior to therapy.
  • Oral: Administer tablets once daily at least 1 hr before or 1 hr after a meal for 21 days. Do not divide daily dose.

Patient/Family Teaching

  • Instruct patient to take lapatinib as directed and to review the Patient Information Sheet prior to therapy and with each refill for new information. If a dose is missed take as soon remembered that day. If a day is missed, skip the dose; do not double doses. Caution patient not to share this medication with others, even with same condition; may be harmful.
  • Advise patient to avoid drinking grapefruit juice or eating grapefruit during therapy.
  • Advise patient to report signs or decreased LVEF (shortness of breath, palpitations, fatigue) to health care professional promptly.
  • Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care professional before taking any new medications, especially St. John's wort.
  • Advise patient that lapatinib may cause diarrhea, which may become severe. Instruct patient in how to prevent and manage diarrhea and to notify health care professional if severe.
  • Advise female patients to notify health care professional if pregnancy is planned or suspected; therapy may be teratogenic.

Evaluation/Desired Outcomes

  • Decreased/slowed spread of metastatic breast cancer.

Tykerb

a trademark for lapatinib.
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