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Lapatinib (Tykerb) for Combination Breast Cancer Chemotherapy

What is lapatinib (Tykerb), and how is it used?

Tykerb is indicated in combination with:

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

Limitation of Use: Patients should have disease progression on trastuzumab prior to initiation of treatment with Tykerb in combination with capecitabine.

  • letrozole for the treatment of postmenopausal women with hormone receptor-positive metastatic breast cancer that overexpresses the HER2 receptor for whom hormonal therapy is indicated. Tykerb in combination with an aromatase inhibitor has not been com

What are the side effects of lapatinib (Tykerb)?


Tykerb may cause serious side effects, including:

  • heart problems, including decreased pumping of blood from the heart and an abnormal heartbeat.
  • Signs and symptoms of an abnormal heartbeat include:
  • feeling like your heart is pounding or racing
  • dizziness
  • tiredness
  • feeling lightheaded
  • shortness of breath Your doctor should check your heart function before you start taking Tykerb and during treatment.
  • liver problems.
  • Liver problems can be severe and deaths have happened. Signs and symptoms of liver problems include:
  • itching
  • yellowing of your skin or the white part of your eyes
  • dark urine
  • pain or discomfort in the right upper stomach area Your doctor should do blood tests to check your liver before you start taking Tykerb and during treatment.
  • diarrhea. Diarrhea is common with Tykerb and may sometimes be severe. Severe diarrhea can cause loss of body fluid (dehydration) and some deaths have happened. Call your doctor right away if you have a change in bowel pattern or if you have severe diarrhea. Follow your doctor’s instructions for what to do to help prevent or treat diarrhea.
  • lung problems. Symptoms of a lung problem with Tykerb include a cough that will not go away or shortness of breath.
  • severe skin reactions. Tykerb may cause severe skin reactions. Tell your doctor right away if you develop a skin rash, red skin, blistering of the lips, eyes, or mouth, peeling of the skin, fever, or any combination of these.

As severe skin reactions can be life-threatening, your doctor may tell you to stop taking Tykerb. Call your doctor right away if you have any of the signs or symptoms of the serious side effects listed above.

Common side effects of Tykerb in combination with capecitabine or letrozole include:

Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of Tykerb. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also get side effects from the other medicines taken with Tykerb. Talk to your doctor about possible side effects you may get during treatment.

What is the dosage for lapatinib (Tykerb)?

HER2-Positive Metastatic Breast Cancer: The recommended dose of Tykerb is 1,250 mg given orally once daily on Days 1-21 continuously in combination with capecitabine 2,000 mg/m2 /day (administered orally in 2 doses approximately 12 hours apart) on Days 1-14 in a repeating 21-day cycle. Tykerb should be taken at least one hour before or one hour after a meal. The dose of Tykerb should be once daily (5 tablets administered all at once); dividing the daily dose is not recommended. Capecitabine should be taken with food or within 30 minutes after food.

If a day’s dose is missed, the patient should not double the dose the next day. Treatment should be continued until disease progression or unacceptable toxicity occurs. Hormone Receptor-Positive, HER2-Positive Metastatic Breast Cancer: The recommended dose of Tykerb is 1,500 mg given orally once daily continuously in combination with letrozole. When coadministered with Tykerb, the recommended dose of letrozole is 2.5 mg once daily. Tykerb should be taken at least one hour before or one hour after a meal. The dose of Tykerb should be once daily (6 tablets administered all at once); dividing the daily dose is not recommended.

What drugs interact with lapatinib (Tykerb)?

Effects of Lapatinib on Drug-Metabolizing Enzymes and Drug Transport Systems Lapatinib inhibits CYP3A4, CYP2C8, and P-glycoprotein (P-gp, ABCB1) in vitro at clinically relevant concentrations and is a weak inhibitor of CYP3A4 in vivo.

Caution should be exercised and dose reduction of the concomitant substrate drug should be considered when dosing Tykerb concurrently with medications with narrow therapeutic windows that are substrates of CYP3A4, CYP2C8, or P-gp.

Lapatinib did not significantly inhibit the following enzymes in human liver microsomes: CYP1A2, CYP2C9, CYP2C19, and CYP2D6 or UGT enzymes in vitro, however, the clinical significance is unknown.

Midazolam: Following coadministration of Tykerb and midazolam (CYP3A4 substrate), 24-hour systemic exposure (AUC) of orally administered midazolam increased 45%, while 24-hour AUC of intravenously administered midazolam increased 22%. Paclitaxel: In cancer patients receiving Tykerb and paclitaxel (CYP2C8 and P-gp substrate), 24-hour systemic exposure (AUC) of paclitaxel was increased 23%. This increase in paclitaxel exposure may have been underestimated from the in vivo evaluation due to study design limitations.

Digoxin: Following coadministration of Tykerb and digoxin (P-gp substrate), systemic AUC of an oral digoxin dose increased approximately 2.8-fold. Serum digoxin concentrations should be monitored prior to initiation of Tykerb and throughout coadministration. If digoxin serum concentration is greater than 1.2 ng/mL, the digoxin dose should be reduced by half. 7.2 Drugs That Inhibit or Induce Cytochrome P450 3A4 Enzymes Lapatinib undergoes extensive metabolism by CYP3A4, and concomitant administration of strong inhibitors or inducers of CYP3A4 alter lapatinib concentrations significantly. Dose adjustment of lapatinib should be considered for patients who must receive concomitant strong inhibitors or concomitant strong inducers of CYP3A4 enzymes.

Ketoconazole: In healthy subjects receiving ketoconazole, a CYP3A4 inhibitor, at 200 mg twice daily for 7 days, systemic exposure (AUC) to lapatinib was increased to approximately 3.6-fold of control and half-life increased to 1.7-fold of control. Carbamazepine: In healthy subjects receiving the CYP3A4 inducer, carbamazepine, at 100 mg twice daily for 3 days and 200 mg twice daily for 17 days, systemic exposure (AUC) to lapatinib was decreased approximately 72%.

Drugs That Inhibit Drug Transport Systems

Lapatinib is a substrate of the efflux transporter P-glycoprotein (P-gp, ABCB1). If Tykerb is administered with drugs that inhibit P-gp, increased concentrations of lapatinib are likely, and caution should be exercised.

Acid-Reducing Agents

The aqueous solubility of lapatinib is pH dependent, with higher pH resulting in lower solubility. However, esomeprazole, a proton pump inhibitor, administered at a dose of 40 mg once daily for 7 days, did not result in a clinically meaningful reduction in lapatinib steady-state exposure.


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Is lapatinib (Tykerb) safe to take while pregnant or breastfeeding?


Based on findings in animals, Tykerb can cause fetal harm when administered to a pregnant woman. Lapatinib administered to rats during organogenesis and through lactation led to death of offspring within the first 4 days after birth. When administered to pregnant animals during the period of organogenesis, lapatinib caused fetal anomalies (rats) or abortions (rabbits) at maternally toxic doses.

There are no adequate and well-controlled studies with Tykerb in pregnant women. Women should be advised not to become pregnant when taking Tykerb. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. In a study where pregnant rats were dosed with lapatinib during organogenesis and through lactation, at a dose of 120 mg/kg/day (approximately 6.4 times the human clinical exposure based on AUC following 1,250-mg dose of lapatinib plus capecitabine), 91% of the pups had died by the fourth day after birth, while 34% of the 60 mg/kg/day pups were dead.

The highest no-effect dose for this study was 20 mg/kg/day (approximately equal to the human clinical exposure based on AUC). Lapatinib was studied for effects on embryo-fetal development in pregnant rats and rabbits given oral doses of 30, 60, and 120 mg/kg/day.

There were no teratogenic effects; however, minor anomalies (left-sided umbilical artery, cervical rib, and precocious ossification) occurred in rats at the maternally toxic dose of 120 mg/kg/day (approximately 6.4 times the human clinical exposure based on AUC following 1,250-mg dose of lapatinib plus capecitabine).

In rabbits, lapatinib was associated with maternal toxicity at 60 and 120 mg/kg/day (approximately 0.07 and 0.2 times the human clinical exposure, respectively, based on AUC following 1,250- mg dose of lapatinib plus capecitabine) and abortions at 120 mg/kg/day. Maternal toxicity was associated with decreased fetal body weights and minor skeletal variations.

Nursing Mothers

It is not known whether lapatinib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Tykerb, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

How does lapatinib (Tykerb) work?

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 Ki app values of 3nM and 13nM, respectively) with a dissociation half-life of greater than or equal to 300 minutes. Lapatinib inhibits ErbB-driven tumor cell growth in vitro and in various animal models.

An additive effect was demonstrated in an in vitro study when lapatinib and 5-FU (the active metabolite of capecitabine) were used in combination in the 4 tumor cell lines tested. The growth inhibitory effects of lapatinib were evaluated in trastuzumab-conditioned cell lines.

Lapatinib retained significant activity against breast cancer cell lines selected for long-term growth in trastuzumab-containing medium in vitro. These in vitro findings suggest non-cross-resistance between these two agents. Hormone receptor-positive breast cancer cells (with ER [Estrogen Receptor] and/or PgR [Progesterone Receptor]) that coexpress the HER2 tend to be resistant to established endocrine therapies. Similarly, hormone receptor-positive breast cancer cells that initially lack EGFR or HER2 upregulate these receptor proteins as the tumor becomes resistant to endocrine therapy.


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