Clinical Trials Experience

The safety of TYKERB has been evaluated in more than 3,500 patients in clinical trials. The efficacy and safety of TYKERB in combination with capecitabine in breast cancer was evaluated in 198 patients in a randomized, Phase 3 trial. [See Clinical Studies] Adverse reactions which occurred in at least 10% of patients in either treatment arm and were higher in the combination arm are shown in Table 1.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The most common adverse reactions ( > 20%) during therapy with TYKERB plus capecitabine were gastrointestinal (diarrhea, nausea, and vomiting), dermatologic (palmar­plantar erythrodysesthesia and rash), and fatigue. Diarrhea was the most common adverse reaction resulting in discontinuation of study medication.

The most common Grade 3 and 4 adverse reactions (NCI CTC v3) were diarrhea and palmar-plantar erythrodysesthesia. Selected laboratory abnormalities are shown in Table 2.

Table 1. Adverse Reactions Occurring in 10% of Patients

Table 2. Selected Laboratory Abnormalities

Decreases in Left Ventricular Ejection Fraction: Due to potential cardiac toxicity with HER2 (ErbB2) inhibitors, LVEF was monitored in clinical trials at approximately 8-week intervals. LVEF decreases were defined as signs or symptoms of deterioration in left ventricular cardiac function that are ≥ Grade 3 (NCI CTCAE), or a ≥ 20% decrease in left ventricular cardiac ejection fraction relative to baseline which is below the institution's lower limit of normal. Among 198 patients who received lapatinib/capecitabine combination treatment, 3 experienced Grade 2 and one had Grade 3 LVEF adverse reactions (NCI CTC 3.0). [See WARNINGS and PRECAUTIONS]

Hepatotoxicity: Lapatinib has been associated with hepatoxicity [see Boxed Warning and WARNINGS and PRECAUTIONS].

Interstitial Lung Disease/Pneumonitis: Lapatinib has been associated with interstitial lung disease and pneumonitis in monotherapy or in combination with other chemotherapies [see WARNINGS and PRECAUTIONS].

Effects of Lapatinib on Drug Metabolizing Enzymes and Drug Transport Systems

Lapatinib inhibits CYP3A4 and CYP2C8 in vitro at clinically relevant concentrations. Caution should be exercised and dose reduction of the concomitant substrate drug should be considered when dosing lapatinib concurrently with medications with narrow therapeutic windows that are substrates of CYP3A4 or CYP2C8. 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.

Lapatinib inhibits human P-glycoprotein. If TYKERB is administered with drugs that are substrates of Pgp, increased concentrations of the substrate drug are likely, and caution should be exercised.

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 (see Ketoconazole and Carbamazepine sections, below). Dose adjustment of lapatinib should be considered for patients who must receive concomitant strong inhibitors or concomitant strong inducers of CYP3A4 enzymes [see DOSAGE AND ADMINISTRATION].

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 (Pgp, ABCB1). If TYKERB is administered with drugs that inhibit Pgp, increased concentrations of lapatinib are likely, and caution should be exercised.

Other Chemotherapy Agents

In a separate study, concomitant administration of lapatinib with capecitabine did not meaningfully alter the pharmacokinetics of either agent (or the metabolites of capecitabine).

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