INTERACTIONS Lapatinib tablets are likely to increase exposure to concomitantly administered drugs which are substrates of CYP3A4, CYP2C8, or P-glycoprotein (ABCB1). (7.1) Avoid strong CYP3A4 inhibitors. If unavoidable, consider dose reduction of lapatinib tablets in patients coadministered a strong CYP3A4 inhibitor. (2.2, 7.2) Avoid strong CYP3A4 inducers. If unavoidable, consider gradual dose increase of lapatinib tablets in patients coadministered a strong CYP3A4 inducer. (2.2, 7.2)
7.1 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 lapatinib tablets 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 lapatinib tablets 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 lapatinib tablets 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 lapatinib tablets 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 lapatinib tablets 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 (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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) ]</span> . 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%.
7.3 Drugs That Inhibit Drug Transport Systems Lapatinib is a substrate of the efflux transporter P-glycoprotein (P-gp, ABCB1). If lapatinib tablets are administered with drugs that inhibit P-gp, increased concentrations of lapatinib are likely, and caution should be exercised.
7.4 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.
Lapatinib tablets are contraindicated in patients with known severe hypersensitivity (e.g., anaphylaxis) to this product or any of its components. Known severe hypersensitivity (e.g., anaphylaxis) to this product or any of its components. ( 4 )
AND PRECAUTIONS Decreases in left ventricular ejection fraction (LVEF) have been reported. Confirm normal LVEF before starting lapatinib tablets and continue evaluations during treatment. ( 5.1 ) Lapatinib has been associated with hepatotoxicity. Monitor liver function tests before initiation of treatment, every 4 to 6 weeks during treatment, and as clinically indicated. Discontinue and do not restart lapatinib tablets if patients experience severe changes in liver function tests. ( 5.2 ) Dose reduction in patients with severe hepatic impairment should be considered. ( 2.2 , 5.3 , 8.7 ) Diarrhea, including severe diarrhea, has been reported during treatment. Manage with antidiarrheal agents, and replace fluids and electrolytes if severe. ( 5.4 ) Lapatinib has been associated with interstitial lung disease and pneumonitis. Discontinue lapatinib tablets if patients experience severe pulmonary symptoms. ( 5.5 ) Lapatinib may prolong the QT interval in some patients. Consider electrocardiogram (ECG) and electrolyte monitoring. ( 5.6 , 12.2 ) Severe cutaneous reactions have been reported. Discontinue lapatinib tablets if life-threatening reactions are suspected. ( 5.7 ) Lapatinib tablets can cause fetal harm. Advise patients of the potential risk to the fetus and to use effective contraception. ( 5.8 , 8.1 , 8.3 ).
5.1 Decreased Left Ventricular Ejection Fraction Lapatinib tablets has been reported to decrease LVEF <span class="opacity-50 text-xs">[see Adverse Reactions (6.1 ) ]</span>. In clinical trials, the majority (greater than 57%) of LVEF decreases occurred within the first 12 weeks of treatment; however, data on long-term exposure are limited. Caution should be taken if lapatinib tablets are to be administered to patients with conditions that could impair left ventricular function. LVEF should be evaluated in all patients prior to initiation of treatment with lapatinib tablets to ensure that the patient has a baseline LVEF that is within the institution's normal limits. LVEF should continue to be evaluated during treatment with lapatinib tablets to ensure that LVEF does not decline below the institution's normal limits <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) ]</span>.
5.2 Hepatotoxicity Hepatotoxicity [alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 3 times the upper limit of normal (ULN) and total bilirubin greater than 2 times the ULN] has been observed in clinical trials (less than 1% of patients) and postmarketing experience. The hepatotoxicity may be severe and deaths have been reported. Causality of the deaths is uncertain. The hepatotoxicity may occur days to several months after initiation of treatment. Liver function tests (transaminases, bilirubin, and alkaline phosphatase) should be monitored before initiation of treatment, every 4 to 6 weeks during treatment, and as clinically indicated. If changes in liver function are severe, therapy with lapatinib tablets should be discontinued and patients should not be retreated with lapatinib tablets <span class="opacity-50 text-xs">[see Adverse Reactions (6.1 )]</span>.
5.3 Patients with Severe Hepatic Impairment If lapatinib tablets are to be administered to patients with severe pre existing hepatic impairment, dose reduction should be considered <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) and Use in Specific Populations (8.7) ]</span>. In patients who develop severe hepatotoxicity while on therapy, lapatinib tablets should be discontinued and patients should not be retreated with lapatinib tablets <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2)]</span>.
5.4 Diarrhea Diarrhea has been reported during treatment with lapatinib <span class="opacity-50 text-xs">[see Adverse Reactions(6.1)]</span>. The diarrhea may be severe, and deaths have been reported. Diarrhea generally occurs early during treatment with lapatinib with almost half of those patients with diarrhea first experiencing it within 6 days. This usually lasts 4 to 5 days. Lapatinib-induced diarrhea is usually low-grade, with severe diarrhea of NCI CTCAE Grades 3 and 4 occurring in less than 10% and less than 1% of patients, respectively. Early identification and intervention is critical for the optimal management of diarrhea. Patients should be instructed to report any change in bowel patterns immediately. Prompt treatment of diarrhea with anti-diarrheal agents (such as loperamide) after the first unformed stool is recommended. Severe cases of diarrhea may require administration of oral or intravenous electrolytes and fluids, use of antibiotics, such as fluoroquinolones (especially if diarrhea is persistent beyond 24 hours, there is fever, or Grade 3 or 4 neutropenia), and interruption or discontinuation of therapy with lapatinib <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) ]</span>.
5.5 Interstitial Lung Disease/Pneumonitis Lapatinib has been associated with interstitial lung disease and pneumonitis in monotherapy or in combination with other chemotherapies <span class="opacity-50 text-xs">[see Adverse Reactions (6.1 )]</span>. Patients should be monitored for pulmonary symptoms indicative of interstitial lung disease or pneumonitis. Lapatinib tablets should be discontinued in patients who experience pulmonary symptoms indicative of interstitial lung disease/pneumonitis, which are greater than or equal to Grade 3 (NCI CTCAE v 3.0).
5.6 QT Prolongation A concentration-dependent QT prolongation has been associated with lapatinib tablets <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.2 )]</span>. Monitor patients who have or may develop prolongation of QTc during treatment with lapatinib tablets. These conditions include patients with hypokalemia or hypomagnesemia, with congenital long QT syndrome, patients taking antiarrhythmic medicines or other medicinal products with known risk for QT prolongation/Torsades de Pointes (TdP), and cumulative high-dose anthracycline therapy. Correct hypokalemia or hypomagnesemia prior to lapatinib tablets administration.
5.7 Severe Cutaneous Reactions Severe cutaneous reactions have been reported with lapatinib tablets. If life-threatening reactions, such as erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis (e.g., progressive skin rash often with blisters or mucosal lesions) are suspected, discontinue treatment with lapatinib tablets.
5.8 Embryo-Fetal Toxicity Based on its mechanism of action and findings in animal studies, lapatinib tablets can cause fetal harm when administered to a pregnant woman. In animal reproductive studies, administration of lapatinib to pregnant rats during the period of organogenesis and through lactation led to death of offspring within the first 4 days after birth at maternal exposures that were ≥ 3.3 times the human clinical exposure based on AUC following 1,250 mg dose of lapatinib plus capecitabine. When administered to pregnant animals during the period of organogenesis, lapatinib caused fetal anomalies (rats) or abortions (rabbits) at maternally toxic doses (with maternal exposures approximately 6.4 and 0.2 times, respectively, the human clinical exposure based on AUC following 1,250 mg dose of lapatinib plus capecitabine). Advise pregnant women and females of reproductive potential of the potential risk to the fetus <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1 ) and Clinical Pharmacology (12.1 )]</span>. Verify the pregnancy status of females of reproductive potential prior to initiation of lapatinib tablets. Advise females of reproductive potential to use effective contraception during treatment with lapatinib tablets and for 1 week after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with lapatinib tablets and for 1 week after the last dose <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1 , 8.3 )]</span>.