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  • CLASSES

    Small Molecule Antineoplastic EGFR (HER1) and HER2/neu Inhibitors

    BOXED WARNING

    Hepatic disease, hepatotoxicity

    Use lapatinib with caution in patients with pre-existing hepatic disease. Hepatotoxicity has been observed rarely in clinical trials and has also been reported in postmarketing experience with lapatinib; deaths have been reported, although causality is uncertain. The onset of hepatotoxicity may be days to several months after initiation of treatment. Monitor liver function tests (transaminases, bilirubin, and alkaline phosphatase) at baseline, every 4 to 6 weeks during treatment, and as clinically indicated. Permanently discontinue lapatinib if severe changes in liver function occur. Because lapatinib is extensively metabolized by the liver, an adjustment to the starting dose is necessary in patients with Child-Pugh Class C hepatic impairment.[33192]

    DEA CLASS

    Rx

    DESCRIPTION

    Kinase inhibitor targeted against intracellular HER2 and EGFR
    Used in combination with capecitabine or letrozole for HER2 positive metastatic breast cancer
    Black box warning for hepatotoxicity; monitor liver function tests during treatment

    COMMON BRAND NAMES

    Tykerb

    HOW SUPPLIED

    Tykerb Oral Tab: 250mg

    DOSAGE & INDICATIONS

    For the treatment of breast cancer.
    For the treatment of HER2-positive advanced or metastatic breast cancer, in combination with capecitabine, in patients have received prior therapy including an anthracycline, a taxane, and trastuzumab.
    Oral dosage
    Adults

    1,250 mg PO once daily on days 1 through 21, in combination with capecitabine (1,000 mg/m2 PO twice daily on days 1 through 14). Repeat every 21 days until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a randomized, phase 3 clinical trial, treatment with lapatinib plus capecitabine (n = 198) significantly improved the median time to progression (TTP) by independent assessment compared with capecitabine alone (n = 201) (27.1 months vs. 18.6 months), with a response rate of 23.7% vs. 13.9%, respectively, in of patients with progressive, locally advanced or metastatic breast cancer. The median TTP was also significantly improved by investigator assessment (23.9 months vs. 18.3 months), with a response rate of 31.8% vs. 17.4%, respectively. Crossover from the capecitabine monotherapy arm to capecitabine plus lapatinib was allowed following analysis of the TTP results, resulting in a median overall survival (OS) was 75 weeks versus 65.9 weeks. Lapatinib-based chemotherapy was less effective than trastuzumab-based chemotherapy in 2 randomized studies; thus, patients should have progressed on trastuzumab prior to treatment with lapatinib plus capecitabine.[33192]

    For the treatment of postmenopausal women with hormone receptor (HR)-positive, HER2-positive metastatic breast cancer, in combination with letrozole.
    Oral dosage
    Adults

    1,500 mg PO once daily, in combination with letrozole (2.5 mg PO once daily). Treatment should be administered continuously. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Treatment with lapatinib plus letrozole significantly improved median progression-free survival (PFS) (35.4 months vs. 13 months) compared with letrozole alone in a randomized, double-blind clinical trial of postmenopausal women with previously untreated HR-positive, HER2-positive metastatic breast cancer; the response rate was 27.9% vs. 14.8%, respectively. These results were confirmed in another phase 3 clinical trial, where postmenopausal women with HR-positive, HER2-positive metastatic breast cancer that progressed on trastuzumab-based chemotherapy and endocrine therapies were randomized to treatment with lapatinib plus an aromatase inhibitor (AI), trastuzumab plus an AI, or lapatinib in combination with both trastuzumab and an AI. In this trial, median PFS was significantly improved in patients receiving lapatinib, trastuzumab, and an AI compared with trastuzumab plus an AI (11 months vs. 5.6 months);[33192] PFS was also significantly improved with lapatinib plus an AI compared with trastuzumab plus an AI (8.3 months vs. 5.6 months).[63830] Progression-free survival was not significantly different among patients treated with trastuzumab plus an AI compared with lapatinib plus an AI (5.6 months vs. 8.3 months).[33192]

    For the treatment of HER2-positive, trastuzumab-refractory metastatic breast cancer† in combination with trastuzumab.
    Oral dosage
    Adults

    1,000 mg PO once daily in combination with trastuzumab (4 mg/kg IV infused over 90 minutes on week 1; starting in week 2, give 2 mg/kg intravenous infused over 30 minutes once weekly). Continue until disease progression or unacceptable toxicity. In a phase III trial of 296 patients with HER2-positive, trastuzumab-refractory metastatic breast cancer, the combination of lapatinib/trastuzumab was compared to lapatinib alone (1,500 mg once daily). In the intent-to-treat population, patients had received a median of 3 prior trastuzumab-containing regimens for metastatic breast cancer. Progression-free survival, the primary endpoint, was significantly greater in the combination arm (12 weeks vs. 8.1 weeks, p = 0.008). The overall response rate was not significantly different between the 2 arms (10.3% vs. 6.9%, p = 0.46). Diarrhea occurred significantly more often in the combination therapy arm (60% vs. 48%, p = 0.03); the incidence of symptomatic and asymptomatic cardiac events were also higher in the combination therapy arm (2%/3.4% vs. 0.7%/1.4%). NOTE: Dosage adjustments of lapatinib may be required if used in combination with strong CYP3A4 inducers or inhibitors. Clinical data are not available assessing proper dosage adjustment recommendations.

    MAXIMUM DOSAGE

    Adults

    1,500 mg per day PO.

    Geriatric

    1,500 mg per day PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Baseline Hepatic Impairment
    Child-Pugh Class A or B: No dosage adjustment necessary.
    Child-Pugh Class C: Reduce the dose of lapatinib from 1,250 mg PO daily to 750 mg PO daily when given with capecitabine (HER2-positive metastatic breast cancer) and from 1,500 mg PO daily to 1,000 mg PO daily when given with letrozole (HR-positive, HER2-positive breast cancer). These doses are predicted to adjust the area under the curve to the range seen in patients without hepatic impairment; however, there are no clinical data with this dose adjustment in patients with severe hepatic impairment.
     
    Treatment-Related Hepatotoxicity
    Severe hepatotoxicity: Permanently discontinue lapatinib therapy.

    Renal Impairment

    No dosage adjustments are needed.

    ADMINISTRATION

    For storage information, see specific product information within the How Supplied section.

    Oral Administration
    Oral Solid Formulations

    Administer at least 1 hour before or 1 hour after a meal.
    Administer once daily; do not divide the daily dose.
    If a dose is missed, make up the missed dose. Do not administer 2 doses at the same time.

    STORAGE

    Tykerb:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Lapatinib is contraindicated for use in patients with a known severe hypersensitivity to lapatinib or any of its components.

    Serious rash

    Severe cutaneous reactions have been reported. If life-threatening serious rash 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.

    Heart failure

    Use lapatinib with caution in patients with a history of heart failure, or in patients with conditions that could impair left ventricular function. Lapatinib has been reported to decrease left ventricular ejection fraction (LVEF); the majority of LVEF decreases occurred within the first 12 weeks of therapy in clinical trials, but data on long-term exposure are limited. Evaluate LVEF prior to initiating treatment with lapatinib in all patients to ensure that the baseline LVEF is within the institutional normal limits; continue to evaluate LVEF treatment to ensure that LVEF does not decline below the institutional normal limit. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for decreases in LVEF.[33192]

    Hepatic disease, hepatotoxicity

    Use lapatinib with caution in patients with pre-existing hepatic disease. Hepatotoxicity has been observed rarely in clinical trials and has also been reported in postmarketing experience with lapatinib; deaths have been reported, although causality is uncertain. The onset of hepatotoxicity may be days to several months after initiation of treatment. Monitor liver function tests (transaminases, bilirubin, and alkaline phosphatase) at baseline, every 4 to 6 weeks during treatment, and as clinically indicated. Permanently discontinue lapatinib if severe changes in liver function occur. Because lapatinib is extensively metabolized by the liver, an adjustment to the starting dose is necessary in patients with Child-Pugh Class C hepatic impairment.[33192]

    Alcoholism, bradycardia, cardiac arrhythmias, cardiac disease, coronary artery disease, diabetes mellitus, females, geriatric, hypocalcemia, hypokalemia, hypomagnesemia, long QT syndrome, malnutrition, myocardial infarction, QT prolongation, thyroid disease, torsade de pointes

    Lapatinib prolongs the QT interval in a dose-dependent manner; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Use lapatinib with caution in patients with cardiac disease or other conditions that may increase the risk of QT prolongation including cardiac arrhythmias, congenital long QT syndrome, heart failure, bradycardia, myocardial infarction, hypertension, coronary artery disease, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances, and high-dose cumulative anthracycline therapy. Females, geriatric patients, patients with diabetes mellitus, thyroid disease, malnutrition, alcoholism, or hepatic disease may also be at increased risk for QT prolongation.[28432] [28457] [56592] [56959] [56961] [56963] Monitor ECGs for QT prolongation and monitor electrolytes. Correct hypokalemia or hypomagnesemia before lapatinib administration.[33192]

    Pneumonitis, pulmonary disease

    Use lapatinib with caution in patients with pre-existing pulmonary disease. Lapatinib has been associated with interstitial lung disease (ILD) and pneumonitis, both when used alone and when used in combination with other chemotherapy. Monitor patients for pulmonary symptoms. Discontinue lapatinib in any patient experiencing grade 3 or higher symptoms indicative of ILD/pneumonitis.

    Diarrhea

    Diarrhea has been reported with lapatinib treatment, and in some cases has been severe or fatal. Early identification and intervention are critical for optimal management. Diarrhea generally occurred early in treatment, with almost half occurring within 6 days of initiation of therapy. Instruct patients to report any change in bowel patterns immediately. Prompt treatment of diarrhea with antidiarrheal agents (e.g., loperamide) after the first unformed stool is recommended. Severe cases may require administration of oral or intravenous electrolytes, fluids, or use of antibiotics, especially if diarrhea persists beyond 24 hours, if there is fever, or if there is concurrent grade 3 or 4 neutropenia. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary.[33192]

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during lapatinib treatment and for at least 1 week after the last dose. Although there are no adequately controlled studies in pregnant women, lapatinib can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving lapatinib should be apprised of the potential hazard to the fetus. In embryo-fetal development studies, minor anomalies (e.g., left-sided umbilical artery, cervical rib, and precocious ossification) occurred in rats at maternally toxic exposures of approximately 6.4 times the human clinical exposure based on AUC after a 1,250 mg dose of lapatinib. In pre- and postnatal development studies, decreased postnatal survival occurred after administration of lapatinib to pregnant rats during organogenesis and through lactation. In this study, lapatinib exposures of approximately 3.3 and 6.4 times the human exposure based on AUC after a 1,250 mg dose resulted in 91% and 34% of pup deaths, respectively, by the fourth day after birth. In rabbits, lapatinib caused maternal toxicity at 0.07 to 0.2 times the human exposure based on AUC after a 1,250 mg dose of lapatinib, and abortions at the higher exposure level. Maternal toxicity was associated with decreased fetal body weights and minor skeletal variations.[33192]

    Contraception requirements, infertility, male-mediated teratogenicity, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during lapatinib treatment. Lapatinib can be teratogenic if taken by the mother during pregnancy. Females of reproductive potential should avoid pregnancy and use effective contraception during and for at least 1 week after treatment with lapatinib. Due to the risk of male-mediated teratogenicity, males with female partners of reproductive potential should also use effective contraception during treatment and for 1 week after the last dose. Females of reproductive potential should undergo pregnancy testing prior to initiation of lapatinib. Women who become pregnant while receiving lapatinib should be apprised of the potential hazard to the fetus. Although there are no data regarding the effect of lapatinib on human fertility, female infertility has been observed in animal studies.

    Breast-feeding

    Due to the potential for serious adverse reactions in nursing infants from lapatinib, advise women to discontinue breast-feeding during treatment and for 1 week after the final dose. It is not known whether lapatinib is present in human milk, although many drugs are excreted in human milk.
     

    ADVERSE REACTIONS

    Severe

    diarrhea / Early / 10.0-14.0
    palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / 12.0-12.0
    elevated hepatic enzymes / Delayed / 0-6.0
    hyperbilirubinemia / Delayed / 0-4.0
    dyspnea / Early / 0-3.0
    nausea / Early / 0-2.0
    vomiting / Early / 0-2.0
    rash / Early / 1.0-2.0
    fatigue / Early / 0-2.0
    headache / Early / 0-2.0
    stomatitis / Delayed / 0-1.0
    anorexia / Delayed / 0-1.0
    dyspepsia / Early / 0-1.0
    alopecia / Delayed / 0-1.0
    xerosis / Delayed / 0-1.0
    pruritus / Rapid / 0-1.0
    insomnia / Early / 0-1.0
    back pain / Delayed / 0-1.0
    arthralgia / Delayed / 0-1.0
    asthenia / Delayed / 0-1.0
    epistaxis / Delayed / 0-1.0
    heart failure / Delayed / 0.5-0.9
    erythema multiforme / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    hepatotoxicity / Delayed / Incidence not known
    torsade de pointes / Rapid / Incidence not known
    serious hypersensitivity reactions or anaphylaxis / Rapid / Incidence not known

    Moderate

    pneumonitis / Delayed / Incidence not known
    QT prolongation / Rapid / Incidence not known

    Mild

    cough / Delayed / 0-8.0

    DRUG INTERACTIONS

    Abarelix: (Major) Lapatinib can prolong the QT interval. Lapatinib should be administered with caution to patients who have or may develop prolongation of QTc such as patients taking medications that lead to QT prolongation including abarelix.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with lapatinib may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of lapatinib could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If lapatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Lapatinib is a weak inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Acetaminophen; Hydrocodone: (Moderate) Concomitant use of hydrocodone with lapatinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of lapatinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If lapatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Lapatinib is a weak inhibitor of CYP3A4.
    Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of lapatinib is necessary. If lapatinib is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a weak CYP3A4 inhibitor like lapatinib can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If lapatinib is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Acetaminophen; Propoxyphene: (Moderate) Propoxyphene, an inhibitor of CYP3A4, may increase the serum concentrations of lapatinib. Use lapatinib and propoxyphene together with caution, and monitor patients closely.
    Afatinib: (Moderate) If the concomitant use of lapatinib and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of lapatinib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and lapatinib is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Alfuzosin: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), alfuzosin and lapatinib should be used together cautiously. Lapatinib can prolong the QT interval. Based on electrophysiology studies performed by the manufacturer, alfuzosin has a slight effect to prolong the QT interval. The QT prolongation appeared less with alfuzosin 10 mg than with 40 mg. The manufacturer warns that the QT effect of alfuzosin should be considered prior to administering the drug to patients taking other medications known to prolong the QT interval.
    Amiodarone: (Major) If possible, avoid coadministration of amiodarone and drugs known to prolong the QT interval. Both lapatinib and amiodarone can prolong the QT interval; therefore coadministration may further increase the risk for QT prolongation. Although the frequency of torsade de pointes (TdP) is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. Lapatinib is a CYP3A4 substrate and a CYP3A4 inhibitor at clinically relevant concentrations in vitro. Also, lapatinib is a substrate and inhibitor of the efflux transporter P-glycoprotein (P-gp, ABCB1). Amiodarone is a P-glycoprotein inhibitor, a CYP3A4 substrate, and a CYP3A4 inhibitor. If lapatinib is coadministered with a CYP3A4 substrate, such as amiodarone, exercise caution and consider dose reduction of amiodarone. Concurrent administration of lapatinib with a P-glycoprotein inhibitor such as amiodarone is likely to cause elevated serum lapatinib concentrations, and caution is recommended.
    Amitriptyline: (Major) Coadministration may result in additive effects on the QT interval. Lapatinib can prolong the QT interval. Tricyclic antidepressants (TCAs) share pharmacologic properties like the Class IA antiarrhythmic agents and may also prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Use caution and monitor for evidence of QT prolongation during concurrent use.
    Amitriptyline; Chlordiazepoxide: (Major) Coadministration may result in additive effects on the QT interval. Lapatinib can prolong the QT interval. Tricyclic antidepressants (TCAs) share pharmacologic properties like the Class IA antiarrhythmic agents and may also prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Use caution and monitor for evidence of QT prolongation during concurrent use.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Lapatinib is a CYP3A4 substrate and a CYP3A4 inhibitor at clinically relevant concentrations in vitro. Also, lapatinib is a substrate and inhibitor of the efflux transporter P-glycoprotein (P-gp, ABCB1). Clarithromycin is a P-glycoprotein (P-gp) inhibitor, a CYP3A4 substrate, and a strong CYP3A4 inhibitor. Concomitant use of lapatinib with strong CYP3A4 inhibitors, such as clarithromycin, should generally be avoided. If concurrent treatment with clarithromycin is necessary, strongly consider a lapatinib dose reduction. If clarithromycin is discontinued, allow 7 days to elapse before increasing the lapatinib dose. Furthermore, if lapatinib will be coadministered with a CYP3A4 substrate, such as clarithromycin, exercise caution and consider dose reduction of clarithromycin. In addition to pharmacokinetic interactions, both lapatinib and clarithromycin can prolong the QT interval; therefore, coadministration may further increase the risk for QT prolongation.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Lapatinib is a CYP3A4 substrate and a CYP3A4 inhibitor at clinically relevant concentrations in vitro. Also, lapatinib is a substrate and inhibitor of the efflux transporter P-glycoprotein (P-gp, ABCB1). Clarithromycin is a P-glycoprotein (P-gp) inhibitor, a CYP3A4 substrate, and a strong CYP3A4 inhibitor. Concomitant use of lapatinib with strong CYP3A4 inhibitors, such as clarithromycin, should generally be avoided. If concurrent treatment with clarithromycin is necessary, strongly consider a lapatinib dose reduction. If clarithromycin is discontinued, allow 7 days to elapse before increasing the lapatinib dose. Furthermore, if lapatinib will be coadministered with a CYP3A4 substrate, such as clarithromycin, exercise caution and consider dose reduction of clarithromycin. In addition to pharmacokinetic interactions, both lapatinib and clarithromycin can prolong the QT interval; therefore, coadministration may further increase the risk for QT prolongation.
    Amprenavir: (Moderate) Lapatinib is a CYP3A4 substrate. Coadministration with amprenavir, a CYP3A4 inhibitor, may result in decreased metabolism and increased serum concentrations of lapatinib.
    Anagrelide: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include lapatinib.
    Apalutamide: (Major) Avoid coadministration of lapatinib with apalutamide if possible due to decreased plasma concentrations of lapatinib. If concomitant use is unavoidable, gradually increase the dose of lapatinib as tolerated from 1,250 mg per day up to 4,500 mg per day for patients being treated for HER2-positive metastatic breast cancer, or from 1,500 mg per day up to 5,500 mg per day for patients being treated for HR-positive, HER2-postiive breast cancer. Lapatinib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased lapatinib exposure by approximately 72%.
    Apomorphine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering lapatinib with apomorphine. Lapatinib can prolong the QT interval. Limited data indicate that QT prolongation is also possible with apomorphine administration. The change in QTc interval is not significant in most patients receiving dosages within the manufacturer's guidelines; however, large increases (> 60 msecs from pre-dose) have occurred in two patients receiving 6 mg doses. Doses <= 6 mg SC are associated with minimal increases in QTc; doses > 6 mg SC do not provide additional clinical benefit and are not recommended.
    Aprepitant, Fosaprepitant: (Major) Use caution if lapatinib and aprepitant, fosaprepitant are used concurrently and monitor for an increase in lapatinib-related adverse effects for several days after administration of a multi-day aprepitant regimen. Lapatinib is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of lapatinib. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important. Lapatinib is also a weak CYP3A4 inhibitor and aprepitant is a CYP3A4 substrate. Coadministration of daily oral aprepitant (230 mg, or 1.8 times the recommended single dose) with a moderate CYP3A4 inhibitor, diltiazem, increased the aprepitant AUC 2-fold with a concomitant 1.7-fold increase in the diltiazem AUC; clinically meaningful changes in ECG, heart rate, or blood pressure beyond those induced by diltiazem alone did not occur. Information is not available regarding the use of aprepitant with weak CYP3A4 inhibitors.
    Aripiprazole: (Major) Because both lapatinib and aripiprazole are associated with a possible risk for QT prolongation and torsade de pointes (TdP), the combination should be used cautiously and with close monitoring. In addition, because aripiprazole is partially metabolized by CYP3A4, increased aripiprazole blood levels may occur when the drug is coadministered with inhibitors of CYP3A4 such as lapatinib. If these agents are used in combination, the patient should be carefully monitored for aripiprazole-related adverse reactions. Because aripiprazole is also metabolized by CYP2D6, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP3A4 inhibitor.
    Arsenic Trioxide: (Major) If possible, drugs that are known to prolong the QT interval should be discontinued prior to initiating arsenic trioxide therapy. QT prolongation should be expected with the administration of arsenic trioxide. Torsade de pointes (TdP) and complete atrioventricular block have been reported. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with arsenic trioxide include lapatinib.
    Artemether; Lumefantrine: (Major) Lapatinib is an inhibitor and both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased concentrations of artemether; lumefantrine. Furthermore, although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Concomitant use of artemether; lumefantrine with drugs that may prolong the QT interval such as lapatinib should be avoided. Consider ECG monitoring if lapatinib must be used with or after artemether; lumefantrine treatment.
    Asenapine: (Major) Asenapine has been associated with QT prolongation. According to the manufacturer, asenapine should be avoided with other agents also known to have this effect (e.g., lapatinib). In vitro, lapatinib, at clinically relevant concentrations, inhibits CYP3A4 and CYP2C8. If lapatinib will be coadministered with a CYP3A4 substrate, exercise caution and consider dose reduction of the concomitant substrate drug, especially for drugs that have a narrow therapeutic index. Asenapine is a CYP3A4 substrate. Use lapatinib with extreme caution, if at all, in patients taking CYP3A4 substrates that also have potential to induce QT prolongation such as asenapine.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with lapatinib may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of lapatinib could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If lapatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Lapatinib is a weak inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of lapatinib is necessary. If lapatinib is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a weak CYP3A4 inhibitor like lapatinib can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If lapatinib is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Atazanavir: (Major) Lapatinib is a CYP3A4 substrate, and concomitant use of lapatinib with strong CYP3A4 inhibitors, such as atazanavir, should generally be avoided. If concurrent treatment with atazanavir is necessary, strongly consider reducing the adult lapatinib dose to 500 mg/day (no clinical data are available to support this dose adjustment). If atazanavir is discontinued, allow 7 days to elapse before increasing the lapatinib dose.
    Atazanavir; Cobicistat: (Major) Avoid coadministration of lapatinib with cobicistat if possible due to increased plasma concentrations of both drugs. If concomitant use is unavoidable, consider a lapatinib dose reduction to 500 mg/day, as this dose is predicted to adjust the lapatinib exposure to the range observed without cobicistat. If cobicistat is discontinued, a washout period of approximately 1 week should be allowed before the lapatinib dose is adjusted upward to the indicated dose. Lapatinib is extensively metabolized by CYP3A4. Cobicistat is a strong CYP3A4 inhibitor. In a drug interaction study, concurrent administration with another strong CYP3A4 inhibitor increased lapatinib systemic exposure (AUC) by approximately 3.6-fold and the half-life increased by 1.7-fold. In addition, lapatinib is a CYP3A4 inhibitor, and cobicistat is a substrate of CYP3A4. (Major) Lapatinib is a CYP3A4 substrate, and concomitant use of lapatinib with strong CYP3A4 inhibitors, such as atazanavir, should generally be avoided. If concurrent treatment with atazanavir is necessary, strongly consider reducing the adult lapatinib dose to 500 mg/day (no clinical data are available to support this dose adjustment). If atazanavir is discontinued, allow 7 days to elapse before increasing the lapatinib dose.
    Atomoxetine: (Major) QT prolongation has occurred during therapeutic use of atomoxetine and following overdose. Atomoxetine is considered a drug with a possible risk of torsade de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with atomoxetine include lapatinib.
    Avanafil: (Major) Avanafil is a substrate of and primarily metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase avanafil exposure. Patients taking moderate CYP3A4 inhibitors including lapatinib, should take avanafil with caution and adhere to a maximum recommended adult avanafil dose of 50 mg/day.
    Azithromycin: (Major) Lapatinib should be used with caution in patients taking medications that may prolong the QT interval, such as azithromycin; consider ECG and electrolyte monitoring. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience. Correct hypokalemia or hypomagnesemia prior to lapatinib administration. There have been case reports of QT prolongation and TdP with the use of azithromycin in postmarketing reports.
    Bedaquiline: (Major) Concurrent use of bedaquiline and a strong CYP3A4 inhibitor, such as lapatinib, for more than 14 days should be avoided unless the benefits justify the risks. When administered together, lapatinib may inhibit the metabolism of bedaquiline resulting in increased systemic exposure (AUC) and potentially more adverse reactions. Furthermore, since both drugs are associated with QT prolongation, coadministration may result in additive prolongation of the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
    Betrixaban: (Major) Avoid betrixaban use in patients with severe renal impairment receiving lapatinib. Reduce betrixaban dosage to 80 mg PO once followed by 40 mg PO once daily in all other patients receiving lapatinib. Bleeding risk may be increased; monitor patients closely for signs and symptoms of bleeding. Betrixaban is a substrate of P-gp; lapatinib inhibits P-gp.
    Bexarotene: (Moderate) Lapatinib is metabolized by CYP3A4 and CYP3A5 enzymes. Drugs that are inducers of CYP3A4 activity, such as bexarotene, will decrease the plasma concentrations of lapatinib. If treatment with bexarotene is necessary, consider a lapatinib dose escalation. If bexarotene is discontinued, reduce the lapatinib dose to the indicated dose.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include lapatinib.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include lapatinib.
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering lapatinib with boceprevir due to an increased potential for lapatinib-related adverse events. If lapatinib dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of lapatinib and boceprevir. Both lapatinib and boceprevir are substrates and inhibitors of the hepatic isoenzyme CYP3A4. Additionally, lapatinib is an inhibitor of the drug efflux transporter P-glycoprotein (PGP); boceprevir is partially metabolized by this efflux protein. When used in combination, the plasma concentrations of both medications may be elevated.
    Bosentan: (Moderate) Lapatinib is metabolized by CYP3A4 and CYP3A5 enzymes. Drugs that are inducers of CYP3A4 activity, such as bosentan, will decrease the plasma concentrations of lapatinib. If treatment with bosentan is necessary, consider a lapatinib dose escalation. If bosentan is discontinued, reduce the lapatinib dose to the indicated dose.
    Brigatinib: (Moderate) Monitor for an increase in lapatinib-related adverse reactions if coadministration with brigatinib is necessary. Lapatinib is a substrate of P-glycoprotein (P-gp). Brigatinib inhibits P-gp in vitro and may have the potential to increase concentrations of P-gp substrates.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with lapatinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of lapatinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If lapatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Lapatinib is a weak inhibitor of CYP3A4.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with lapatinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of lapatinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If lapatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Lapatinib is a weak inhibitor of CYP3A4.
    Bupivacaine; Lidocaine: (Major) Concomitant use of systemic lidocaine and lapatinib may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; lapatinib inhibits CYP3A4. Lapatinib can also prolong the QT interval. Lapatinib should be administered with caution to patients who have or may develop prolongation of QTc such as patients taking anti-arrhythmic medicines that lead to QT prolongation.
    Buprenorphine: (Major) Buprenorphine should be used cautiously and with close monitoring with lapatinib. Both lapatinib and buprenorphine have a possible risk of QT prolongation and torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. In addition, the plasma concentrations of buprenorphine, a CYP3A4 substrate, may be increased when administered concurrently with lapatinib, a CYP3A4 inhibitor, further increasing the risk of toxicity. If these drugs are used together, consider dose reduction of buprenorphine. Monitor for evidence of QT prolongation and other buprenorphine-related adverse reactions, such as respiratory depression and sedation.
    Buprenorphine; Naloxone: (Major) Buprenorphine should be used cautiously and with close monitoring with lapatinib. Both lapatinib and buprenorphine have a possible risk of QT prolongation and torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. In addition, the plasma concentrations of buprenorphine, a CYP3A4 substrate, may be increased when administered concurrently with lapatinib, a CYP3A4 inhibitor, further increasing the risk of toxicity. If these drugs are used together, consider dose reduction of buprenorphine. Monitor for evidence of QT prolongation and other buprenorphine-related adverse reactions, such as respiratory depression and sedation.
    Cabozantinib: (Minor) Monitor for an increase in lapatinib-related adverse reactions if coadministration with cabozantinib is necessary. Lapatinib is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Carbamazepine: (Major) Lapatinib is metabolized by CYP3A4 and CYP3A5 enzymes. Drugs that are inducers of CYP3A4 activity will decrease the plasma concentrations of lapatinib. In patients receiving lapatinib and carbamazepine (100 mg twice daily for 3 days then 200 mg twice daily for 17 days), systemic exposure to lapatinib was decreased by approximately 72%. Strong CYP3A4 inducers, such as carbamazepine, should be avoided when patients are receiving lapatinib. If treatment with carbamazepine is necessary, consider a lapatinib dose escalation. If carbamazepine is discontinued, reduce the lapatinib dose to the indicated dose.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with lapatinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of lapatinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If lapatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Lapatinib is a weak inhibitor of CYP3A4.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with lapatinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of lapatinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If lapatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Lapatinib is a weak inhibitor of CYP3A4.
    Ceritinib: (Major) Avoid coadministration of ceritinib with lapatinib due to increased lapatinib exposure. If coadministration is unavoidable, monitor for lapatinib-related adverse reactions. Correct hypokalemia or hypomagnesemia prior to lapatinib administration, and periodically monitor electrolytes and ECGs; an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib is a CYP3A4 inhibitor that causes concentration-dependent prolongation of the QT interval. Lapatinib is primarily metabolized by CYP3A4 and is also associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience.
    Chloramphenicol: (Moderate) Lapatinib is a CYP3A4 substrate, and concomitant use of lapatinib with chloramphenicol, a CYP3A4 inhibitor, may result in decreased metabolism and increased serum concentrations of lapatinib.
    Chloroquine: (Major) Coadminister chloroquine with other drugs known to prolong the QT interval, such as lapatinib, with caution; consider ECG and electrolyte monitoring. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); fatalities have been reported. The risk of QT prolongation is increased with higher chloroquine doses. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and TdP have been reported in postmarketing experience. Correct hypokalemia or hypomagnesemia prior to lapatinib administration.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with lapatinib may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of lapatinib could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If lapatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Lapatinib is a weak inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with lapatinib may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of lapatinib could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If lapatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Lapatinib is a weak inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with lapatinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of lapatinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If lapatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Lapatinib is a weak inhibitor of CYP3A4.
    Chlorpheniramine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with lapatinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of lapatinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If lapatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Lapatinib is a weak inhibitor of CYP3A4.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with lapatinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of lapatinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If lapatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Lapatinib is a weak inhibitor of CYP3A4.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with lapatinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of lapatinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If lapatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Lapatinib is a weak inhibitor of CYP3A4.
    Chlorpromazine: (Major) Phenothiazines have been associated with a risk of QT prolongation and/or torsade de pointes (TdP). This risk is generally higher at elevated drugs concentrations of phenothiazines. Chlorpromazine is specifically associated with an established risk of QT prolongation and TdP ; case reports have included patients receiving therapeutic doses of chlorpromazine. Agents that prolong the QT interval could lead to torsade de pointes when combined with a phenothiazine, and therefore are generally not recommended for combined use. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with chlorpromazine include lapatinib.
    Ciprofloxacin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering lapatinib with ciprofloxacin. Lapatinib can prolong the QT interval, and ciprofloxacin has been associated with a potential risk for QT prolongation and TdP.
    Cisapride: (Severe) Lapatinib can prolong the QT interval. Because of the potential for torsade de pointes (TdP), use of cisapride with lapatinib is contraindicated.
    Citalopram: (Major) Citalopram causes dose-dependent QT interval prolongation. According to the manufacturer, concurrent use of citalopram with other drugs that prolong the QT interval is not recommended. If concurrent therapy is considered essential, ECG monitoring is recommended. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with citalopram include lapatinib. Additionally, in vitro, lapatinib, at clinically relevant concentrations, inhibits CYP3A4 and CYP2C8. If lapatinib will be coadministered with a CYP3A4 substrate, such as citalopram, exercise caution and consider dose reduction of citalopram.
    Clarithromycin: (Major) Lapatinib is a CYP3A4 substrate and a CYP3A4 inhibitor at clinically relevant concentrations in vitro. Also, lapatinib is a substrate and inhibitor of the efflux transporter P-glycoprotein (P-gp, ABCB1). Clarithromycin is a P-glycoprotein (P-gp) inhibitor, a CYP3A4 substrate, and a strong CYP3A4 inhibitor. Concomitant use of lapatinib with strong CYP3A4 inhibitors, such as clarithromycin, should generally be avoided. If concurrent treatment with clarithromycin is necessary, strongly consider a lapatinib dose reduction. If clarithromycin is discontinued, allow 7 days to elapse before increasing the lapatinib dose. Furthermore, if lapatinib will be coadministered with a CYP3A4 substrate, such as clarithromycin, exercise caution and consider dose reduction of clarithromycin. In addition to pharmacokinetic interactions, both lapatinib and clarithromycin can prolong the QT interval; therefore, coadministration may further increase the risk for QT prolongation.
    Clomipramine: (Major) Coadministration may result in additive effects on the QT interval. Lapatinib can prolong the QT interval. Tricyclic antidepressants (TCAs) share pharmacologic properties like the Class IA antiarrhythmic agents and may also prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Use caution and monitor for evidence of QT prolongation during concurrent use.
    Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist. Additionally, clozapine therapy may lead to S-T segment depression and flattening or inversion of T waves. Lapatinib can prolong the QT interval. In theory, coadministration could produce clinically significant prolongation of the QTc interval. Finally, clozapine is a substrate of CYP2D6, CYP3A4, and CYP1A2. Lapatinib is an inhibitor of CYP3A4. Elevated plasma concentrations of clozapine occurring through inhibition of CYP1A2, CYP2D6, or CYP3A4 may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with an inhibitor of CYP3A4 should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Cobicistat: (Major) Avoid coadministration of lapatinib with cobicistat if possible due to increased plasma concentrations of both drugs. If concomitant use is unavoidable, consider a lapatinib dose reduction to 500 mg/day, as this dose is predicted to adjust the lapatinib exposure to the range observed without cobicistat. If cobicistat is discontinued, a washout period of approximately 1 week should be allowed before the lapatinib dose is adjusted upward to the indicated dose. Lapatinib is extensively metabolized by CYP3A4. Cobicistat is a strong CYP3A4 inhibitor. In a drug interaction study, concurrent administration with another strong CYP3A4 inhibitor increased lapatinib systemic exposure (AUC) by approximately 3.6-fold and the half-life increased by 1.7-fold. In addition, lapatinib is a CYP3A4 inhibitor, and cobicistat is a substrate of CYP3A4.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid coadministration of lapatinib with cobicistat if possible due to increased plasma concentrations of both drugs. If concomitant use is unavoidable, consider a lapatinib dose reduction to 500 mg/day, as this dose is predicted to adjust the lapatinib exposure to the range observed without cobicistat. If cobicistat is discontinued, a washout period of approximately 1 week should be allowed before the lapatinib dose is adjusted upward to the indicated dose. Lapatinib is extensively metabolized by CYP3A4. Cobicistat is a strong CYP3A4 inhibitor. In a drug interaction study, concurrent administration with another strong CYP3A4 inhibitor increased lapatinib systemic exposure (AUC) by approximately 3.6-fold and the half-life increased by 1.7-fold. In addition, lapatinib is a CYP3A4 inhibitor, and cobicistat is a substrate of CYP3A4.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of lapatinib with cobicistat if possible due to increased plasma concentrations of both drugs. If concomitant use is unavoidable, consider a lapatinib dose reduction to 500 mg/day, as this dose is predicted to adjust the lapatinib exposure to the range observed without cobicistat. If cobicistat is discontinued, a washout period of approximately 1 week should be allowed before the lapatinib dose is adjusted upward to the indicated dose. Lapatinib is extensively metabolized by CYP3A4. Cobicistat is a strong CYP3A4 inhibitor. In a drug interaction study, concurrent administration with another strong CYP3A4 inhibitor increased lapatinib systemic exposure (AUC) by approximately 3.6-fold and the half-life increased by 1.7-fold. In addition, lapatinib is a CYP3A4 inhibitor, and cobicistat is a substrate of CYP3A4. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as lapatinib. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Cobimetinib: (Moderate) If concurrent use of cobimetinib and lapatinib is necessary, use caution and monitor for increased cobimetinib-related adverse effects. Cobimetinib is a CYP3A substrate in vitro as well as a P-glycoprotein (P-gp) substrate; lapatinib is a weak inhibitor of CYP3A and a moderate P-gp inhibitor. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7). Simulations showed that predicted steady-state concentrations of cobimetinib at a reduced dose of 20 mg administered concurrently with short-term (less than 14 days) treatment of a moderate CYP3A inhibitor were similar to observed steady-state concentrations of cobimetinib 60 mg alone. The manufacturer of cobimetinib recommends avoiding coadministration with moderate to strong CYP3A inhibitors, and significantly reducing the dose of cobimetinib if coadministration with moderate CYP3A inhibitors cannot be avoided. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inhibitors.
    Codeine; Phenylephrine; Promethazine: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include lapatinib.
    Codeine; Promethazine: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include lapatinib.
    Colchicine: (Major) Coadministration of colchicine and lapatinib should be avoided due to the potential for serious and life-threatening toxicity. Colchicine is a P-glycoprotein (P-gp) and CYP3A4 substrate and lapatinib is a P-gp inhibitor and CYP3A4 inhibitor; increased concentrations of colchicine are expected with concurrent use. Colchicine accumulation may be greater in patients with renal or hepatic impairment; therefore, the coadministration of colchicine and combined P-gp/CYP3A4 inhibitors is contraindicated in this population. If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine either by reducing the daily dose or reducing the dose frequency, and carefully monitor for colchicine toxicity.
    Conivaptan: (Moderate) Lapatinib is a CYP3A4 substrate, and concomitant use of lapatinib with conivaptan, a CYP3A4 inhibitor, may result in decreased metabolism and increased serum concentrations of lapatinib.
    Crizotinib: (Major) Avoid coadministration of crizotinib with lapatinib due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; correct any electrolyte abnormalities. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Both drugs have been associated with concentration-dependent QT prolongation. Ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
    Cyclosporine: (Major) Lapatinib is a CYP3A4 substrate and a CYP3A4 inhibitor at clinically relevant concentrations in vitro. Cyclosporine is a P-glycoprotein inhibitor, a CYP3A4 substrate, and a CYP3A4 inhibitor. Concomitant use of lapatinib with strong CYP3A4 inhibitors should generally be avoided. Furthermore, because lapatinib inhibits CYP3A4, exercise caution and consider cyclosporine dose reduction; careful monitoring of cyclosporine serum concentrations may be advisable. Lastly, concurrent administration of lapatinib with a P-glycoprotein inhibitor such as cyclosporine is likely to cause elevated serum lapatinib concentrations, and caution is recommended.
    Dabigatran: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with lapatinib, a P-gp inhibitor. Patients should be monitored for increased adverse effects of dabigatran. When dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE) or prophylaxis of DVT or PE following hip replacement surgery, avoid coadministration with P-gp inhibitors like lapatinib in patients with CrCl less than 50 mL/minute. When dabigatran is used in patients with non-valvular atrial fibrillation and severe renal impairment (CrCl less than 30 mL/minute), avoid coadministration with lapatinib, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Danazol: (Moderate) Lapatinib is a CYP3A4 substrate, and concomitant use of lapatinib with danazol, a CYP3A4 inhibitor, may result in decreased metabolism and increased serum concentrations of lapatinib.
    Dapagliflozin; Saxagliptin: (Minor) Monitor patients for hypoglycemia if saxagliptin and lapatinib are used together. The metabolism of saxagliptin is primarily mediated by CYP3A4/5; saxagliptin plasma concentrations may increase in the presence of moderate CYP 3A4/5 inhibitors such as lapatinib.
    Darunavir: (Moderate) Lapatinib is a CYP3A4 substrate, and concomitant use of lapatinib with darunavir, a CYP3A4 inhibitor, may result in decreased metabolism and increased serum concentrations of lapatinib.
    Darunavir; Cobicistat: (Major) Avoid coadministration of lapatinib with cobicistat if possible due to increased plasma concentrations of both drugs. If concomitant use is unavoidable, consider a lapatinib dose reduction to 500 mg/day, as this dose is predicted to adjust the lapatinib exposure to the range observed without cobicistat. If cobicistat is discontinued, a washout period of approximately 1 week should be allowed before the lapatinib dose is adjusted upward to the indicated dose. Lapatinib is extensively metabolized by CYP3A4. Cobicistat is a strong CYP3A4 inhibitor. In a drug interaction study, concurrent administration with another strong CYP3A4 inhibitor increased lapatinib systemic exposure (AUC) by approximately 3.6-fold and the half-life increased by 1.7-fold. In addition, lapatinib is a CYP3A4 inhibitor, and cobicistat is a substrate of CYP3A4. (Moderate) Lapatinib is a CYP3A4 substrate, and concomitant use of lapatinib with darunavir, a CYP3A4 inhibitor, may result in decreased metabolism and increased serum concentrations of lapatinib.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid coadministration of lapatinib with cobicistat if possible due to increased plasma concentrations of both drugs. If concomitant use is unavoidable, consider a lapatinib dose reduction to 500 mg/day, as this dose is predicted to adjust the lapatinib exposure to the range observed without cobicistat. If cobicistat is discontinued, a washout period of approximately 1 week should be allowed before the lapatinib dose is adjusted upward to the indicated dose. Lapatinib is extensively metabolized by CYP3A4. Cobicistat is a strong CYP3A4 inhibitor. In a drug interaction study, concurrent administration with another strong CYP3A4 inhibitor increased lapatinib systemic exposure (AUC) by approximately 3.6-fold and the half-life increased by 1.7-fold. In addition, lapatinib is a CYP3A4 inhibitor, and cobicistat is a substrate of CYP3A4. (Moderate) Lapatinib is a CYP3A4 substrate, and concomitant use of lapatinib with darunavir, a CYP3A4 inhibitor, may result in decreased metabolism and increased serum concentrations of lapatinib.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of lapatinib with ritonavir if possible due to increased plasma concentrations of lapatinib. If concomitant use is unavoidable, consider a lapatinib dose reduction to 500 mg/day, as this dose is predicted to adjust the lapatinib exposure to the range observed without ritonavir. If ritonavir is discontinued, a washout period of approximately 1 week should be allowed before the lapatinib dose is adjusted upward to the indicated dose. Lapatinib is extensively metabolized by CYP3A4. ritonavir is a strong CYP3A4 inhibitor. In a drug interaction study, concurrent administration with another strong CYP3A4 inhibitor increased lapatinib systemic exposure (AUC) by approximately 3.6-fold and the half-life increased by 1.7-fold. (Major) Concurrent administration of lapatinib with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of all 5 drugs. If coadministration is necessary, consider a lapatinib dosage reduction. Both lapatinib and ritonavir have been associated with QT prolongation; concomitant use increases the risk for developing Torsade de Pointed (TdP). Both ritonavir and lapatinib are substrates and inhibitors of the hepatic isoenzyme CYP3A4 and the drug transporter P-glycoprotein (P-gp). Lapatinib is also an inhibitor of CYP2C8. Dasabuvir is primarily metabolized by CYP2C8, while lapatinib, ritonavir, paritaprevir, and dasabuvir (minor) are CYP3A4 substrates. In addition, dasabuvir, ombitasvir, paritaprevir and ritonavir are substrates of P-gp. Caution and close monitoring are advised if these drugs are administered together.
    Degarelix: (Major) Lapatinib can prolong the QT interval. Lapatinib should be administered with caution to patients who have or may develop prolongation of QTc such as patients taking anti-arrhythmic medicines or other medicinal products that lead to QT prolongation. Administer lapatinib with caution in patients taking drugs with the potential to induce QT prolongation. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously with lapatinib include degarelix.
    Delavirdine: (Moderate) Lapatinib is a CYP3A4 substrate, and concomitant use of lapatinib with delavirdine, a CYP3A4 inhibitor, may result in decreased metabolism and increased serum concentrations of lapatinib.
    Desflurane: (Major) Lapatinib can prolong the QT interval. Lapatinib should be administered with caution to patients who have or may develop prolongation of QTc such as patients taking anti-arrhythmic medicines or other medicinal products that lead to QT prolongation. Administer lapatinib with caution in patients taking drugs with the potential to induce QT prolongation. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously and with close monitoring with lapatinib include halogenated anesthetics.
    Desipramine: (Major) Coadministration may result in additive effects on the QT interval. Lapatinib can prolong the QT interval. Tricyclic antidepressants (TCAs) share pharmacologic properties like the Class IA antiarrhythmic agents and may also prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Use caution and monitor for evidence of QT prolongation during concurrent use.
    Deutetrabenazine: (Major) Use lapatinib with caution in patients taking medications that may prolong the QT interval; consider ECG and electrolyte monitoring. Correct hypokalemia or hypomagnesemia prior to lapatinib administration. For patients taking a deutetrabenazine dosage more than 24 mg/day, assess the QTc interval before and after increasing the dosage of either medication. Clinically relevant QTc prolongation may occur with deutetrabenazine. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience.
    Dexamethasone: (Major) Lapatinib is metabolized by CYP3A4 and CYP3A5 enzymes. Drugs that are inducers of CYP3A4 activity, such as dexamethasone, will decrease the plasma concentrations of lapatinib. The combination may also result in additive immunosuppression.
    Dextromethorphan; Promethazine: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include lapatinib.
    Dextromethorphan; Quinidine: (Major) Lapatinib is a CYP3A4 inhibitor at clinically relevant concentrations in vitro. Also, lapatinib is a substrate and inhibitor of the efflux transporter P-glycoprotein (P-gp, ABCB1). Quinidine is a CYP3A4 substrate and a P-gp inhibitor and substrate. If lapatinib will be coadministered with a CYP3A4 and P-gp substrate, such as quinidine, exercise caution and consider dose reduction of quinidine. Concurrent administration of lapatinib with a P-gp inhibitor, such as quinidine, is likely to cause elevated serum lapatinib concentrations, and caution is recommended. In addition to pharmacokinetic interactions, both lapatinib and quinidine can prolong the QT interval; therefore coadministration may further increase the risk for QT prolongation.
    Diclofenac: (Minor) An increased risk of bleeding may occur when NSAIDs, such as diclofenac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Diclofenac; Misoprostol: (Minor) An increased risk of bleeding may occur when NSAIDs, such as diclofenac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Digoxin: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with lapatinib may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of lapatinib could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If lapatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Lapatinib is a weak inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Diltiazem: (Major) Lapatinib is a CYP3A4 substrate, and concomitant use of lapatinib with strong CYP3A4 inhibitors, such as diltiazem, should generally be avoided. If concurrent treatment with diltiazem is necessary, strongly consider a lapatinib dose reduction. If diltiazem is discontinued, allow 7 days to elapse before increasing the lapatinib dose.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with lapatinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of lapatinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If lapatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Lapatinib is a weak inhibitor of CYP3A4.
    Diphenhydramine; Ibuprofen: (Major) An increased risk of bleeding may occur when NSAIDs, such as ibuprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Diphenhydramine; Naproxen: (Major) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Disopyramide: (Major) In vitro, lapatinib, at clinically relevant concentrations, inhibits CYP3A4 and CYP2C8. If lapatinib will be coadministered with a CYP3A4 substrate, exercise caution and consider dose reduction of the concomitant substrate drug, especially for drugs that have a narrow therapeutic index. Several CYP3A4 substrates can prolong the QT interval, and lapatinib can also prolong the QT interval. Use lapatinib with extreme caution, if at all, in patients taking CYP3A4 substrates that also have potential to induce QT prolongation such as a disopyramide.
    Docetaxel: (Moderate) Docetaxel is a substrate of both CYP3A4 and P-glycoprotein. In vitro, lapatinib, at clinically relevant concentrations, inhibits CYP3A4. Also, lapatinib is a substrate and inhibitor of the efflux transporter P-glycoprotein (Pgp, ABCB1). Coadministration of lapatinib and any CYP3A4 and/or P-glycoprotein substrate may lead to increased serum concentrations of the CYP3A4 and/or P-glycoprotein substrate. As increased serum concentrations are likely, cautious coadministration is recommended, and consider a dose reduction of the CYP3A4 and/or P-glycoprotein substrate.
    Dofetilide: (Severe) Concurrent use of dofetilide and lapatinib is contraindicated because of the potential for torsade de pointes (TdP). Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP. Lapatinib can prolong the QT interval.
    Dolasetron: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), dolasetron and lapatinib should be used together cautiously. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram. Lapatinib can also prolong the QT interval. Concurrent use may increase the risk of QT prolongation.
    Dolutegravir; Rilpivirine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with lapatinib. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Lapatinib can also prolong the QT interval. Additionally, lapatinib may inhibit the CYP3A4 metabolism of rilpivirine, potentially resulting in elevated rilpivirine serum concentrations and risk of adverse events, such as QT prolongation.
    Donepezil: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include lapatinib.
    Donepezil; Memantine: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include lapatinib.
    Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as lapatinib. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Doxepin: (Major) Coadministration may result in additive effects on the QT interval. Lapatinib can prolong the QT interval. Tricyclic antidepressants (TCAs) share pharmacologic properties like the Class IA antiarrhythmic agents and may also prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Use caution and monitor for evidence of QT prolongation during concurrent use.
    Doxorubicin: (Major) Avoid coadministration of lapatinib with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Lapatinib is a CYP3A4 and P-glycoprotein (P-gp) inhibitor; doxorubicin is a major substrate of CYP3A4 and P-gp. Concurrent use of CYP3A4 or P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    Dronabinol: (Moderate) Use caution if coadministration of dronabinol with lapatinib is necessary, and monitor for an increase in dronabinol-related adverse reactions (e.g., feeling high, dizziness, confusion, somnolence). Dronabinol is a CYP2C9 and 3A4 substrate; lapatinib is a weak inhibitor of CYP3A4. Concomitant use may result in elevated plasma concentrations of dronabinol.
    Dronedarone: (Severe) Concomitant use of dronedarone and lapatinib is contraindicated. Dronedarone is metabolized by CYP3A and is a moderate inhibitor of CYP3A. Lapatinib is an inhibitor and a substrate of CYP3A4. Coadministration of dronedarone and lapatinib may result in elevated plasma concentrations of lapatinib and/or dronedarone. In addition, lapatinib has been established to have a possible risk of QT prolongation and Torsade de Pointes (TdP). Dronedarone is associated with dose-related increases in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Droperidol: (Major) Any drug known to have potential to prolong the QT interval should not be coadministered with droperidol. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with droperidol include lapatinib. In addition, droperidol is a substrate of both CYP3A4 and P-glycoprotein. In vitro, lapatinib inhibits CYP3A4. Also, lapatinib is a substrate and inhibitor of the efflux transporter P-glycoprotein (Pgp, ABCB1). Coadministration with lapatinib may lead to increased droperidol serum concentrations. As increased serum concentrations are likely, cautious coadministration is recommended, and consider a droperidol dose reduction.
    Drospirenone; Ethinyl Estradiol: (Minor) Lapatinib is a CYP3A4 substrate, and concomitant use of lapatinib with ethinyl estradiol, a CYP3A4 inhibitor, may result in decreased metabolism and increased serum concentrations of lapatinib.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Minor) Lapatinib is a CYP3A4 substrate, and concomitant use of lapatinib with ethinyl estradiol, a CYP3A4 inhibitor, may result in decreased metabolism and increased serum concentrations of lapatinib.
    Edoxaban: (Moderate) Coadministration of edoxaban and lapatinib may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and lapatinib is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of lapatinib; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Efavirenz: (Major) Although data are limited, coadministration of efavirenz and lapatinib may increase the risk for QT prolongation and torsade de pointes (TdP). Both drugs can prolong the QT interval. Also, lapatinib is metabolized by CYP3A4 and CYP3A5 enzymes. Drugs that are inducers of CYP3A4 activity, such as efavirenz, will decrease the plasma concentrations of lapatinib. In patients receiving lapatinib and carbamazepine (100 mg twice daily for 3 days then 200 mg twice daily for 17 days), systemic exposure to lapatinib was decreased by approximately 72%. If concomitant treatment is necessary, consider a lapatinib dose escalation. If a strong CYP3A4 inducer is discontinued, reduce the lapatinib dose to the indicated dose.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Although data are limited, coadministration of efavirenz and lapatinib may increase the risk for QT prolongation and torsade de pointes (TdP). Both drugs can prolong the QT interval. Also, lapatinib is metabolized by CYP3A4 and CYP3A5 enzymes. Drugs that are inducers of CYP3A4 activity, such as efavirenz, will decrease the plasma concentrations of lapatinib. In patients receiving lapatinib and carbamazepine (100 mg twice daily for 3 days then 200 mg twice daily for 17 days), systemic exposure to lapatinib was decreased by approximately 72%. If concomitant treatment is necessary, consider a lapatinib dose escalation. If a strong CYP3A4 inducer is discontinued, reduce the lapatinib dose to the indicated dose. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as lapatinib. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Although data are limited, coadministration of efavirenz and lapatinib may increase the risk for QT prolongation and torsade de pointes (TdP). Both drugs can prolong the QT interval. Also, lapatinib is metabolized by CYP3A4 and CYP3A5 enzymes. Drugs that are inducers of CYP3A4 activity, such as efavirenz, will decrease the plasma concentrations of lapatinib. In patients receiving lapatinib and carbamazepine (100 mg twice daily for 3 days then 200 mg twice daily for 17 days), systemic exposure to lapatinib was decreased by approximately 72%. If concomitant treatment is necessary, consider a lapatinib dose escalation. If a strong CYP3A4 inducer is discontinued, reduce the lapatinib dose to the indicated dose. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as lapatinib. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Elagolix: (Severe) Concomitant use of elagolix and strong organic anion transporting polypeptide (OATP) 1B1 inhibitors such as lapatinib is contraindicated. Use of elagolix with drugs that inhibit OATP1B1 may increase elagolix plasma concentrations. Elagolix is a substrate of CYP3A, P-gp, and OATP1B1. Lapatinib inhibits CYP3A4, P-gp, and also OATP1B1 in vitro at clinically relevant concentrations; thus lapatinib inhibits all three of the affected enzymes/transporters for elagolix metablism. Another OATP1B1 potent inhibitor increased elagolix AUC in the range of 2- to 5.58-fold. Increased elagolix concentrations increase the risk for dose-related side effects, including loss of bone mineral density.
    Eliglustat: (Major) In poor CYP2D6 metabolizers (PMs), coadministration of lapatinib and eliglustat is not recommended. In extensive CYP2D6 metabolizers (EM) with mild hepatic impairment, coadministration of these agents requires dosage reduction of eliglustat to 84 mg PO once daily. These agents should be used concomitantly with caution in any patient; both eliglustat (at significantly elevated concentrations) and lapatinib can independently prolong the QT interval, and coadministration increases this risk. Lapatanib is a weak CYP3A inhibitor in vivo; eliglustat is a CYP3A and CYP2D6 substrate. Because CYP3A plays a significant role in the metabolism of eliglustat in CYP2D6 PMs, coadministration with CYP3A inhibitors may significantly increase eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias) in these patients.
    Eltrombopag: (Moderate) Use caution and monitor for signs of lapatinib toxicity if these drugs are coadministered; a lapatinib dosage reduction may be necessary.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with lapatinib. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Lapatinib can also prolong the QT interval. Additionally, lapatinib may inhibit the CYP3A4 metabolism of rilpivirine, potentially resulting in elevated rilpivirine serum concentrations and risk of adverse events, such as QT prolongation.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with lapatinib. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Lapatinib can also prolong the QT interval. Additionally, lapatinib may inhibit the CYP3A4 metabolism of rilpivirine, potentially resulting in elevated rilpivirine serum concentrations and risk of adverse events, such as QT prolongation. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as lapatinib. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Emtricitabine; Tenofovir disoproxil fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as lapatinib. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Encorafenib: (Major) Avoid coadministration of encorafenib and lapatinib due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience.
    Enflurane: (Major) Lapatinib can prolong the QT interval. Lapatinib should be administered with caution to patients who have or may develop prolongation of QTc such as patients taking anti-arrhythmic medicines or other medicinal products that lead to QT prolongation. Administer lapatinib with caution in patients taking drugs with the potential to induce QT prolongation. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously and with close monitoring with lapatinib include halogenated anesthetics.
    Enzalutamide: (Major) Avoid coadministration of lapatinib with enzalutamide if possible due to decreased plasma concentrations of lapatinib. If concomitant use is unavoidable, gradually increase the dose of lapatinib as tolerated from 1,250 mg per day up to 4,500 mg per day for patients being treated for HER2-positive metastatic breast cancer, or from 1,500 mg per day up to 5,500 mg per day for patients being treated for HR-positive, HER2-postiive breast cancer. Lapatinib is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased lapatinib exposure by approximately 72%.
    Eribulin: (Major) Lapatinib can prolong the QT interval. Lapatinib should be administered with caution to patients who have or may develop prolongation of QTc such as patients taking anti-arrhythmic medicines or other medicinal products that lead to QT prolongation. Administer lapatinib with caution in patients taking drugs with the potential to induce QT prolongation. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously with lapatinib include eribulin. ECG monitoring is recommended; closely monitor the patient for QT interval prolongation.
    Erythromycin: (Major) Lapatinib should be used with caution in patients taking medications that may prolong the QT interval; consider ECG and electrolyte monitoring. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience. Correct hypokalemia or hypomagnesemia prior to lapatinib administration. Also, lapatinib is a CYP3A4 substrate at clinically relevant concentrations in vitro and a substrate of the efflux transporter P-glycoprotein (P-gp, ABCB1). Erythromycin is a P-gp and CYP3A4inhibitor. Concurrent administration of lapatinib with a P-gp and CYP3A4 inhibitor such as erythromycin is likely to cause elevated serum lapatinib concentrations.
    Erythromycin; Sulfisoxazole: (Major) Lapatinib should be used with caution in patients taking medications that may prolong the QT interval; consider ECG and electrolyte monitoring. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience. Correct hypokalemia or hypomagnesemia prior to lapatinib administration. Also, lapatinib is a CYP3A4 substrate at clinically relevant concentrations in vitro and a substrate of the efflux transporter P-glycoprotein (P-gp, ABCB1). Erythromycin is a P-gp and CYP3A4inhibitor. Concurrent administration of lapatinib with a P-gp and CYP3A4 inhibitor such as erythromycin is likely to cause elevated serum lapatinib concentrations.
    Escitalopram: (Major) Escitalopram has been associated with QT prolongation. Coadministration with other drugs that have a possible risk for QT prolongation and torsade de pointes (TdP), such as lapatinib, should be done with caution and close monitoring.
    Eslicarbazepine: (Moderate) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Lapatinib is metabolized by CYP3A4 and CYP3A5 enzymes. In patients receiving lapatinib and carbamazepine (100 mg twice daily for 3 days then 200 mg twice daily for 17 days), systemic exposure to lapatinib was decreased by approximately 72%. If treatment with eslicarbazepine is necessary, monitor for reduced efficacy of lapatinib and consider a lapatinib dose escalation. If eslicarbazepine is discontinued, a reduction in the lapatinib dose to the indicated dose may be necessary.
    Esomeprazole; Naproxen: (Major) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Eszopiclone: (Moderate) Monitor for an increase in ethosuximide-related adverse reactions (e.g., next-day psychomotor and/or memory impairment) if coadministration with lapatinib is necessary. Ethosuximide is a CYP3A4 substrate with a narrow therapeutic index and lapatinib is a weak CYP3A4 inhibitor.
    Ethinyl Estradiol: (Minor) Lapatinib is a CYP3A4 substrate, and concomitant use of lapatinib with ethinyl estradiol, a CYP3A4 inhibitor, may result in decreased metabolism and increased serum concentrations of lapatinib.
    Ethinyl Estradiol; Desogestrel: (Minor) Lapatinib is a CYP3A4 substrate, and concomitant use of lapatinib with ethinyl estradiol, a CYP3A4 inhibitor, may result in decreased metabolism and increased serum concentrations of lapatinib.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Minor) Lapatinib is a CYP3A4 substrate, and concomitant use of lapatinib with ethinyl estradiol, a CYP3A4 inhibitor, may result in decreased metabolism and increased serum concentrations of lapatinib.
    Ethinyl Estradiol; Etonogestrel: (Minor) Lapatinib is a CYP3A4 substrate, and concomitant use of lapatinib with ethinyl estradiol, a CYP3A4 inhibitor, may result in decreased metabolism and increased serum concentrations of lapatinib.
    Ethinyl Estradiol; Levonorgestrel: (Minor) Lapatinib is a CYP3A4 substrate, and concomitant use of lapatinib with ethinyl estradiol, a CYP3A4 inhibitor, may result in decreased metabolism and increased serum concentrations of lapatinib.
    Ethinyl Estradiol; Levonorgestrel; Ferrous bisglycinate: (Minor) Lapatinib is a CYP3A4 substrate, and concomitant use of lapatinib with ethinyl estradiol, a CYP3A4 inhibitor, may result in decreased metabolism and increased serum concentrations of lapatinib.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Minor) Lapatinib is a CYP3A4 substrate, and concomitant use of lapatinib with ethinyl estradiol, a CYP3A4 inhibitor, may result in decreased metabolism and increased serum concentrations of lapatinib.
    Ethinyl Estradiol; Norelgestromin: (Minor) Lapatinib is a CYP3A4 substrate, and concomitant use of lapatinib with ethinyl estradiol, a CYP3A4 inhibitor, may result in decreased metabolism and increased serum concentrations of lapatinib.
    Ethinyl Estradiol; Norethindrone Acetate: (Minor) Lapatinib is a CYP3A4 substrate, and concomitant use of lapatinib with ethinyl estradiol, a CYP3A4 inhibitor, may result in decreased metabolism and increased serum concentrations of lapatinib.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Minor) Lapatinib is a CYP3A4 substrate, and concomitant use of lapatinib with ethinyl estradiol, a CYP3A4 inhibitor, may result in decreased metabolism and increased serum concentrations of lapatinib.
    Ethinyl Estradiol; Norethindrone: (Minor) Lapatinib is a CYP3A4 substrate, and concomitant use of lapatinib with ethinyl estradiol, a CYP3A4 inhibitor, may result in decreased metabolism and increased serum concentrations of lapatinib.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Minor) Lapatinib is a CYP3A4 substrate, and concomitant use of lapatinib with ethinyl estradiol, a CYP3A4 inhibitor, may result in decreased metabolism and increased serum concentrations of lapatinib.
    Ethinyl Estradiol; Norgestimate: (Minor) Lapatinib is a CYP3A4 substrate, and concomitant use of lapatinib with ethinyl estradiol, a CYP3A4 inhibitor, may result in decreased metabolism and increased serum concentrations of lapatinib.
    Ethinyl Estradiol; Norgestrel: (Minor) Lapatinib is a CYP3A4 substrate, and concomitant use of lapatinib with ethinyl estradiol, a CYP3A4 inhibitor, may result in decreased metabolism and increased serum concentrations of lapatinib.
    Etodolac: (Minor) An increased risk of bleeding may occur when NSAIDs, such as etodolac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Etoposide, VP-16: (Major) Monitor for an increased incidence of etoposide-related adverse effects if used concomitantly with lapatinib. Lapatinib is a weak inhibitor of CYP3A4 as well as a P-glycoprotein (P-gp) inhibitor; etoposide, VP-16 is a CYP3A4 and P-gp substrate. Coadministration may cause accumulation of etoposide and decreased metabolism, resulting in increased etoposide concentrations.
    Everolimus: (Major) Monitor for clinical response in patients taking everolimus concurrently with lapatinib. For indications where therapeutic drug monitoring is appropriate, monitor everolimus trough concentrations and adjust the dose of everolimus accordingly. Everolimus is a substrate of P-glycoprotein (P-gp). Lapatinib is a P-gp inhibitor.
    Ezogabine: (Major) Ezogabine has been associated with QT prolongation. The manufacturer of ezogabine recommends caution during concurrent use of medications known to increase the QT interval, such as lapatinib.
    Famotidine; Ibuprofen: (Major) An increased risk of bleeding may occur when NSAIDs, such as ibuprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Fentanyl: (Moderate) Concurrent use of fentanyl with lapatinib may increase the risk of increased fentanyl-related adverse reactions, such as fatal respiratory depression. Consider a dose reduction of fentanyl until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. Discontinuation of lapatinib in a patient taking fentanyl may decrease fentanyl plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to fentanyl. If lapatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Fentanyl is a substrate of both CYP3A4 and P-glycoprotein. In vitro, lapatinib, at clinically relevant concentrations, inhibits CYP3A4. Also, lapatinib is a substrate and inhibitor of the efflux transporter P-glycoprotein (Pgp, ABCB1).
    Fingolimod: (Major) Use lapatinib with caution in patients taking medications that may prolong the QT interval, such as fingolimod; consider ECG and electrolyte monitoring. Correct hypokalemia or hypomagnesemia prior to lapatinib administration. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of TdP. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
    Flecainide: (Major) Flecainide is a Class IC antiarrhythmic associated with a possible risk for QT prolongation and/or torsades de pointes (TdP); flecainide increases the QT interval, but largely due to prolongation of the QRS interval. Although causality for TdP has not been established for flecainide, patients receiving concurrent drugs which have the potential for QT prolongation may have an increased risk of developing proarrhythmias. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with flecainide include lapatinib.
    Flibanserin: (Moderate) The concomitant use of flibanserin and multiple weak CYP3A4 inhibitors, including lapatinib, may increase flibanserin concentrations, which may increase the risk of flibanserin-induced adverse reactions. Therefore, patients should be monitored for hypotension, syncope, somnolence, or other adverse reactions, and the risks of combination therapy with multiple weak CYP3A4 inhibitors and flibanserin should be discussed with the patient.
    Fluconazole: (Severe) Due to the risk of life-threatening arrhythmias such as torsade de pointes (TdP), coadministration of fluconazole with drugs that both prolong the QT interval and are CYP3A4 substrates, like lapatinib, is contraindicated. Fluconazole has been associated with QT prolongation and rare cases of TdP. Additonally, fluconazole is an inhibitor of CYP3A4. Coadministration may result in elevated plasma concentrations of lapatinib, causing an increased risk for adverse events such as QT prolongation.
    Fluoxetine: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include lapatinib.
    Fluoxetine; Olanzapine: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include lapatinib. (Major) Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Therefore, caution is advised when administering olanzapine with drugs having an established causal association with QT prolongation and torsade de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with olanzapine include lapatinib.
    Fluphenazine: (Minor) Lapatinib can prolong the QT interval. Lapatinib should be administered with caution to patients who have or may develop prolongation of QTc such as patients taking anti-arrhythmic medicines or other medicinal products that lead to QT prolongation. Administer lapatinib with caution in patients taking drugs with the potential to induce QT prolongation. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with lapatinib include fluphenazine.
    Flurbiprofen: (Major) An increased risk of bleeding may occur when NSAIDs, such as flurbiprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Fluvoxamine: (Major) There may be an increased risk for QT prolongation, torsade de pointes (TdP), and increased lapatinib concentrations during concurrent use of fluvoxamine and lapatinib. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and TdP have been reported in postmarketing experience. In addition, lapatinib is a CYP3A4 substrate and concomitant use with fluvoxamine, a moderate CYP3A4 inhibitor, may result in decreased metabolism and increased serum concentrations of lapatinib. If concurrent use is required, consider ECG and electrolyte monitoring. Correct hypokalemia or hypomagnesemia prior to lapatinib administration.
    Food: (Severe) Lapatinib must be taken either 1 hour before or after food. If taken with food, lapatinib systemic exposure is increased. Patients need to be effectively counseled about how to take lapatinib, as the drug is approved for use with capecitabine, and capecitabine, in contrast to lapatinib, must be taken with food or within 30 minutes after food (Moderate) The incidence of marijuana associated adverse effects may change following coadministration with lapatinib. Lapatinib is an inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of marijuana's most psychoactive compound, delta-9-tetrahydrocannabinol (Delta-9-THC). When given concurrently with lapatinib, the amount of Delta-9-THC converted to the active metabolite 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) may be reduced. These changes in Delta-9-THC and 11-OH-THC plasma concentrations may result in an altered marijuana adverse event profile.
    Fosamprenavir: (Moderate) Lapatinib is a CYP3A4 substrate, and concomitant use of lapatinib with fosamprenavir, a CYP3A4 inhibitor, may result in decreased metabolism and increased serum concentrations of lapatinib.
    Foscarnet: (Major) When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as lapatinib. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes (TdP). Lapatinib can also prolong the QT interval. If these drugs are administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment.
    Fosphenytoin: (Major) Lapatinib is metabolized by CYP3A4 and CYP3A5 enzymes. Drugs that are inducers of CYP3A4 activity, such as fosphenytoin, will decrease the plasma concentrations of lapatinib. If treatment with fosphenytoin is necessary, consider a lapatinib dose escalation. If fosphenytoin is discontinued, reduce the lapatinib dose to the indicated dose.
    Fostamatinib: (Moderate) Monitor for lapatinib toxicities that may require lapatinib dose reduction if given concurrently with fostamatinib. Concomitant use of fostamatinib with a P-gp substrate may increase the concentration of the P-gp substrate. Fostamatinib is a P-gp inhibitor; lapatinib is a P-gp substrate. Coadministration of fostamatinib with another P-gp substrate increased the P-gp substrate AUC by 37% and Cmax by 70%.
    Gemifloxacin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering lapatinib with gemifloxacin. Lapatinib can prolong the QT interval. Gemifloxacin may also prolong the QT interval in some patients, with the maximal change in the QTc interval occurring approximately 5 to 10 hours following oral administration. The likelihood of QTc prolongation may increase with increasing dose of gemifloxacin; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
    Gemtuzumab Ozogamicin: (Major) Use gemtuzumab ozogamicin and lapatinib together with caution due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If these agents are used together, obtain an ECG and serum electrolytes prior to the start of gemtuzumab and as needed during treatment. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and TdP have been reported in postmarketing experience.
    Glasdegib: (Major) Avoid coadministration of glasdegib with lapatinib due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring; consider electrolyte monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience.
    Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and lapatinib as coadministration may increase serum concentrations of both drugs and increase the risk of adverse effects. Both drugs are substrates and inhibitors of P-glycoprotein (P-gp). (Moderate) Caution is advised with the coadministration of pibrentasvir and lapatinib as coadministration may increase serum concentrations of pibrentasvir and increase the risk of adverse effects. Pibrentasvir is a substrate of P-glycoprotein (P-gp); lapatinib is an inhibitor of P-gp.
    Goserelin: (Major) Lapatinib can prolong the QT interval. Lapatinib should be administered with caution to patients who have or may develop prolongation of QTc such as patients taking anti-arrhythmic medicines or other medicinal products that lead to QT prolongation. Androgen deprivation therapy (e.g., goserelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Granisetron: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), granisetron and lapatinib should be used together cautiously. Granisetron has been associated with QT prolongation. According to the manufacturer, use of granisetron with drugs known to prolong the QT interval or are arrhythmogenic, may result in clinical consequences. In vitro, lapatinib, at clinically relevant concentrations, inhibits CYP3A4 and CYP2C8. If lapatinib will be coadministered with granisetron, a CYP3A4 substrate, exercise caution and consider granisetron dose reduction.
    Grapefruit juice: (Major) Avoid administration of lapatinib with grapefruit juice due to increased plasma concentrations of lapatinib. Lapatinib is a CYP3A4 substrate and grapefruit juice is a strong CYP3A4 inhibitor. Concomitant use with another strong CYP3A4 inhibitor increased lapatinib exposure by 3.6-fold and increased the half-life of lapatinib by 1.7-fold.
    Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with lapatinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of lapatinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If lapatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Lapatinib is a weak inhibitor of CYP3A4.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with lapatinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of lapatinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If lapatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Lapatinib is a weak inhibitor of CYP3A4.
    Halofantrine: (Severe) Lapatinib can prolong the QT interval. Avoid coadministration with halofantrine as halofantrine has been established to have a causal association with QT prolongation and torsade de pointe.
    Halogenated Anesthetics: (Major) Lapatinib can prolong the QT interval. Lapatinib should be administered with caution to patients who have or may develop prolongation of QTc such as patients taking anti-arrhythmic medicines or other medicinal products that lead to QT prolongation. Administer lapatinib with caution in patients taking drugs with the potential to induce QT prolongation. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously and with close monitoring with lapatinib include halogenated anesthetics.
    Haloperidol: (Major) Concurrent use of lapatinib and haloperidol should be avoided if possible. Lapatinib can prolong the QT interval. QT prolongation and torsade de pointes (TdP) have been observed during haloperidol treatment. According to the manufacturer of haloperidol, caution is advisable when prescribing the drug concurrently with medications known to prolong the QT interval. In vitro, lapatinib is an inhibitor of CYP3A4. Elevated haloperidol concentrations occurring through inhibition of CYP3A4 may increase the risk of adverse effects, including QT prolongation. Monitor closely. Lapatinib can prolong the QT interval. Lapatinib should be administered with caution to patients who have or may develop prolongation of QTc such as patients taking medications that lead to QT prolongation such as haloperidol. Additionally, mild to moderate increases in haloperidol plasma concentrations have been reported during concurrent use of haloperidol and inhibitors of CYP3A4 or CYP2D6. Therefore, it is advisable to closely monitor for adverse events when haloperidol is co-administered with inhibitors of CYP3A4 or CYP2D6 including lapatinib.
    Halothane: (Major) Lapatinib can prolong the QT interval. Lapatinib should be administered with caution to patients who have or may develop prolongation of QTc such as patients taking anti-arrhythmic medicines or other medicinal products that lead to QT prolongation. Administer lapatinib with caution in patients taking drugs with the potential to induce QT prolongation. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously and with close monitoring with lapatinib include halogenated anesthetics.
    Histrelin: (Major) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and lapatinib is necessary; correct any electrolyte abnormalities. Androgen deprivation therapy (e.g., histrelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Lapatinib has also been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience.
    Homatropine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with lapatinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of lapatinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If lapatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Lapatinib is a weak inhibitor of CYP3A4.
    Hydrocodone: (Moderate) Concomitant use of hydrocodone with lapatinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of lapatinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If lapatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Lapatinib is a weak inhibitor of CYP3A4.
    Hydrocodone; Ibuprofen: (Major) An increased risk of bleeding may occur when NSAIDs, such as ibuprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding. (Moderate) Concomitant use of hydrocodone with lapatinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of lapatinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If lapatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Lapatinib is a weak inhibitor of CYP3A4.
    Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with lapatinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of lapatinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If lapatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Lapatinib is a weak inhibitor of CYP3A4.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Concomitant use of hydrocodone with lapatinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of lapatinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If lapatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Lapatinib is a weak inhibitor of CYP3A4.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with lapatinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of lapatinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If lapatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Lapatinib is a weak inhibitor of CYP3A4.
    Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with lapatinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of lapatinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If lapatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Lapatinib is a weak inhibitor of CYP3A4.
    Hydroxychloroquine: (Major) Avoid coadministration of hydroxychloroquine and lapatinib. Hydroxychloroquine increases the QT interval and should not be administered with other drugs known to prolong the QT interval. Ventricular arrhythmias and torsade de pointes have been reported with the use of hydroxychloroquine. Lapatinib can prolong the QT interval.
    Hydroxyzine: (Major) Post-marketing data indicate that hydroxyzine causes QT prolongation and Torsade de Pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with hydroxyzine include lapatinib.
    Ibrutinib: (Moderate) Consider an ibrutinib dose reduction if ibrutinib and lapatinib are coadministered; increased ibrutinib levels may occur. Monitor patients for signs and symptoms of ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a sensitive CYP3A4 substrate; lapatinib is a weak CYP3A4 inhibitor (in vivo). Coadministration of lapatinib with a sensitive CYP3A4 substrate (given IV or PO) increased the AUC value of the CYP3A4 substrate by 22% after IV administration and by 45% after oral administration.
    Ibuprofen: (Major) An increased risk of bleeding may occur when NSAIDs, such as ibuprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Ibuprofen; Oxycodone: (Major) An increased risk of bleeding may occur when NSAIDs, such as ibuprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding. (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of lapatinib is necessary. If lapatinib is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a weak CYP3A4 inhibitor like lapatinib can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If lapatinib is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Ibuprofen; Pseudoephedrine: (Major) An increased risk of bleeding may occur when NSAIDs, such as ibuprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Ibutilide: (Major) Use caution during concurrent administration of lapatinib and ibutilide. Lapatinib can prolong the QT interval. Lapatinib should be administered with caution to patients who have or may develop prolongation of QTc such as patients taking anti-arrhythmic medicines or other medicinal products that lead to QT prolongation. Ibutilide administration can cause QT prolongation and torsades de pointes (TdP); proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval.
    Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with lapatinib, a CYP3A substrate, as lapatinib toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Iloperidone: (Major) Iloperidone has been associated with QT prolongation; however, torsade de pointes (TdP) has not been reported. According to the manufacturer, since iloperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as lapatinib. In vitro, lapatinib, at clinically relevant concentrations, inhibits CYP3A4 and CYP2C8. If lapatinib will be coadministered with a CYP3A4 substrate, such as iloperidone, exercise caution and consider dose reduction of the concomitant substrate drug, especially for drugs that have a narrow therapeutic index.
    Imatinib: (Moderate) Imatinib, an inhibitor of CYP3A4, may increase the serum concentrations of lapatinib. Use lapatinib and imatinib together with caution, and monitor patients closely.
    Imipramine: (Major) Coadministration may result in additive effects on the QT interval. Lapatinib can prolong the QT interval. Tricyclic antidepressants (TCAs) share pharmacologic properties like the Class IA antiarrhythmic agents and may also prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Use caution and monitor for evidence of QT prolongation during concurrent use.
    Indinavir: (Major) Lapatinib is a CYP3A4 substrate, and concomitant use of lapatinib with strong CYP3A4 inhibitors, such as indinavir, should generally be avoided. If concurrent treatment with indinavir is necessary, strongly consider reducing the adult lapatinib dose to 500 mg/day; clinical data for this dose adjustment are lacking. If indinavir is discontinued, allow 7 days to elapse before increasing the lapatinib dose.
    Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with lapatinib due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and TdP have been reported in postmarketing experience.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with lapatinib may result in increased serum concentrations of both drugs. Lapatinib is a substrate and inhibitor of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate and moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
    Isoflurane: (Major) Lapatinib can prolong the QT interval. Lapatinib should be administered with caution to patients who have or may develop prolongation of QTc such as patients taking anti-arrhythmic medicines or other medicinal products that lead to QT prolongation. Administer lapatinib with caution in patients taking drugs with the potential to induce QT prolongation. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously and with close monitoring with lapatinib include halogenated anesthetics.
    Itraconazole: (Major) Avoid use of lapatinib during and for 2 weeks after discontinuation of itraconazole therapy. If concurrent treatment is necessary, consider a lapatinib dose reduction to 500 mg/day; monitor for lapatinib toxicity and for evidence of QT prolongation. If itraconazole is discontinued, allow 7 days to elapse before increasing the lapatinib dose. Itraconazole is a strong CYP3A4; lapatinib is a CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased the AUC and half-life of lapatinib by 3.6-fold and 1.7-fold, respectively. Additionally, both lapatinib and itraconazole are associated with QT prolongation; coadministration may increase this risk.
    Ivabradine: (Moderate) Use caution during coadministration of ivabradine and lapatinib as increased concentrations of ivabradine are possible. Ivabradine is primarily metabolized by CYP3A4; in vitro, lapatinib, at clinically relevant concentrations, inhibits CYP3A4. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Ivosidenib: (Major) Avoid coadministration of ivosidenib with lapatinib due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience.
    Ixabepilone: (Major) Ixabepilone is a CYP3A4 substrate, and concomitant use of ixabepilone with strong CYP3A4 inhibitors such as lapatinib should be avoided. In addition, ixabepilone is a P-glycoprotein (Pgp) substrate and lapatinib is a Pgp inhibitor. Alternative therapies that do not inhibit the CYP3A4 isoenzyme should be considered. If concurrent treatment with a strong CYP3A4 inhibitor is necessary, strongly consider an ixabepilone dose reduction. Closely monitor patients for ixabepilone-related toxicities. If a strong CYP3A4 inhibitor is discontinued, allow 7 days to elapse before increasing the ixabepilone dose (see Dosage).
    Ketoconazole: (Major) Avoid concurrent administration of ketoconazole and lapatinib. If concurrent treatment is necessary, strongly consider a lapatinib dose reduction. If ketoconazole is discontinued, allow 7 days to elapse before increasing the lapatinib dose. Both lapatinib and ketoconazole are associated with QT prolongation; coadministration may increase this risk. In addition, coadministration of ketoconazole (a potent CYP3A4 inhibitor) with lapatinib (a CYP3A4 substrate) results in elevated lapatinib plasma concentrations and may increase the risk for adverse events, including QT prolongation. When given concomitantly with ketoconazole 200 mg twice daily for 7 days, lapatinib AUC was increased by approximately 3.6-fold and the half-life was increased by 1.7-fold.
    Ketoprofen: (Major) An increased risk of bleeding may occur when NSAIDs, such as ketoprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Ketorolac: (Major) An increased risk of bleeding may occur when NSAIDs, such as ketorolac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as lapatinib. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Lansoprazole; Naproxen: (Major) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Ledipasvir; Sofosbuvir: (Moderate) Caution and close monitoring of adverse reactions is advised with concomitant administration of lapatinib and ledipasvir. Taking these drugs together may increase plasma concentrations of both drugs. Both lapatinib and ledipasvir are inhibitors and substrates of the drug transporter P-glycoprotein (P-gp). According to the manufacturer, no dosage adjustments are required when ledipasvir is administered concurrently with P-gp inhibitors. (Moderate) Caution and close monitoring of adverse reactions is advised with concomitant administration of lapatinib and sofosbuvir. Taking these drugs together may increase plasma concentrations of sofosbuvir. Lapatinib is an inhibitor of the drug transporter P-glycoprotein (P-gp); sofosbuvir is a P-gp substrate. According to the manufacturer, no dosage adjustments are required when sofosbuvir is administered concurrently with P-gp inhibitors.
    Lenvatinib: (Major) Avoid coadministration of lenvatinib with lenvatinib due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. QT prolongation was reported during clinical trials of lenvatinib.
    Lesinurad: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of lapatinib; monitor for potential reduction in efficacy. Lapatinib is primarily metabolized by CYP3A, and lesinurad is a weak CYP3A inducer.
    Lesinurad; Allopurinol: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of lapatinib; monitor for potential reduction in efficacy. Lapatinib is primarily metabolized by CYP3A, and lesinurad is a weak CYP3A inducer.
    Letermovir: (Moderate) Concurrent use of lapatinib and letermovir may result in elevated lapatinib plasma concentrations. Avoid coadministration in patients also receiving cyclosporine, because the magnitude of this interaction may be amplified. If concurrent use of lapatinib with both letermovir and cyclosporine cannot be avoided, consider a lapatinib dose reduction to 500 mg/day, as this dose is predicted to adjust the lapatinib exposure to the range observed without letermovir and cyclosporine. If either letermovir or cyclosporine is discontinued, a washout period of approximately 1 week should be allowed before the lapatinib dose is adjusted upward to the indicated dose. Lapatinib is extensively metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. In a drug interaction study, concurrent administration with another strong CYP3A4 inhibitor increased lapatinib systemic exposure (AUC) by approximately 3.6-fold and the half-life increased by 1.7-fold.
    Leuprolide: (Major) Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with leuprolide include lapatinib.
    Leuprolide; Norethindrone: (Major) Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with leuprolide include lapatinib.
    Levofloxacin: (Major) Concurrent use of lapatinib and levofloxacin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Levofloxacin has been associated with prolongation of the QT interval and infrequent cases of arrhythmia. Additionally, rare cases of TdP have been spontaneously reported during postmarketing surveillance in patients receiving levofloxacin. Lapatinib can also prolong the QT interval.
    Levomethadyl: (Severe) Lapatinib can prolong the QT interval. Avoid coadministration with levomethadyl as levomethadyl has been established to have a causal association with QT prolongation and torsade de pointe.
    Lidocaine: (Major) Concomitant use of systemic lidocaine and lapatinib may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; lapatinib inhibits CYP3A4. Lapatinib can also prolong the QT interval. Lapatinib should be administered with caution to patients who have or may develop prolongation of QTc such as patients taking anti-arrhythmic medicines that lead to QT prolongation.
    Lithium: (Major) Lithium should be used cautiously and with close monitoring with lapatinib. Lithium has been associated with QT prolongation. Lapatinib can prolong the QT interval. Lapatinib should be administered with caution to patients who have or may develop prolongation of QTc such as patients taking anti-arrhythmic medicines or other medicinal products that lead to QT prolongation. Administer lapatinib with caution in patients taking drugs with the potential to induce QT prolongation.
    Lofexidine: (Major) Monitor ECG and electrolytes if lofexidine is coadministered with lapatinib due to the potential for additive QT prolongation and torsade de pointes (TdP). Correct hypokalemia or hypomagnesemia prior to lapatinib administration. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of TdP. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and TdP have been reported in postmarketing experience.
    Lomitapide: (Major) Concomitant use of lomitapide and lapatinib may significantly increase the serum concentration of lomitapide. Therefore, the lomitapide dose should not exceed 30 mg/day PO during concurrent use. Lapatinib is a weak CYP3A4 inhibitor; the exposure to lomitapide is increased by approximately 2-fold in the presence of weak CYP3A4 inhibitors. In addition, concomitant use may result in increased serum concentrations of lapatinib. According to the manufacturer of lomitapide, dose reduction of lapatinib should be considered during concurrent use. Lomitapide is an inhibitor of P-glycoprotein (P-gp) and lapatinib is a P-gp substrate.
    Long-acting beta-agonists: (Moderate) Lapatinib can prolong the QT interval. Lapatinib should be administered with caution to patients who have or may develop prolongation of QTc such as patients taking anti-arrhythmic medicines or other medicinal products that lead to QT prolongation. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with lapatinib include the long-acting beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Loperamide: (Major) Loperamide should be used cautiously and with close monitoring with lapatinib. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Lapatinib can prolong the QT interval and should be administered with caution to patients taking other medicinal products that lead to QT prolongation. In addition, the plasma concentrations of loperamide, a CYP3A4, CYP2C8, and P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with lapatinib, a CYP3A4, CYP2C8, and P-gp inhibitor, further increasing the risk of toxicity. If these drugs are used together, monitor for cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, TdP, cardiac arrest) and other loperamide-associated adverse reactions, such as CNS effects.
    Loperamide; Simethicone: (Major) Loperamide should be used cautiously and with close monitoring with lapatinib. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Lapatinib can prolong the QT interval and should be administered with caution to patients taking other medicinal products that lead to QT prolongation. In addition, the plasma concentrations of loperamide, a CYP3A4, CYP2C8, and P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with lapatinib, a CYP3A4, CYP2C8, and P-gp inhibitor, further increasing the risk of toxicity. If these drugs are used together, monitor for cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, TdP, cardiac arrest) and other loperamide-associated adverse reactions, such as CNS effects.
    Lopinavir; Ritonavir: (Major) Avoid coadministration of lapatinib with ritonavir if possible due to increased plasma concentrations of lapatinib. If concomitant use is unavoidable, consider a lapatinib dose reduction to 500 mg/day, as this dose is predicted to adjust the lapatinib exposure to the range observed without ritonavir. If ritonavir is discontinued, a washout period of approximately 1 week should be allowed before the lapatinib dose is adjusted upward to the indicated dose. Lapatinib is extensively metabolized by CYP3A4. ritonavir is a strong CYP3A4 inhibitor. In a drug interaction study, concurrent administration with another strong CYP3A4 inhibitor increased lapatinib systemic exposure (AUC) by approximately 3.6-fold and the half-life increased by 1.7-fold. (Major) QT prolongation in patients taking lopinavir; ritonavir has been reported. Lopinavir; ritonavir should be used with extreme caution when given with other drugs that prolong the QT interval, such as lapatinib. Moreover, lapatinib is a substrate and inhibitor of the CYP3A4 isoenzyme, and lopinavir; ritonavir is an inhibitor of this isoenzyme. Concomitant use of lapatinib with strong CYP3A4 inhibitors, such as lopinavir; ritonavir, should generally be avoided.
    Luliconazole: (Moderate) Theoretically, luliconazole may increase the side effects of lapatinib, which is a CYP2C19 and CYP3A4 substrate. Monitor patients for adverse effects of lapatinib, such as GI or dermatologic effects and QT prolongation. In vitro, therapeutic doses of luliconazole inhibit the activity of CYP2C19 and CYP3A4 and small systemic concentrations may be noted with topical application, particularly when applied to patients with moderate to severe tinea cruris. No in vivo drug interaction trials were conducted prior to the approval of luliconazole.
    Lurasidone: (Major) Lapatinib is a moderate inhibitor of CYP3A4 and has the potential for interactions with substrates of CYP3A4 such as lurasidone. Concurrent use of these medications may lead to an increased risk of lurasidone-related adverse reactions. If a moderate inhibitor of CYP3A4 is being prescribed and lurasidone is added in an adult patient, the recommended starting dose of lurasidone is 20 mg/day and the maximum recommended daily dose of lurasidone is 80 mg/day. If a moderate CYP3A4 inhibitor is added to an existing lurasidone regimen, reduce the lurasidone dose to one-half of the original dose. Patients should be monitored for efficacy and toxicity.
    Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as lapatinib. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience. Correct hypokalemia or hypomagnesemia prior to lapatinib administration.
    Maprotiline: (Major) Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with maprotiline include lapatinib.
    Maraviroc: (Moderate) Use caution if coadministration of maraviroc with lapatinib is necessary due to a possible increase in maraviroc exposure. Maraviroc is a CYP3A and P-glycoprotein (P-gp) substrate and lapatinib is a CYP3A4 and P-gp inhibitor. Monitor for an increase in adverse effects with concomitant use.
    Meclofenamate Sodium: (Major) An increased risk of bleeding may occur when NSAIDs, such as meclofenamate sodium, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Mefenamic Acid: (Major) An increased risk of bleeding may occur when NSAIDs, such as mefenamic acid, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Mefloquine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering lapatinib with mefloquine. There is evidence that the use of halofantrine after mefloquine causes significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation; however due to the lack of clinical data, mefloquine should be used with caution in patients receiving drugs that prolong the QT interval, such as lapatinib. In addition, mefloquine is metabolized by CYP3A4 and P-glycoprotein (P-gp), while lapatinib is an inhibitor of CYP3A4 and a substrate/inhibitor of P-gp. Thus, coadministration may lead to increased mefloquine serum concentrations.
    Meloxicam: (Minor) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. However, meloxicam may be associated with less risk than other NSAIDs due to its relative minimal platelet inhibitory effects and gastric ulceration or hemorrhagic potential. Monitor closely for bleeding.
    Meperidine; Promethazine: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include lapatinib.
    Mesoridazine: (Severe) Lapatinib can prolong the QT interval. Avoid coadministration with mesoridazine as mesoridazine has been established to have a causal association with QT prolongation and torsade de pointe.
    Metformin; Repaglinide: (Moderate) In vitro, lapatinib, at clinically relevant concentrations, inhibits CYP3A4 and CYP2C8. Repaglinide is a substrate of both CYP3A4 and CYP2C8. Use caution if lapatinib is coadministered with repaglinide. A repaglinide dose reduction may be needed.
    Metformin; Saxagliptin: (Minor) Monitor patients for hypoglycemia if saxagliptin and lapatinib are used together. The metabolism of saxagliptin is primarily mediated by CYP3A4/5; saxagliptin plasma concentrations may increase in the presence of moderate CYP 3A4/5 inhibitors such as lapatinib.
    Methadone: (Major) The need to coadminister methadone with drugs known to prolong the QT interval should be done with extreme caution and a careful assessment of treatment risks versus benefits. Methadone is considered to be associated with an increased risk for QT prolongation and torsades de pointes (TdP), especially at higher doses (> 200 mg/day but averaging approximately 400 mg/day in adult patients). In addition, methadone is a substrate for CYP3A4, CYP2D6, and P-glycoprotein (P-gp). Concurrent use of methadone with inhibitors of these enzymes may result in increased serum concentrations of methadone. Drugs with a possible risk for QT prolongation and TdP that inhibit CYP3A4 and P-gp include lapatinib. If coadministration is necessary, exercise caution and consider dose reduction of methadone.
    Metronidazole: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include lapatinib.
    Midazolam: (Moderate) After the coadministration of lapatinib and midazolam, the 24-hour systemic exposure (AUC) of orally administered midazolam increased by 45% and 24-hour AUC of intravenously administered midazolam increased by 22%. Lapatinib is a CYP3A4 enzyme inhibitor and midazolam is a CYP3A4 substrate.
    Midostaurin: (Major) The concomitant use of midostaurin and lapatinib may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram and electrolyte monitoring. Correct hypokalemia or hypomagnesemia prior to lapatinib administration. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes have been reported in postmarketing experience.
    Mifepristone: (Major) Avoid use together if possible. Coadministration may increase mifepristone concentrations and may also increae the risk for QT prolongation or mifepristone-related side effects. Lapatinib and mifepristone have both been noted to prolong the QT interval; therefore coadministration may further increase the risk for QT prolongation. If use together is not avoidable, monitor closely. Caution should be exercised. Lapatinib might increase mifepristone concentrations via inhibition of CYP3A4 in vivo. In some patients receiving mifepristone for chronic conditions, a dosage reduction of mifepristone may be necessary to achieve clinical treatment goals and tolerance. Due to the slow elimination of mifepristone from the body, interactions that occur may be prolonged.
    Mirtazapine: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and lapatinib. Coadminister with caution and consider ECG and electrolyte monitoring. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and TdP have been reported in postmarketing experience. Correct hypokalemia or hypomagnesemia prior to lapatinib administration. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Mitotane: (Major) Avoid the concomitant use of mitotane with lapatinib. If coadministration cannot be avoided, based on pharmacokinetic studies, consider a gradual lapatinib dose titration from the usual dose of 1,250 mg PO once daily 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. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inducers. If mitotane is discontinued, the lapatinib dose should be reduced to the original indicated dose. Mitotane is a strong CYP3A4 inducer and lapatinib is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of lapatinib. In patients receiving lapatinib and carbamazepine (100 mg twice daily for 3 days then 200 mg twice daily for 17 days), systemic exposure to lapatinib was decreased by approximately 72%.
    Modafinil: (Moderate) Lapatinib is metabolized by CYP3A4 enzymes. Drugs that are inducers of CYP3A4 activity, such as modafinil, may decrease the plasma concentrations of lapatinib. If coadministration is necessary, consider dose adjustments of lapatinib.
    Moxifloxacin: (Major) Concurrent use of lapatinib and moxifloxacin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Lapatinib can prolong the QT interval. Moxifloxacin has also been associated with prolongation of the QT interval. Additionally, post-marketing surveillance has identified very rare cases of ventricular arrhythmias including TdP, usually in patients with severe underlying proarrhythmic conditions. The likelihood of QT prolongation may increase with increasing concentrations of moxifloxacin, therefore the recommended dose or infusion rate should not be exceeded.
    Nabumetone: (Minor) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. However, nabumetone may be associated with less risk than other NSAIDs due to its relative minimal platelet inhibitory effects and gastric ulceration or hemorrhagic potential. Monitor closely for bleeding.
    Nafcillin: (Moderate) Lapatinib is metabolized by CYP3A4 and CYP3A5 enzymes. Drugs that are inducers of CYP3A4 activity, such as nafcillin, will decrease the plasma concentrations of lapatinib. If treatment with nafcillin is necessary, consider a lapatinib dose escalation. If nevirapine is discontinued, reduce the lapatinib dose to the indicated dose.
    Naproxen: (Major) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Naproxen; Pseudoephedrine: (Major) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Naproxen; Sumatriptan: (Major) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Nefazodone: (Major) Lapatinib is a CYP3A4 substrate, and concomitant use of lapatinib with strong CYP3A4 inhibitors, such as nefazodone, should generally be avoided. If concurrent treatment with nefazodone is necessary, strongly consider a lapatinib dose reduction. If nefazodone is discontinued, allow 7 days to elapse before increasing the lapatinib dose.
    Nelfinavir: (Major) Lapatinib is a CYP3A4 substrate, and concomitant use of lapatinib with strong CYP3A4 inhibitors, such as nelfinavir, should generally be avoided. If concurrent treatment is necessary, strongly consider reducing the adult lapatinib dose to 500 mg/day; clinical data to support this dose adjustment are lacking. If nelfinavir is discontinued, allow 7 days to elapse before increasing the lapatinib dose.
    Netupitant, Fosnetupitant; Palonosetron: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as lapatinib. The plasma concentrations of lapatinib can increase when co-administered with netupitant; the inhibitory effect on CYP3A4 can last for multiple days.
    Nevirapine: (Moderate) Lapatinib is metabolized by CYP3A4 and CYP3A5 enzymes. Drugs that are inducers of CYP3A4 activity, such as nevirapine, will decrease the plasma concentrations of lapatinib. If treatment with nevirapine is necessary, consider a lapatinib dose escalation. If nevirapine is discontinued, reduce the lapatinib dose to the indicated dose.
    Nisoldipine: (Major) Avoid coadministration of nisoldipine with lapatinib due to increased plasma concentrations of nisoldipine. If coadministration is unavoidable, monitor blood pressure closely during concurrent use of these medications. Nisoldipine is a CYP3A4 substrate and lapatinib is a CYP3A4 inhibitor.
    Norfloxacin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering lapatinib with norfloxacin. Lapatinib can prolong the QT interval. Quinolones have also been associated with QT prolongation and TdP. For norfloxacin specifically, extremely rare cases of TdP were reported during post-marketing surveillance. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Nortriptyline: (Major) Coadministration may result in additive effects on the QT interval. Lapatinib can prolong the QT interval. Tricyclic antidepressants (TCAs) share pharmacologic properties like the Class IA antiarrhythmic agents and may also prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Use caution and monitor for evidence of QT prolongation during concurrent use.
    Octreotide: (Major) Consider ECG and electrolyte monitoring if coadministration of lapatinib and octreotide is necessary. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience. Correct hypokalemia or hypomagnesemia prior to lapatinib administration. Arrhythmias, sinus bradycardia, and conduction disturbances have occurred during octreotide therapy. Since bradycardia is a risk factor for development of TdP, the potential occurrence of bradycardia during octreotide administration could theoretically increase the risk of TdP in patients receiving drugs that prolong the QT interval.
    Ofloxacin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering lapatinib with ofloxacin. Lapatinib can prolong the QT interval. Some quinolones, including ofloxacin, have also been associated with QT prolongation. Additionally, post-marketing surveillance for ofloxacin has identified very rare cases of TdP.
    Olanzapine: (Major) Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Therefore, caution is advised when administering olanzapine with drugs having an established causal association with QT prolongation and torsade de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with olanzapine include lapatinib.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of lapatinib with ritonavir if possible due to increased plasma concentrations of lapatinib. If concomitant use is unavoidable, consider a lapatinib dose reduction to 500 mg/day, as this dose is predicted to adjust the lapatinib exposure to the range observed without ritonavir. If ritonavir is discontinued, a washout period of approximately 1 week should be allowed before the lapatinib dose is adjusted upward to the indicated dose. Lapatinib is extensively metabolized by CYP3A4. ritonavir is a strong CYP3A4 inhibitor. In a drug interaction study, concurrent administration with another strong CYP3A4 inhibitor increased lapatinib systemic exposure (AUC) by approximately 3.6-fold and the half-life increased by 1.7-fold. (Major) Concurrent administration of lapatinib with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of all 5 drugs. If coadministration is necessary, consider a lapatinib dosage reduction. Both lapatinib and ritonavir have been associated with QT prolongation; concomitant use increases the risk for developing Torsade de Pointed (TdP). Both ritonavir and lapatinib are substrates and inhibitors of the hepatic isoenzyme CYP3A4 and the drug transporter P-glycoprotein (P-gp). Lapatinib is also an inhibitor of CYP2C8. Dasabuvir is primarily metabolized by CYP2C8, while lapatinib, ritonavir, paritaprevir, and dasabuvir (minor) are CYP3A4 substrates. In addition, dasabuvir, ombitasvir, paritaprevir and ritonavir are substrates of P-gp. Caution and close monitoring are advised if these drugs are administered together.
    Ondansetron: (Major) Monitor serum electrolytes and ECG for evidence of QT prolongation if coadministration of ondansetron and lapatinib is necessary. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP). Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and TdP have been reported in postmarketing experience. Correct hypokalemia or hypomagnesemia prior to lapatinib administration.
    Oritavancin: (Moderate) Lapatinib is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of lapatinib may be reduced if these drugs are administered concurrently.
    Osimertinib: (Major) Avoid coadministration of lapatinib with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor for an increase in lapatinib-related adverse reactions, periodically monitor ECGs for QT prolongation, and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Correct hypokalemia or hypomagnesemia prior to administration. Lapatinib is a P-glycoprotein (P-gp) substrate that has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and TdP have been reported in postmarketing experience. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib, which is a P-gp inhibitor.
    Oxaliplatin: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of lapatinib with oxaliplatin is necessary; correct electrolyte abnormalities prior to treatment. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience. QT prolongation and ventricular arrhythmias including fatal TdP have also been reported with oxaliplatin use in postmarketing experience.
    Oxaprozin: (Minor) An increased risk of bleeding may occur when NSAIDs, such as oxaprozin, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of lapatinib is necessary. If lapatinib is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a weak CYP3A4 inhibitor like lapatinib can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If lapatinib is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Paclitaxel: (Moderate) In vitro, lapatinib, at clinically relevant concentrations, inhibits CYP3A4 and CYP2C8. Also, lapatinib is a substrate and inhibitor of the efflux transporter P-glycoprotein (Pgp, ABCB1). Paclitaxel is a CYP3A4 substrate, a CYP2C8 substrate, and a P-glycoprotein substrate. As increased paclitaxel concentrations are likely, cautious coadministration is recommended, and consider a paclitaxel dose reduction.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Paliperidone: (Major) Paliperidone has been associated with QT prolongation. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as lapatinib. However, if coadministration is considered necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
    Panobinostat: (Major) The co-administration of panobinostat with lapatinib is not recommended; QT prolongation has been reported with both agents. Lapatinib is a CYP3A4 inhibitor and panobinostat is a CYP3A4 substrate. The panobinostat Cmax and AUC (0-48hr) values were increased by 62% and 73%, respectively, in patients with advanced cancer who received a single 20 mg-dose of panobinostat after taking 14 days of a strong CYP3A4 inhibitor. Although an initial panobinostat dose reduction is recommended in patients taking concomitant strong CYP3A4 inhibitors, no dose recommendations with mild or moderate CYP3A4 inhibitors are provided by the manufacturer. If concomitant use of lapatinib and panobinostat cannot be avoided, closely monitor electrocardiograms and for signs and symptoms of panobinostat toxicity such as cardiac arrhythmias, diarrhea, bleeding, infection, and hepatotoxicity. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve.
    Pasireotide: (Major) Lapatinib can prolong the QT interval. Lapatinib should be administered with caution to patients who have or may develop prolongation of QTc such as patients taking anti-arrhythmic medicines or other medicinal products that lead to QT prolongation. Administer lapatinib with caution in patients taking drugs with the potential to induce QT prolongation, such as pasireotide.
    Pazopanib: (Major) Coadministration of pazopanib and lapatinib is not recommended due to the potential for serious and fatal toxicity; additive risk of QT prolongation is also possible. Clinical trials of pazopanib in combination with pemetrexed and lapatinib were terminated early due to concerns over increased toxicity and mortality. The fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens. Administration of lapatinib, a substrate and weak inhibitor of CYP3A4, P-gp, and BCRP, increased the mean AUC and Cmax of pazopanib by approximately 50% to 60%.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Pentamidine: (Major) Lapatinib can prolong the QT interval. Lapatinib should be administered with caution to patients who have or may develop prolongation of the QT interval such as patients taking medications that might prolong the QT interval. Pentamidine has been associated with QT prolongation.
    Perphenazine: (Minor) Lapatinib can prolong the QT interval. Lapatinib should be administered with caution to patients who have or may develop prolongation of QTc such as patients taking anti-arrhythmic medicines or other medicinal products that lead to QT prolongation. Administer lapatinib with caution in patients taking drugs with the potential to induce QT prolongation. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously and with close monitoring with lapatinib include perphenazine.
    Perphenazine; Amitriptyline: (Major) Coadministration may result in additive effects on the QT interval. Lapatinib can prolong the QT interval. Tricyclic antidepressants (TCAs) share pharmacologic properties like the Class IA antiarrhythmic agents and may also prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Use caution and monitor for evidence of QT prolongation during concurrent use. (Minor) Lapatinib can prolong the QT interval. Lapatinib should be administered with caution to patients who have or may develop prolongation of QTc such as patients taking anti-arrhythmic medicines or other medicinal products that lead to QT prolongation. Administer lapatinib with caution in patients taking drugs with the potential to induce QT prolongation. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously and with close monitoring with lapatinib include perphenazine.
    Phenylephrine; Promethazine: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include lapatinib.
    Phenytoin: (Major) Lapatinib is metabolized by CYP3A4 and CYP3A5 enzymes. Drugs that are inducers of CYP3A4 activity, such as phenytoin, will decrease the plasma concentrations of lapatinib. If treatment with phenytoin is necessary, consider a lapatinib dose escalation. If phenytoin is discontinued, reduce the lapatinib dose to the indicated dose.
    Pimavanserin: (Major) Lapatinib inhibits CYP3A4 at clinically relevant concentrations in vitro and can prolong the QT interval. If lapatinib will be co-administered with another CYP3A4 substrate that can prolong the QT interval, such as pimavanserin, use this combination with extreme caution.
    Pimozide: (Severe) Pimozide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Because of the potential for TdP, use of lapatinib with pimozide is contraindicated.
    Piroxicam: (Minor) An increased risk of bleeding may occur when NSAIDs, such as piroxicam, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Ponatinib: (Moderate) Concomitant use of ponatinib, a CYP3A4 substrate, and lapatinib, a CYP3A4 inhibitor, may increase the exposure of ponatinib. The manufacturer recommends a reduced starting ponatinib dose when use of a strong CYP3A4 inhibitor cannot be avoided. Additionally, ponatinib may increase the plasma concentration of P-gp and ABCG2 (BCRP) substrates, such as lapatinib.
    Posaconazole: (Severe) The concurrent use of posaconazole and lapatinib is contraindicated due to the risk of life threatening arrhythmias such as torsades de pointes (TdP). Both posaconazole and lapatinib are inhibitors of CYP3A4, an isoenzyme responsible for the metabolism of lapatinib. Further, lapatinib is an inhibitor of the drug efflux protein, P-glycoprotein, for which posaconazole is a substrate and an inhibitor. This complex interaction may ultimately result in altered plasma concentrations of both posaconazole and lapatinib. Additionally, posaconazole has been associated with prolongation of the QT interval as well as rare cases of TdP; avoid use with other drugs that may prolong the QT interval and are metabolized through CYP3A4, such as lapatinib.
    Primaquine: (Major) Due to the potential for QT interval prolongation with primaquine, caution is advised with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with primaquine include lapatinib.
    Procainamide: (Major) Lapatinib can prolong the QT interval. Lapatinib should be administered with caution to patients who have or may develop prolongation of QTc such as patients taking anti-arrhythmic medicines or other medicinal products that lead to QT prolongation. Administer lapatinib with caution in patients taking drugs with the potential to induce QT prolongation. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously and with close monitoring with lapatinib include procainamide.
    Prochlorperazine: (Minor) Lapatinib can prolong the QT interval. Lapatinib should be administered with caution to patients who have or may develop prolongation of QTc such as patients taking anti-arrhythmic medicines or other medicinal products that lead to QT prolongation. Administer lapatinib with caution in patients taking drugs with the potential to induce QT prolongation. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously and with close monitoring with lapatinib include prochlorperazine.
    Promethazine: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include lapatinib.
    Propafenone: (Major) Propafenone is a P-glycoprotein inhibitor, and lapatinib is a substrate and inhibitor of the efflux transporter P-glycoprotein (Pgp, ABCB1); concurrent administration with a P-glycoprotein inhibitor is likely to cause elevated serum lapatinib concentrations, and caution is recommended. Also, lapatinib and propafenone may prolong the QT interval. Lapatinib should be administered with caution to patients who have or may develop prolongation of QTc such as patients taking other drugs that lead to QT prolongation. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval..
    Propoxyphene: (Moderate) Propoxyphene, an inhibitor of CYP3A4, may increase the serum concentrations of lapatinib. Use lapatinib and propoxyphene together with caution, and monitor patients closely.
    Protriptyline: (Major) Coadministration may result in additive effects on the QT interval. Lapatinib can prolong the QT interval. Tricyclic antidepressants (TCAs) share pharmacologic properties like the Class IA antiarrhythmic agents and may also prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Use caution and monitor for evidence of QT prolongation during concurrent use.
    Quetiapine: (Major) Limited data, including some case reports, suggest that quetiapine may be associated with a significant prolongation of the QTc interval in rare instances. According to the manufacturer, use of quetiapine should be avoided in combination with drugs known to increase the QT interval, such as lapatinib. Also, in vitro, lapatinib, at clinically relevant concentrations, inhibits CYP3A4 and CYP2C8. If lapatinib will be coadministered with a CYP3A4 substrate, such as quetiapine, exercise caution and consider dose reduction of quetiapine.
    Quinidine: (Major) Lapatinib is a CYP3A4 inhibitor at clinically relevant concentrations in vitro. Also, lapatinib is a substrate and inhibitor of the efflux transporter P-glycoprotein (P-gp, ABCB1). Quinidine is a CYP3A4 substrate and a P-gp inhibitor and substrate. If lapatinib will be coadministered with a CYP3A4 and P-gp substrate, such as quinidine, exercise caution and consider dose reduction of quinidine. Concurrent administration of lapatinib with a P-gp inhibitor, such as quinidine, is likely to cause elevated serum lapatinib concentrations, and caution is recommended. In addition to pharmacokinetic interactions, both lapatinib and quinidine can prolong the QT interval; therefore coadministration may further increase the risk for QT prolongation.
    Quinine: (Major) Concurrent use of quinine and lapatinib should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Both drugs have been associated with prolongation of the QT interval and rare cases of TdP. In addition, both drugs are substrates and inhibitors of CYP3A4; coadministration may increase concentrations of both drugs.
    Ranolazine: (Major) Lapatinib is a CYP3A4 substrate and a CYP3A4 inhibitor at clinically relevant concentrations in vitro. Also, lapatinib is a substrate and inhibitor of the efflux transporter P-glycoprotein (P-gp, ABCB1). Ranolazine is a P-glycoprotein (P-gp) inhibitor, a CYP3A4 substrate, and a CYP3A4 inhibitor. If lapatinib will be coadministered with a CYP3A4 substrate, such as ranolazine, exercise caution and consider dose reduction of ranolazine. According to the manufacturer, the ranolazine dosage should be limited to 500 mg PO twice daily for patients receiving drugs known to be moderate CYP3A inhibitors. Concurrent administration of lapatinib with a P-gp and CYP3A4 inhibitor such as ranolazine is likely to cause elevated serum lapatinib concentrations, and caution is recommended. In addition to pharmacokinetic interactions, both lapatinib and ranolazine can prolong the QT interval; therefore coadministration may further increase the risk for QT prolongation.
    Repaglinide: (Moderate) In vitro, lapatinib, at clinically relevant concentrations, inhibits CYP3A4 and CYP2C8. Repaglinide is a substrate of both CYP3A4 and CYP2C8. Use caution if lapatinib is coadministered with repaglinide. A repaglinide dose reduction may be needed.
    Ribociclib: (Major) Avoid coadministration of ribociclib with lapatinib due to an increased risk for QT prolongation; systemic exposure to lapatinib may also be increased resulting in an increase in treatment-related adverse reactions. Lapatinib is a CYP3A4 substrate that has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience. Ribociclib is a strong CYP3A4 inhibitor that has also been shown to prolong the QT interval in a concentration-dependent manner. Concomitant use may increase the risk for QT prolongation.
    Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with lapatinib due to an increased risk for QT prolongation; systemic exposure to lapatinib may also be increased resulting in an increase in treatment-related adverse reactions. Lapatinib is a CYP3A4 substrate that has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience. Ribociclib is a strong CYP3A4 inhibitor that has also been shown to prolong the QT interval in a concentration-dependent manner. Concomitant use may increase the risk for QT prolongation.
    Rifamycins: (Major) Lapatinib is metabolized by CYP3A4 and CYP3A5 enzymes. Rifabutin, rifampin, and rifapentine are inducers of CYP3A4 activity and will decrease the plasma concentrations of lapatinib.
    Rifaximin: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and lapatinib, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Rilpivirine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with lapatinib. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Lapatinib can also prolong the QT interval. Additionally, lapatinib may inhibit the CYP3A4 metabolism of rilpivirine, potentially resulting in elevated rilpivirine serum concentrations and risk of adverse events, such as QT prolongation.
    Risperidone: (Major) Use lapatinib and risperidone together with caution since there is an increased risk for QT prolongation and torsade de pointes (TdP). If used together, consider ECG and electrolyte monitoring; correct hypokalemia and/or hypomagnesemia prior to lapatinib administration. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and TdP have been reported in postmarketing experience. Risperidone has also been associated with a possible risk for QT prolongation and/or TdP, primarily in the overdose setting.
    Ritonavir: (Major) Avoid coadministration of lapatinib with ritonavir if possible due to increased plasma concentrations of lapatinib. If concomitant use is unavoidable, consider a lapatinib dose reduction to 500 mg/day, as this dose is predicted to adjust the lapatinib exposure to the range observed without ritonavir. If ritonavir is discontinued, a washout period of approximately 1 week should be allowed before the lapatinib dose is adjusted upward to the indicated dose. Lapatinib is extensively metabolized by CYP3A4. ritonavir is a strong CYP3A4 inhibitor. In a drug interaction study, concurrent administration with another strong CYP3A4 inhibitor increased lapatinib systemic exposure (AUC) by approximately 3.6-fold and the half-life increased by 1.7-fold.
    Rivaroxaban: (Minor) The coadministration of rivaroxaban and lapatinib should be undertaken with caution in patients with renal impairment; it is unclear whether a clinically significant interaction occurs when these two drugs are coadministered to patients with normal renal function. Lapatinib is a combined CYP3A4 and P-glycoprotein (P-gp) inhibitor. Rivaroxaban is a substrate of CYP3A4/5 and the P-gp transporter. Coadministration in patients with renal impairment may result in increased exposure to rivaroxaban compared with patients with normal renal function and no inhibitor use since both pathways of elimination are affected. While an increase in exposure to rivaroxaban may be expected, results from an analysis of the ROCKET-AF trial which allowed concomitant administration of rivaroxaban and a combined P-gp inhibitor and weak or moderate CYP3A4 inhibitor did not show an increased risk of bleeding in patients with CrCl 30 to < 50 ml/min [HR (95% CI): 1.05 (0.77, 1.42)].
    Romidepsin: (Major) Romidepsin is a substrate for CYP3A4 and P-glycoprotein (P-gp). Lapatinib is an inhibitor of CYP3A4 and P-gp. Concurrent administration of romidepsin with an inhibitor of CYP3A4 and P-gp may cause an increase in systemic romidepsin concentrations. If lapatinib will be coadministered with a CYP3A4 substrate, exercise caution and consider dose reduction of the concomitant substrate drug. In addition, coadministration of romidepsin and other drugs that prolong the QT interval is not advised; romidepsin has been reported to prolong the QT interval. Lapatinib may also prolong the QT interval. If romidepsin and lapatinib must be continued, closely monitor the patient for QT interval prolongation.
    Ruxolitinib: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as lapatinib, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure.
    Saquinavir: (Major) Lapatinib is a CYP3A4 substrate, and concomitant use of lapatinib with strong CYP3A4 inhibitors, such as saquinavir boosted with ritonavir, should generally be avoided. If concurrent treatment with a strong CYP3A4 inhibitor is necessary, strongly consider a lapatinib dose reduction. If a strong CYP3A4 inhibitor is discontinued, allow 7 days to elapse before increasing the lapatinib dose. Administer lapatinib with extreme caution in patients taking CYP3A4 inhibitors that also have potential to induce QT prolongation, as lapatinib can prolong the QT interval. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsades de pointes (TdP). Further, saquinavir is a P-glycoprotein inhibitor; concurrent administration of lapatinib with a P-glycoprotein inhibitor is likely to cause elevated serum lapatinib concentrations, and caution is recommended.
    Saxagliptin: (Minor) Monitor patients for hypoglycemia if saxagliptin and lapatinib are used together. The metabolism of saxagliptin is primarily mediated by CYP3A4/5; saxagliptin plasma concentrations may increase in the presence of moderate CYP 3A4/5 inhibitors such as lapatinib.
    Selexipag: (Major) Consider a less frequent dosing regimen (e.g., once daily) when initiating selexipag in patients receiving lapatinib. Reduce the selexipag dose when lapatinib is initiated in patients already taking selexipag. Coadministration can be expected to increase exposure to selexipag and its active metabolite. Selexipag is a substrate of CYP2C8; lapatinib is a moderate CYP2C8 inhibitor.
    Sertraline: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and TdP have been reported in postmarketing experience. Correct hypokalemia or hypomagnesemia prior to lapatinib administration. Consider ECG and electrolyte monitoring if concurrent use is required.
    Sevoflurane: (Major) Lapatinib can prolong the QT interval. Lapatinib should be administered with caution to patients who have or may develop prolongation of QTc such as patients taking anti-arrhythmic medicines or other medicinal products that lead to QT prolongation. Administer lapatinib with caution in patients taking drugs with the potential to induce QT prolongation. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously and with close monitoring with lapatinib include halogenated anesthetics.
    Short-acting beta-agonists: (Minor) Lapatinib can prolong the QT interval. Lapatinib should be administered with caution to patients who have or may develop prolongation of QTc such as patients taking anti-arrhythmic medicines or other medicinal products that lead to QT prolongation. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with lapatinib include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Simeprevir: (Major) Avoid concurrent use of simeprevir and lapatinib. Inhibition of CYP3A4 and P-glycoprotein (P-gp) by lapatinib may increase the plasma concentrations of simeprevir, resulting in adverse effects, such as rash. Additionally, simeprivir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of lapatinib, a CYP3A4 substrate.
    Sirolimus: (Moderate) In vitro, lapatinib, at clinically relevant concentrations, inhibits CYP3A4. Lapatinib is also a substrate and inhibitor of the efflux transporter P-glycoprotein (Pgp, ABCB1). Sirolimus is a substrate of both CYP3A4 and P-glycoprotein. As increased sirolimus concentrations are likely, cautious coadministration is recommended, and consider a sirolimus dose reduction. In addition, because sirolimus is an immunosuppressant, additive affects may be seen with antineoplastic agents such as lapatinib. While therapy is designed to take advantage of this effect, patients may be predisposed to over-immunosuppression resulting in an increased risk of infection or other side effects.
    Sofosbuvir: (Moderate) Caution and close monitoring of adverse reactions is advised with concomitant administration of lapatinib and sofosbuvir. Taking these drugs together may increase plasma concentrations of sofosbuvir. Lapatinib is an inhibitor of the drug transporter P-glycoprotein (P-gp); sofosbuvir is a P-gp substrate. According to the manufacturer, no dosage adjustments are required when sofosbuvir is administered concurrently with P-gp inhibitors.
    Sofosbuvir; Velpatasvir: (Moderate) Caution and close monitoring of adverse reactions is advised with concomitant administration of lapatinib and sofosbuvir. Taking these drugs together may increase plasma concentrations of sofosbuvir. Lapatinib is an inhibitor of the drug transporter P-glycoprotein (P-gp); sofosbuvir is a P-gp substrate. According to the manufacturer, no dosage adjustments are required when sofosbuvir is administered concurrently with P-gp inhibitors. (Moderate) Use caution when administering velpatasvir with lapatinib. Taking these medications together may increase the plasma concentrations of velpatasvir, potentially resulting in adverse events. Velpatasvir is a substrate of the drug transporter P-glycoprotein (P-gp); lapatinib is an inhibitor of P-gp.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Caution and close monitoring of adverse reactions is advised with concomitant administration of lapatinib and sofosbuvir. Taking these drugs together may increase plasma concentrations of sofosbuvir. Lapatinib is an inhibitor of the drug transporter P-glycoprotein (P-gp); sofosbuvir is a P-gp substrate. According to the manufacturer, no dosage adjustments are required when sofosbuvir is administered concurrently with P-gp inhibitors. (Moderate) Use caution when administering velpatasvir with lapatinib. Taking these medications together may increase the plasma concentrations of velpatasvir, potentially resulting in adverse events. Velpatasvir is a substrate of the drug transporter P-glycoprotein (P-gp); lapatinib is an inhibitor of P-gp.
    Solifenacin: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering solifenacin with lapatinib. Solifenacin has been associated with dose-dependent prolongation of the QT interval; TdP has been reported during post-marketing use, although causality was not determined. Lapatinib can also prolong the QT interval. In addition, concentrations of solifenacin may be increased during concomitant use with lapatinib. Solifenacin is a CYP3A4 substrate and lapatinib is a CYP3A4 inhibitor. Patients receiving CYP3A4 inhibitors should not receive solifenacin doses greater than 5 mg per day.
    Sorafenib: (Major) Monitor for an increase in lapatinib-related adverse reactions, monitor ECGs for QT prolongation, and monitor electrolytes if coadministration of sorafenib; correct any electrolyte abnormalities prior to treatment. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Lapatinib is a P-glycoprotein (P-gp) substrate that has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience. Sorafenib inhibits P-gp in vitro and has also been associated with QT prolongation. Sorafenib may increase the concentrations of concomitantly administered drugs that are P-gp substrates.
    Sotalol: (Major) Sotalol administration is associated with QT prolongation and torsades de pointes (TdP). Proarrhythmic events should be anticipated after initiation of therapy and after each upward dosage adjustment. Drugs with a possible risk for QT prolongation and TdP should be used cautiously with sotalol. Lapatinib can prolong the QT interval. Lapatinib should be administered with caution to patients who have or may develop prolongation of QTc such as patients taking anti-arrhythmic medicines or other medicinal products that lead to QT prolongation.
    Sparfloxacin: (Severe) Lapatinib can prolong the QT interval. Avoid coadministration with sparfloxacin as sparfloxacin has been established to have a causal association with QT prolongation and torsade de pointe.
    St. John's Wort, Hypericum perforatum: (Major) Lapatinib is metabolized by CYP3A4 and CYP3A5 enzymes. St. John's Wort induces CYP3A4 activity and will decrease the plasma concentrations of lapatinib. If treatment with St. John's Wort is necessary, consider a lapatinib dose escalation. If St. John's Wort is discontinued, reduce the lapatinib dose to the indicated dose.
    Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if lapatinib must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of lapatinib is necessary. If lapatinibis discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a CYP3A4 substrate, and coadministration with a weak CYP3A4 inhibitor like lapatinib can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil. If lapatinib is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil.
    Sulindac: (Minor) An increased risk of bleeding may occur when NSAIDs, such as sulindac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Sunitinib: (Major) Monitor ECGs for QT prolongation and consider monitoring electrolytes if coadministration of lapatinib with sunitinib is necessary. Correct hypokalemia or hypomagnesemia prior to lapatinib administration. Sunitinib can cause dose-dependent QT prolongation, which may increase the risk for ventricular arrhythmias, including torsades de points (TdP). Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and TdP have been reported in postmarketing experience.
    Suvorexant: (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends a dose reduction to 5 mg of suvorexant during concurrent use with moderate CYP3A inhibitors and a maximum recommended dose of 10 mg/day. Lapatinib is a moderate CYP3A4 inhibitor, and increased plasma concentrations of suvorexant are possible during concurrent use of these drugs.
    Tacrolimus: (Major) Tacrolimus is a substrate of both CYP3A4 and P-glycoprotein. In vitro, lapatinib, at clinically relevant concentrations, inhibits CYP3A4. Also, lapatinib is a substrate and inhibitor of the efflux transporter P-glycoprotein. Coadministration with lapatinib may lead to increased tacrolimus serum concentrations. As increased serum concentrations are likely, reducing the tacrolimus dose, close monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended. Also, both lapatinib and tacrolimus can prolong the QT interval. Use lapatinib with extreme caution, if at all, in patients taking CYP3A4 substrates that also have potential to induce QT prolongation such as tacrolimus. Tacrolimus is also a P-glycoprotein inhibitor; concurrent administration with a P-glycoprotein inhibitor is likely to cause elevated serum lapatinib concentrations, and caution is recommended.
    Talazoparib: (Moderate) Monitor for an increase in talazoparib-related adverse reactions if coadministration with lapatinib is necessary. Talazoparib is a P-glycoprotein (P-gp) substrate and lapatinib is a P-gp inhibitor. Coadministration with other P-gp inhibitors increased talazoparib exposure by 8% to 45%.
    Tamoxifen: (Major) Consider ECG monitoring for QT prolongation and monitor electrolytes if coadministration of lapatinib with tamoxifen is necessary. Correct hypokalemia or hypomagnesemia prior to lapatinib administration. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Tasimelteon: (Moderate) Caution is recommended during concurrent use of tasimelteon and lapatinib. Because tasimelteon is partially metabolized via CYP3A4, use with CYP3A4 inhibitors, such as lapatinib, may increase exposure to tasimelteon with the potential for adverse reactions.
    Telaprevir: (Moderate) Close clinical monitoring is advised when administering lapatinib with telaprevir due to an increased potential for lapatinib-related adverse events. If lapatinib dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of lapatinib and telaprevir. Both lapatinib and telaprevir are substrates and inhibitors of the hepatic isoenzyme CYP3A4. Additionally, lapatinib is an inhibitor of the drug efflux transporter P-glycoprotein (PGP); telaprevir is partially metabolized by this efflux protein. When used in combination, the plasma concentrations of both medications may be elevated.
    Telavancin: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering telavancin with lapatinib. Both lapatinib and telavancin have been associated with QT prolongation.
    Telithromycin: (Major) Lapatinib is a CYP3A4 substrate and a CYP3A4 inhibitor at clinically relevant concentrations in vitro. Also, lapatinib is a substrate and inhibitor of the efflux transporter P-glycoprotein (Pgp, ABCB1). Telithromycin is a P-gp inhibitor and a strong CYP3A4 inhibitor. Concomitant use of lapatinib with strong CYP3A4 inhibitors, such as telithromycin, should generally be avoided. If concurrent treatment with telithromycin is necessary, strongly consider a lapatinib dose reduction. If telithromycin is discontinued, allow 7 days to elapse before increasing the lapatinib dose. In addition to pharmacokinetic interactions, both lapatinib and telithromycin can prolong the QT interval; therefore, coadministration may further increase the risk for QT prolongation.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and lapatinib is necessary, as the systemic exposure of lapatinib may be decreased resulting in reduced efficacy; exposure to telotristat ethyl may also be increased. If these drugs are used together, monitor patients for suboptimal efficacy of lapatinib as well as an increase in adverse reactions related to telotristat ethyl. Consider increasing the dose of lapatinib if necessary. Lapatinib is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate. Additionally, the active metabolite of telotristat ethyl, telotristat, is a substrate of P-glycoprotein (P-gp) and lapatinib is a P-gp inhibitor. Exposure to telotristat ethyl may increase.
    Temsirolimus: (Moderate) Monitor for an increase in both temsirolimus- and lapatinib-related adverse reactions if coadministration is necessary. Both drugs are P-glycoprotein (P-gp) substrates and inhibitors. Concomitant use is likely to lead to increased concentrations of temsirolimus and lapatinib.
    Teniposide: (Moderate) Teniposide is a substrate of both CYP3A4 and P-glycoprotein. In vitro, lapatinib, at clinically relevant concentrations, inhibits CYP3A4. Also, lapatinib is a substrate and inhibitor of the efflux transporter P-glycoprotein (Pgp, ABCB1). Coadministration of lapatinib and teniposide may lead to increased serum concentrations of teniposide. Cautious coadministration is recommended, and consider a dose reduction of teniposide.
    Tenofovir Alafenamide: (Minor) Close clinical monitoring is advised when administering lapatinib with tenofovir alafenamide due to an increased potential for adverse events. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of these drugs. Lapatinib is an inhibitor of the drug transporter P-glycoprotein (P-gp). Tenofovir alafenamide is a substrate for P-gp. Coadministration may result in increased tenofovir plasma concentrations. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Tenofovir, PMPA: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as lapatinib. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Terbinafine: (Moderate) Due to the risk for terbinafine related adverse effects, caution is advised when coadministering lapatinib. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may increase the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP2C8 and CYP3A4; lapatinib is an inhibitor of these enzymes. Monitor patients for adverse reactions if these drugs are coadministered.
    Tetrabenazine: (Major) Tetrabenazine causes a small increase in the corrected QT interval. The manufacturer recommends avoiding concurrent use of tetrabenazine with other drugs known to prolong QTc including lapatinib.
    Thioridazine: (Severe) Thioridazine is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Thioridazine is considered contraindicated for use along with agents that, when combined with a phenothiazine, may prolong the QT interval and increase the risk of TdP, and/or cause orthostatic hypotension. Because of the potential for TdP, use of lapatinib with thioridazine is contraindicated.
    Ticagrelor: (Moderate) Coadministration of ticagrelor and lapatinib may result in increased exposure to ticagrelor which may increase the bleeding risk. Ticagrelor is a P-glycoprotein (P-gp) substrate and lapatinib is a P-gp inhibitor. Based on drug information data with cyclosporine, no dose adjustment is recommended by the manufacturer of ticagrelor. Use combination with caution and monitor for evidence of bleeding.
    Tipranavir: (Major) Lapatinib is a CYP3A4 substrate, and concomitant use of lapatinib with strong CYP3A4 inhibitors should generally be avoided. Also, lapatinib is a substrate and inhibitor of the efflux transporter P-glycoprotein (Pgp, ABCB1). In vitro, lapatinib, at clinically relevant concentrations, inhibits CYP3A4. Tipranavir is a substrate of both CYP3A4 and P-glycoprotein and a net inhibitor of CYP3A4 when administered as approved by the FDA (i.e., 'boosted' with ritonavir). Coadministration of these drugs may lead to increased tipranavir and lapatinib serum concentrations. Cautious coadministration is recommended, and consider reducing the lapatinib dose to 500 mg/day; clinical data are lacking for this dose adjustment.
    Tolmetin: (Minor) An increased risk of bleeding may occur when NSAIDs, such as tolmetin, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Tolterodine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering lapatinib with tolterodine. Lapatinib is associated with QT prolongation. Tolterodine has also been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. In a small portion of patients who poorly metabolize tolterodine via CYP2D6, the CYP3A4 pathway becomes important in tolterodine elimination. Because it is difficult to assess who are poor CYP2D6 metabolizers, patients receiving CYP3A4 inhibitors, such as lapatinib, should be monitored closely for adverse events. Pharmacokinetic studies of the use of tolterodine concomitantly with CYP3A4 inhibitors have not been performed.
    Tolvaptan: (Major) Tolvaptan is metabolized by CYP3A4 and is a substrate for P-gp. Lapatinib is a moderate inhibitor of CYP3A4 and P-gp. Coadministration may cause a marked increased in tolvaptan concentrations and should be avoided.
    Topotecan: (Major) Avoid coadministration of lapatinib with oral topotecan due to increased topotecan exposure; lapatinib may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and lapatinib is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Toremifene: (Major) Avoid coadministration of lapatinib with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Both drugs have been shown to prolong the QTc interval in a dose- and concentration-related manner; ventricular arrhythmias and torsade de pointes (TdP) have been reported with lapatinib use in postmarketing experience.
    Trabectedin: (Moderate) Use caution if coadministration of trabectedin and lapatinib is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and lapatinib is a weak CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Trandolapril; Verapamil: (Major) Lapatinib is a CYP3A4 substrate, and concomitant use of verapamil may decrease the metabolism and increase the serum concentrations of lapatinib. Further, verapamil is also a P-glycoprotein inhibitor; concurrent administration of lapatinib with a P-glycoprotein inhibitor is likely to cause elevated serum lapatinib concentrations, and caution is recommended.
    Trazodone: (Major) Avoid coadministration of lapatinib and trazodone. Lapatinib can prolong the QT interval. Lapatinib should be administered with caution to patients who have or may develop prolongation of QTc such as patients taking anti-arrhythmic medicines or other medicinal products that lead to QT prolongation. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval.
    Tricyclic antidepressants: (Major) Coadministration may result in additive effects on the QT interval. Lapatinib can prolong the QT interval. Tricyclic antidepressants (TCAs) share pharmacologic properties like the Class IA antiarrhythmic agents and may also prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Use caution and monitor for evidence of QT prolongation during concurrent use.
    Trifluoperazine: (Minor) Lapatinib can prolong the QT interval. Lapatinib should be administered with caution to patients who have or may develop prolongation of QTc such as patients taking anti-arrhythmic medicines or other medicinal products that lead to QT prolongation. Administer lapatinib with caution in patients taking drugs with the potential to induce QT prolongation. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously and with close monitoring with lapatinib include trifluoperazine.
    Trimipramine: (Major) Coadministration may result in additive effects on the QT interval. Lapatinib can prolong the QT interval. Tricyclic antidepressants (TCAs) share pharmacologic properties like the Class IA antiarrhythmic agents and may also prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Use caution and monitor for evidence of QT prolongation during concurrent use.
    Triptorelin: (Major) Androgen deprivation therapy (e.g., triptorelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with triptorelin include lapatinib.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
    Ulipristal: (Minor) Ulipristal is a substrate of CYP3A4 and lapatinib is a CYP3A4 inhibitor. Concomitant use may increase the plasma concentration of ulipristal resulting in an increased risk for adverse events.
    Vandetanib: (Major) Avoid coadministration of vandetanib with lapatinib due to an increased risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; correct hypocalcemia, hypomagnesemia, and/or hypomagnesemia prior to vandetanib administration. An interruption of vandetanib therapy or dose reduction may be necessary for QT prolongation. Vandetanib can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib. Lapatinib has also been associated with concentration-dependent QT prolongation; ventricular arrhythmias and TdP have been reported in postmarketing experience.
    Vardenafil: (Major) In vitro, lapatinib, at clinically relevant concentrations, inhibits CYP3A4 and CYP2C8. If lapatinib will be coadministered with a CYP3A4 substrate, exercise caution and consider dose reduction of the concomitant substrate drug, especially for drugs that have a narrow therapeutic index. Several CYP3A4 substrates can prolong the QT interval, and lapatinib can also prolong the QT interval. Use lapatinib with extreme caution, if at all, in patients taking CYP3A4 substrates that also have potential to induce QT prolongation such as vardenafil.
    Vemurafenib: (Major) Lapatinib is a CYP3A4 inhibitor at clinically relevant concentrations in vitro. Also, lapatinib is a substrate and inhibitor of the efflux transporter P-glycoprotein (P-gp, ABCB1). Vemurafenib is a CYP3A4 substrate and a P-gp inhibitor. If lapatinib will be coadministered with a CYP3A4 substrate, such as vemurafenib, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Consider dose reduction of vemurafenib. Concurrent administration of lapatinib with a P-gp inhibitor, such as vemurafenib, is likely to cause elevated serum lapatinib concentrations, and caution is recommended. In addition to pharmacokinetic interactions, both lapatinib and vemurafenib can prolong the QT interval; therefore coadministration may further increase the risk for QT prolongation.
    Venetoclax: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with lapatinib due to the potential for increased venetoclax exposure. Additionally, lapatinib exposure may be increased. Resume the original venetoclax dose 2 to 3 days after discontinuation of lapatinib. Both venetoclax and lapatinib are P-glycoprotein (P-gp) substrates and inhibitors. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Venlafaxine: (Major) In vitro, lapatinib, at clinically relevant concentrations, inhibits CYP3A4 and CYP2C8. If lapatinib will be coadministered with a CYP3A4 substrate, exercise caution and consider dose reduction of the concomitant substrate drug, especially for drugs that have a narrow therapeutic index. Several CYP3A4 substrates can prolong the QT interval, and lapatinib can also prolong the QT interval. Use lapatinib with extreme caution, if at all, in patients taking CYP3A4 substrates that also have potential to induce QT prolongation such as venlafaxine.
    Verapamil: (Major) Lapatinib is a CYP3A4 substrate, and concomitant use of verapamil may decrease the metabolism and increase the serum concentrations of lapatinib. Further, verapamil is also a P-glycoprotein inhibitor; concurrent administration of lapatinib with a P-glycoprotein inhibitor is likely to cause elevated serum lapatinib concentrations, and caution is recommended.
    Vinblastine: (Moderate) Vinblastine is a substrate of both CYP3A4 and P-glycoprotein. In vitro, lapatinib, at clinically relevant concentrations, inhibits CYP3A4. Also, lapatinib is a substrate and inhibitor of the efflux transporter P-glycoprotein (Pgp, ABCB1). Coadministration of lapatinib and vinblastine may lead to increased serum concentrations of vinblastine. Cautious coadministration is recommended, and consider a dose reduction of vinblastine.
    Vincristine Liposomal: (Moderate) Vincristine is a substrate of both CYP3A4 and P-glycoprotein. In vitro, lapatinib, at clinically relevant concentrations, inhibits CYP3A4. Also, lapatinib is a substrate and inhibitor of the efflux transporter P-glycoprotein (Pgp, ABCB1). Coadministration of lapatinib and vincristine may lead to increased serum concentrations of vincristine. Cautious coadministration is recommended, and consider a dose reduction of vincristine.
    Vincristine: (Moderate) Vincristine is a substrate of both CYP3A4 and P-glycoprotein. In vitro, lapatinib, at clinically relevant concentrations, inhibits CYP3A4. Also, lapatinib is a substrate and inhibitor of the efflux transporter P-glycoprotein (Pgp, ABCB1). Coadministration of lapatinib and vincristine may lead to increased serum concentrations of vincristine. Cautious coadministration is recommended, and consider a dose reduction of vincristine.
    Vinorelbine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with lapatinib is necessary. Vinorelbine is a CYP3A4 substrate and lapatinib is a weak CYP3A4 inhibitor.
    Vorapaxar: (Moderate) Use caution during concurrent use of vorapaxar and lapatinib. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with lapatinib, a CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Voriconazole: (Major) Avoid coadministration of lapatinib with voriconazole if possible due to increased plasma concentrations of lapatinib; additive QT prolongation is also possible. If concomitant use is unavoidable, consider a lapatinib dose reduction to 500 mg/day, as this dose is predicted to adjust the lapatinib exposure to the range observed without voriconazole. If voriconazole is discontinued, a washout period of approximately 1 week should be allowed before the lapatinib dose is adjusted upward to the indicated dose. Lapatinib is a CYP3A4 substrate that has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience. Voriconazole is a strong CYP3A4 inhibitor that has been associated with QT prolongation. In a drug interaction study, concurrent administration with another strong CYP3A4 inhibitor increased lapatinib systemic exposure (AUC) by approximately 3.6-fold and the half-life increased by 1.7-fold.
    Vorinostat: (Major) Lapatinib can prolong the QT interval. Lapatinib should be administered with caution to patients who have or may develop prolongation of QTc such as patients taking anti-arrhythmic medicines or other medicinal products that lead to QT prolongation. Vorinostat therapy is associated with a risk of QT prolongation and should be used cautiously with lapatinib.
    Zafirlukast: (Moderate) Lapatinib is a CYP3A4 substrate, and concomitant use of lapatinib with zafirlukast, a CYP3A4 inhibitor, may result in decreased metabolism and increased serum concentrations of lapatinib.
    Ziprasidone: (Major) Concomitant use of ziprasidone and lapatinib should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. If coadministration is necessary, consider ECG and electrolyte monitoring. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and TdP have been reported in postmarketing experience. Correct hypokalemia or hypomagnesemia prior to lapatinib administration.

    PREGNANCY AND LACTATION

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during lapatinib treatment and for at least 1 week after the last dose. Although there are no adequately controlled studies in pregnant women, lapatinib can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving lapatinib should be apprised of the potential hazard to the fetus. In embryo-fetal development studies, minor anomalies (e.g., left-sided umbilical artery, cervical rib, and precocious ossification) occurred in rats at maternally toxic exposures of approximately 6.4 times the human clinical exposure based on AUC after a 1,250 mg dose of lapatinib. In pre- and postnatal development studies, decreased postnatal survival occurred after administration of lapatinib to pregnant rats during organogenesis and through lactation. In this study, lapatinib exposures of approximately 3.3 and 6.4 times the human exposure based on AUC after a 1,250 mg dose resulted in 91% and 34% of pup deaths, respectively, by the fourth day after birth. In rabbits, lapatinib caused maternal toxicity at 0.07 to 0.2 times the human exposure based on AUC after a 1,250 mg dose of lapatinib, and abortions at the higher exposure level. Maternal toxicity was associated with decreased fetal body weights and minor skeletal variations.[33192]

    Due to the potential for serious adverse reactions in nursing infants from lapatinib, advise women to discontinue breast-feeding during treatment and for 1 week after the final dose. It is not known whether lapatinib is present in human milk, although many drugs are excreted in human milk.
     

    MECHANISM OF ACTION

    Lapatinib is a 4-anilinoquinazoline kinase inhibitor of the intracellular tyrosine kinase domains of the EGFR and HER2 receptors, with an estimated Ki value of 3nM and 13 nM, respectively; the dissociation half-life is 300 minutes or more. Lapatinib inhibits ErbB-driven tumor cell growth in vitro and in various animal models. Lapatinib and 5-fluorouracil (the active metabolite of capecitabine) demonstrated an additive effect in vitro. Hormone receptor-positive breast cancer cells that co-express HER2 tend to be resistant to established endocrine therapies; similarly, HR-positive breast cancer cells that initially lack EGFR or HER2 upregulate these receptor proteins as the tumor becomes resistant to endocrine therapy. Lapatinib retained significant activity against breast cancer cells selected for long-term growth in trastuzumab-containing medium in vitro, suggesting non-cross-resistance between these two agents.[33192]

    PHARMACOKINETICS

    Lapatinib is administered orally. Lapatinib is more than 99% protein bound to albumin and alpha-1 acid glycoprotein. It is extensively metabolized by the liver to a variety of oxidated metabolites, none of which accounts for more than 14% of the dose recovered in the feces or 10% of lapatinib plasma concentrations. The terminal phase half-life of lapatinib after a single dose was 14.2 hours; accumulation with repeated dosing indicates an effective half-life of 24 hours. Steady-state concentrations are achieved within 6 to 7 days. Less than 2% of an administered dose is excreted in the urine; the median lapatinib recovery in the feces is 27% (range, 3% to 67%) of an oral dose.[33192]
     
    Affected cytochrome P450 isoenzymes: CYP3A4, CYP2C8, P-glycoprotein (P-gp)
    Lapatinib undergoes extensive metabolism via CYP3A4/5, with minor contributions from CYP2C19 and CYP2C8. In vitro studies indicate that it is also a substrate for BCRP (ABCG2) and P-gp (ABCB1). Lapatinib is a weak CYP3A4 inhibitor in vivo and also inhibits CYP2C8 (weak), P-gp, BCRP, and OATP 1B1 in vitro at clinically relevant concentrations.[33192]

    Oral Route

    Lapatinib absorption is incomplete and variable following oral administration. Serum concentrations appear after a median lag time of 0.25 hours (range, 0 to 1.5 hours), with peak plasma concentrations (Cmax) at about 4 hours after dosing. At the 1,250 mg daily dose, the steady-state geometric mean Cmax was 2.43 mcg/mL (95% CI, 1.57 to 3.77 mcg/mL) and AUC was 36.2 mcg x h/mL (95% CI, 23.4 to 56 mcg x h/mL). Administering lapatinib in divided daily doses increases the steady-state AUC by approximately 2-fold compared to the same total dose administered once daily.
     
    The AUC of lapatinib was approximately 3-fold higher when administered with a low-fat meal (5% fat; 500 calories) and 4-fold higher with a high-fat meal (50% fat; 1,000 calories); the Cmax was approximately 2.5-fold and 3-fold higher, respectively. The aqueous solubility of lapatinib is pH dependent, with higher pH resulting in lower solubility. However, coadministration with a proton pump inhibitor daily for 7 days did not have a clinically meaningful reduction in the steady-state exposure of lapatinib.