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  • CLASSES

    Small Molecule Antineoplastic 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. Heart failure may increase the risk of prolonging the QT interval when using lapatinib and 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.[28432] [28457] [33192] [56592]

    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]

    Apheresis, AV block, bradycardia, cardiomyopathy, celiac disease, females, fever, geriatric, human immunodeficiency virus (HIV) infection, hyperparathyroidism, hypocalcemia, hypokalemia, hypomagnesemia, hypothermia, hypothyroidism, long QT syndrome, myocardial infarction, pheochromocytoma, QT prolongation, rheumatoid arthritis, sickle cell disease, sleep deprivation, stroke, systemic lupus erythematosus (SLE), torsade de pointes

    Lapatinib prolongs the QT interval in a dose-dependent manner; ventricular arrhythmias and torsade de pointes (TdP) have been reported with postmarketing experience. Monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia before lapatinib administration. Use lapatinib with caution in patients with conditions that may increase the risk of QT prolongation including congenital long QT syndrome, bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, geriatric patients, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation.[28432] [28457] [33192] [56592]

    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

    Acetaminophen; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of codeine with lapatinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of lapatinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If lapatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. lapatinib is a weak inhibitor of CYP3A4.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Consider a reduced dose of dihydrocodeine with frequent monitoring for respiratory depression and sedation if concurrent use of lapatinib is necessary. If lapatinib is discontinued, consider increasing the dihydrocodeine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. 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 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; Codeine: (Moderate) Concomitant use of codeine with lapatinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of lapatinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If lapatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. lapatinib is a weak inhibitor of CYP3A4.
    Acetaminophen; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of lapatinib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like lapatinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If lapatinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    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; Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with lapatinib is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of lapatinib, a weak CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
    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.
    Alfentanil: (Moderate) Consider a reduced dose of alfentanil with frequent monitoring for respiratory depression and sedation if concurrent use of lapatinib is necessary. If lapatinib is discontinued, consider increasing the alfentanil dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Alfentanil is a sensitive CYP3A4 substrate, and coadministration with weak CYP3A4 inhibitors like lapatinib can increase alfentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of alfentanil. If lapatinib is discontinued, alfentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to alfentanil.
    Alfuzosin: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with alfuzosin. Both alfuzosin and lapatinib have been associated with concentration-dependent QT prolongation. Ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
    Amiodarone: (Major) Avoid coadministration of amiodarone and lapatinib if possible due to the risk of QT prolongation; lapatinib exposure may also increase. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes, as well as monitoring for an increase in lapatinib-related adverse reactions. Correct any electrolyte abnormalities prior to treatment. 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 also been reported in postmarketing experience. Amiodarone, a Class III antiarrhythmic agent and P-gp inhibitor, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Increased plasma concentrations of lapatinib are likely when administered with P-gp inhibitors. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
    Amitriptyline: (Minor) Monitor for evidence of QT prolongation if lapatinib is administered with tricyclic antidepressants. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Amitriptyline; Chlordiazepoxide: (Minor) Monitor for evidence of QT prolongation if lapatinib is administered with tricyclic antidepressants. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Avoid coadministration of lapatinib with clarithromycin due to increased plasma concentrations of lapatinib; QT prolongation may also occur. If concomitant use is unavoidable, decrease the dose of lapatinib to 500 mg PO once daily. Monitor ECGs for QT prolongation and monitor electrolytes; correct any electrolyte abnormalities prior to treatment. If clarithromycin is discontinued, increase lapatinib to the indicated dose after a washout period of approximately 1 week. Lapatinib is a CYP3A4 substrate that has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have also been reported in postmarketing experience. Clarithromycin is a strong CYP3A4 inhibitor that is associated with an established risk for QT prolongation and TdP. 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.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of lapatinib with clarithromycin due to increased plasma concentrations of lapatinib; QT prolongation may also occur. If concomitant use is unavoidable, decrease the dose of lapatinib to 500 mg PO once daily. Monitor ECGs for QT prolongation and monitor electrolytes; correct any electrolyte abnormalities prior to treatment. If clarithromycin is discontinued, increase lapatinib to the indicated dose after a washout period of approximately 1 week. Lapatinib is a CYP3A4 substrate that has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have also been reported in postmarketing experience. Clarithromycin is a strong CYP3A4 inhibitor that is associated with an established risk for QT prolongation and TdP. 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.
    Anagrelide: (Major) Do not use anagrelide with lapatinib due to the risk of QT prolongation and torsade de pointes (TdP). TdP and ventricular tachycardia have been reported with anagrelide; in addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. Lapatinib has also been associated with concentration-dependent QT prolongation; ventricular arrhythmias and TdP have additionally been reported in postmarketing experience with lapatinib.
    Apalutamide: (Major) Avoid coadministration of lapatinib with apalutamide due to decreased plasma concentrations of lapatinib. If concomitant use is unavoidable, gradually titrate the dose of lapatinib from 1,250 mg per day to 4,500 mg per day in patients receiving concomitant capecitabine (HER2-positive metastatic breast cancer), and from 1,500 mg per day to 5,500 mg per day in patients receiving concomitant aromatase inhibitor therapy (HR-positive, HER2-positive breast cancer) based on tolerability. If apalutamide is discontinued, reduce lapatinib to the indicated dose. Lapatinib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Concomitant use with another strong CYP3A4 inducer decreased lapatinib exposure by 72%.
    Apomorphine: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with apomorphine since concurrent use may increase the risk of QT prolongation. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure.
    Aripiprazole: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with aripiprazole. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.
    Arsenic Trioxide: (Major) Avoid coadministration of arsenic trioxide with lapatinib due to the risk of QT prolongation; discontinue or select an alternative drug that does not prolong the QT interval prior to starting arsenic trioxide therapy. If concomitant use is unavoidable, frequently monitor ECGs for QT prolongation and monitor electrolytes; 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 with lapatinib. Prolongation of the QT interval, TdP, and complete atrioventricular block have been reported with arsenic trioxide use.
    Artemether; Lumefantrine: (Major) Avoid coadministration of artemether with lapatinib if possible due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; 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 with lapatinib. Artemether; lumefantrine is also associated with prolongation of the QT interval. (Major) Avoid coadministration of lumefantrine with lapatinib if possible due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; 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 with lapatinib. Artemether; lumefantrine is also associated with prolongation of the QT interval.
    Asenapine: (Major) Avoid coadministration of asenapine with lapatinib due to the risk of QT prolongation. Asenapine has been associated with QT prolongation. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of codeine with lapatinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of lapatinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If lapatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. lapatinib is a weak inhibitor of CYP3A4.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Consider a reduced dose of dihydrocodeine with frequent monitoring for respiratory depression and sedation if concurrent use of lapatinib is necessary. If lapatinib is discontinued, consider increasing the dihydrocodeine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. 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 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; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with lapatinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of lapatinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If lapatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. lapatinib is a weak inhibitor of CYP3A4.
    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) Avoid coadministration of lapatinib with atazanavir due to increased plasma concentrations of lapatinib. If concomitant use is unavoidable, decrease the dose of lapatinib to 500 mg PO once daily. If atazanavir is discontinued, increase lapatinib to the indicated dose after a washout period of approximately 1 week. Lapatinib is a CYP3A4 substrate and atazanavir 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.
    Atazanavir; Cobicistat: (Major) Avoid coadministration of lapatinib with atazanavir due to increased plasma concentrations of lapatinib. If concomitant use is unavoidable, decrease the dose of lapatinib to 500 mg PO once daily. If atazanavir is discontinued, increase lapatinib to the indicated dose after a washout period of approximately 1 week. Lapatinib is a CYP3A4 substrate and atazanavir 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. (Major) Avoid coadministration of lapatinib with cobicistat due to increased plasma concentrations of lapatinib. If concomitant use is unavoidable, decrease the dose of lapatinib to 500 mg PO once daily. If cobicistat is discontinued, increase lapatinib to the indicated dose after a washout period of approximately 1 week. Lapatinib is a CYP3A4 substrate and cobicistat 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.
    Atomoxetine: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with atomoxetine. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Prolongation of the QT interval has occurred during therapeutic use of atomoxetine as well as following overdose.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Avoid coadministration of lapatinib with phenobarbital due to decreased plasma concentrations of lapatinib. If concomitant use is unavoidable, gradually titrate the dose of lapatinib from 1,250 mg per day to 4,500 mg per day in patients receiving concomitant capecitabine (HER2-positive metastatic breast cancer), and from 1,500 mg per day to 5,500 mg per day in patients receiving concomitant aromatase inhibitor therapy (HR-positive, HER2-positive breast cancer) based on tolerability. If phenobarbital is discontinued, reduce lapatinib to the indicated dose. Lapatinib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Concomitant use with another strong CYP3A4 inducer decreased lapatinib exposure by 72%.
    Azithromycin: (Major) Avoid coadministration of azithromycin with lapatinib due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. QT prolongation and torsade de pointes (TdP) have been spontaneously reported during azithromycin postmarketing surveillance. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and TdP have been reported in postmarketing experience with lapatinib.
    Bedaquiline: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of lapatinib with bedaquiline 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 with lapatinib. Bedaquiline has also been reported to prolong the QT interval. Coadministration with other QT prolonging drugs may result in additive or synergistic prolongation of the QT interval.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid coadministration of lapatinib with phenobarbital due to decreased plasma concentrations of lapatinib. If concomitant use is unavoidable, gradually titrate the dose of lapatinib from 1,250 mg per day to 4,500 mg per day in patients receiving concomitant capecitabine (HER2-positive metastatic breast cancer), and from 1,500 mg per day to 5,500 mg per day in patients receiving concomitant aromatase inhibitor therapy (HR-positive, HER2-positive breast cancer) based on tolerability. If phenobarbital is discontinued, reduce lapatinib to the indicated dose. Lapatinib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Concomitant use with another strong CYP3A4 inducer decreased lapatinib exposure by 72%. (Moderate) Use caution if coadministration of lapatinib, a weak CYP3A4 inhibitor, with ergotamine, a CYP3A4 substrate, is necessary, as the systemic exposure of ergotamine may be increased resulting in an increase in ergotamine-related adverse reactions including the risk for vasospasm leading to cerebral ischemia and/or ischemia of the extremities; adjust the dose of ergotamine if necessary.
    Benzhydrocodone; Acetaminophen: (Moderate) Consider a dose reduction of benzhydrocodone if coadministration with lapatinib is necessary until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. Discontinuation of lapatinib in a patient taking benzhydrocodone may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If lapatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Benzhydrocodone is a prodrug for hydrocodone, which is a substrate for CYP3A4. Lapatinib is a weak inhibitor of CYP3A4.
    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. Concurrent use may increase betrixaban exposure resulting in an increased bleeding risk; monitor patients closely for signs and symptoms of bleeding. Betrixaban is a P-gp substrate; lapatinib is a P-gp inhibitor. Coadministration of other P-gp inhibitors increased betrixaban exposure by 2- to 3-fold.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with metronidazole. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Potential QT prolongation has been reported in limited case reports with metronidazole.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with metronidazole. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Potential QT prolongation has been reported in limited case reports with metronidazole.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of lapatinib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like lapatinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If lapatinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of lapatinib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like lapatinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If lapatinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Bupivacaine; Lidocaine: (Major) Monitor for lidocaine toxicity if coadministration with lapatinib is necessary. Concomitant use of systemic lidocaine and lapatinib may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Lidocaine is a CYP3A4 substrate and lapatinib is a weak CYP3A4 inhibitor.
    Buprenorphine: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of lapatinib with buprenorphine 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 with lapatinib. Buprenorphine has been associated with QT prolongation and has a possible risk of 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.
    Buprenorphine; Naloxone: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of lapatinib with buprenorphine 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 with lapatinib. Buprenorphine has been associated with QT prolongation and has a possible risk of 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.
    Cabozantinib: (Moderate) Monitor for an increase in lapatinib-related adverse reactions if coadministration with cabozantinib is necessary. Lapatinib is a P-glycoprotein (P-gp) substrate and cabozantinib is a P-gp inhibitor. Increased plasma concentrations of lapatinib are likely.
    Caffeine; Ergotamine: (Moderate) Use caution if coadministration of lapatinib, a weak CYP3A4 inhibitor, with ergotamine, a CYP3A4 substrate, is necessary, as the systemic exposure of ergotamine may be increased resulting in an increase in ergotamine-related adverse reactions including the risk for vasospasm leading to cerebral ischemia and/or ischemia of the extremities; adjust the dose of ergotamine if necessary.
    Capmatinib: (Moderate) Monitor for an increase in lapatinib-related adverse reactions if coadministration with capmatinib is necessary. Lapatinib is a P-glycoprotein (P-gp) substrate and capmatinib is a P-gp inhibitor. Increased plasma concentrations of lapatinib are likely.
    Carbamazepine: (Major) Avoid coadministration of lapatinib with carbamazepine due to decreased plasma concentrations of lapatinib. If concomitant use is unavoidable, gradually titrate the dose of lapatinib from 1,250 mg per day to 4,500 mg per day in patients receiving concomitant capecitabine (HER2-positive metastatic breast cancer), and from 1,500 mg per day to 5,500 mg per day in patients receiving concomitant aromatase inhibitor therapy (HR-positive, HER2-positive breast cancer) based on tolerability. If carbamazepine is discontinued, reduce lapatinib to the indicated dose. Lapatinib is a CYP3A4 substrate and carbamazepine is a strong CYP3A4 inducer. Concomitant use with carbamazepine decreased lapatinib exposure by 72%.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of lapatinib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like lapatinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If lapatinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of lapatinib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like lapatinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If lapatinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Ceritinib: (Major) Avoid coadministration of lapatinib with ceritinib due to increased plasma concentrations of lapatinib and the risk of QT prolongation. If concomitant use is unavoidable, decrease the dose of lapatinib to 500 mg PO once daily. Monitor ECGs for QT prolongation and monitor electrolytes; correct any electrolyte abnormalities prior to treatment. If ceritinib is discontinued, increase lapatinib to the indicated dose after a washout period of approximately 1 week. Lapatinib is a CYP3A4 substrate that has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have also been reported in postmarketing experience. Ceritinib is a strong CYP3A4 inhibitor that also causes concentration-dependent QT prolongation. 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.
    Chloramphenicol: (Major) Avoid coadministration of lapatinib with chloramphenicol due to increased plasma concentrations of lapatinib. If concomitant use is unavoidable, decrease the dose of lapatinib to 500 mg PO once daily. If chloramphenicol is discontinued, increase lapatinib to the indicated dose after a washout period of approximately 1 week. Lapatinib is a CYP3A4 substrate and chloramphenicol 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.
    Chloroquine: (Major) Avoid coadministration of chloroquine with lapatinib due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); 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 with lapatinib.
    Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with lapatinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of lapatinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If lapatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. lapatinib is a weak inhibitor of CYP3A4.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Consider a reduced dose of dihydrocodeine with frequent monitoring for respiratory depression and sedation if concurrent use of lapatinib is necessary. If lapatinib is discontinued, consider increasing the dihydrocodeine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. 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 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) Consider a reduced dose of dihydrocodeine with frequent monitoring for respiratory depression and sedation if concurrent use of lapatinib is necessary. If lapatinib is discontinued, consider increasing the dihydrocodeine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. 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 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) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of lapatinib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like lapatinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If lapatinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Chlorpheniramine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of lapatinib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like lapatinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If lapatinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of lapatinib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like lapatinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If lapatinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of lapatinib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like lapatinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If lapatinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Chlorpromazine: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of lapatinib with chlorpromazine 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 with lapatinib. Chlorpromazine, a phenothiazine, is associated with an established risk of QT prolongation and torsade de pointes (TdP).
    Ciprofloxacin: (Moderate) Monitor for evidence of QT prolongation if lapatinib is used with ciprofloxacin. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Rare cases of QT prolongation and TdP have also been reported with ciprofloxacin during postmarketing surveillance.
    Cisapride: (Severe) Because of the potential for torsade de pointes (TdP), use of lapatinib with cisapride is contraindicated. Prolongation of the QT interval and ventricular arrhythmias, including and death, have been reported with cisapride. Lapatinib has also been associated with concentration-dependent QT prolongation; ventricular arrhythmias and TdP have been reported in postmarketing experience with lapatinib.
    Citalopram: (Major) Concurrent use of citalopram with lapatinib is not recommended due to the risk of QT prolongation. If concurrent therapy is considered essential, monitor ECGs for QT prolongation and monitor electrolytes; 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 with lapatinib. Citalopram also causes dose-dependent QT interval prolongation.
    Clarithromycin: (Major) Avoid coadministration of lapatinib with clarithromycin due to increased plasma concentrations of lapatinib; QT prolongation may also occur. If concomitant use is unavoidable, decrease the dose of lapatinib to 500 mg PO once daily. Monitor ECGs for QT prolongation and monitor electrolytes; correct any electrolyte abnormalities prior to treatment. If clarithromycin is discontinued, increase lapatinib to the indicated dose after a washout period of approximately 1 week. Lapatinib is a CYP3A4 substrate that has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have also been reported in postmarketing experience. Clarithromycin is a strong CYP3A4 inhibitor that is associated with an established risk for QT prolongation and TdP. 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.
    Clofazimine: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of lapatinib with clofazimine 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 with lapatinib. QT prolongation and TdP have been reported in patients receiving clofazimine in combination with QT prolonging medications.
    Clomipramine: (Minor) Monitor for evidence of QT prolongation if lapatinib is administered with tricyclic antidepressants. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Clozapine: (Moderate) Consider a clozapine dose reduction if coadministered with lapatinib and monitor for adverse reactions. Also, monitor for evidence of QT prolongation and torsade de pointes (TdP). If lapatinib is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A4. Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death. Lapatinib is a weak CYP3A4 inhibitor that has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and TdP have been reported in postmarketing experience with lapatinib.
    Cobicistat: (Major) Avoid coadministration of lapatinib with cobicistat due to increased plasma concentrations of lapatinib. If concomitant use is unavoidable, decrease the dose of lapatinib to 500 mg PO once daily. If cobicistat is discontinued, increase lapatinib to the indicated dose after a washout period of approximately 1 week. Lapatinib is a CYP3A4 substrate and cobicistat 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.
    Cobimetinib: (Moderate) Monitor for an increase in cobimetinib-related adverse reactions if coadministration with lapatinib is necessary. Cobimetinib is a P-glycoprotein (P-gp) substrate and lapatinib is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of cobimetinib.
    Codeine: (Moderate) Concomitant use of codeine with lapatinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of lapatinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If lapatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. lapatinib is a weak inhibitor of CYP3A4.
    Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with lapatinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of lapatinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If lapatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. lapatinib is a weak inhibitor of CYP3A4.
    Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with lapatinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of lapatinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If lapatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. lapatinib is a weak inhibitor of CYP3A4. (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with promethazine. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
    Codeine; Promethazine: (Moderate) Concomitant use of codeine with lapatinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of lapatinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If lapatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. lapatinib is a weak inhibitor of CYP3A4. (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with promethazine. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
    Colchicine: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and lapatinib in patients with normal renal and hepatic function unless the use of both agents is imperative. Coadministration is contraindicated in patients with renal or hepatic impairment because colchicine accumulation may be greater in these populations. Colchicine is a CYP3A4 and P-glycoprotein (P-gp) substrate. Lapatinib is a weak CYP3A4 inhibitor and a P-gp inhibitor, resulting in increased colchicine exposure. If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine by either reducing the daily dose or the dosage frequency, and carefully monitor for colchicine toxicity. Specific dosage adjustment recommendations are available for the Colcrys product for patients who have taken lapatinib in the past 14 days or require concurrent use: for prophylaxis of gout flares, if the original dose is 0.6 mg twice daily, decrease to 0.3 mg once daily or if the original dose is 0.6 mg once daily, decrease to 0.3 mg once every other day; for treatment of gout flares, give 0.6 mg as a single dose, then 0.3 mg 1 hour later, and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed a 0.6 mg/day.
    Colchicine; Probenecid: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and lapatinib in patients with normal renal and hepatic function unless the use of both agents is imperative. Coadministration is contraindicated in patients with renal or hepatic impairment because colchicine accumulation may be greater in these populations. Colchicine is a CYP3A4 and P-glycoprotein (P-gp) substrate. Lapatinib is a weak CYP3A4 inhibitor and a P-gp inhibitor, resulting in increased colchicine exposure. If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine by either reducing the daily dose or the dosage frequency, and carefully monitor for colchicine toxicity. Specific dosage adjustment recommendations are available for the Colcrys product for patients who have taken lapatinib in the past 14 days or require concurrent use: for prophylaxis of gout flares, if the original dose is 0.6 mg twice daily, decrease to 0.3 mg once daily or if the original dose is 0.6 mg once daily, decrease to 0.3 mg once every other day; for treatment of gout flares, give 0.6 mg as a single dose, then 0.3 mg 1 hour later, and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed a 0.6 mg/day.
    Conivaptan: (Major) Avoid coadministration of lapatinib with conivaptan due to increased plasma concentrations of lapatinib. If concomitant use is unavoidable, decrease the dose of lapatinib to 500 mg PO once daily. If conivaptan is discontinued, increase lapatinib to the indicated dose after a washout period of approximately 1 week. Lapatinib is a CYP3A4 substrate and conivaptan 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.
    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: (Moderate) Cyclosporine therapeutic drug monitoring is recommended when administered concurrently with lapatinib. Use of these medications together may result in elevated cyclosporine serum concentrations, causing an increased risk for cyclosporine-related adverse events. Lapatinib is a weak inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of cyclosporine.
    Dabigatran: (Moderate) Monitor patients for increased dabigatran-related adverse reactions if coadministration with lapatinib is necessary. Avoid coadministration of lapatinib in patients with CrCL less than 50 mL/minute 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 lapatinib when dabigatran is used in patients with non-valvular atrial fibrillation and severe renal impairment (CrCL less than 30 mL/minute), as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. Dabigatran is a P-glycoprotein (P-gp) substrate and lapatinib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased the dabigatran AUC and Cmax by 58% and 50%, respectively. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Darunavir: (Major) Avoid coadministration of lapatinib with darunavir due to increased plasma concentrations of lapatinib; darunavir exposure may also increase. If concomitant use is unavoidable, decrease the dose of lapatinib to 500 mg PO once daily and monitor for an increase in treatment-related adverse reactions. If darunavir is discontinued, increase lapatinib to the indicated dose after a washout period of approximately 1 week. Lapatinib is a CYP3A4 substrate and a P-glycoprotein (P-gp) inhibitor. Darunavir is a strong CYP3A4 inhibitor and a P-gp substrate. 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.
    Darunavir; Cobicistat: (Major) Avoid coadministration of lapatinib with cobicistat due to increased plasma concentrations of lapatinib. If concomitant use is unavoidable, decrease the dose of lapatinib to 500 mg PO once daily. If cobicistat is discontinued, increase lapatinib to the indicated dose after a washout period of approximately 1 week. Lapatinib is a CYP3A4 substrate and cobicistat 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. (Major) Avoid coadministration of lapatinib with darunavir due to increased plasma concentrations of lapatinib; darunavir exposure may also increase. If concomitant use is unavoidable, decrease the dose of lapatinib to 500 mg PO once daily and monitor for an increase in treatment-related adverse reactions. If darunavir is discontinued, increase lapatinib to the indicated dose after a washout period of approximately 1 week. Lapatinib is a CYP3A4 substrate and a P-glycoprotein (P-gp) inhibitor. Darunavir is a strong CYP3A4 inhibitor and a P-gp substrate. 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.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid coadministration of lapatinib with cobicistat due to increased plasma concentrations of lapatinib. If concomitant use is unavoidable, decrease the dose of lapatinib to 500 mg PO once daily. If cobicistat is discontinued, increase lapatinib to the indicated dose after a washout period of approximately 1 week. Lapatinib is a CYP3A4 substrate and cobicistat 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. (Major) Avoid coadministration of lapatinib with darunavir due to increased plasma concentrations of lapatinib; darunavir exposure may also increase. If concomitant use is unavoidable, decrease the dose of lapatinib to 500 mg PO once daily and monitor for an increase in treatment-related adverse reactions. If darunavir is discontinued, increase lapatinib to the indicated dose after a washout period of approximately 1 week. Lapatinib is a CYP3A4 substrate and a P-glycoprotein (P-gp) inhibitor. Darunavir is a strong CYP3A4 inhibitor and a P-gp substrate. 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.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of lapatinib with ritonavir due to increased plasma concentrations of lapatinib. If concomitant use is unavoidable, decrease the dose of lapatinib to 500 mg PO once daily. If ritonavir is discontinued, increase lapatinib to the indicated dose after a washout period of approximately 1 week. Lapatinib is a CYP3A4 substrate and ritonavir 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. (Major) Monitor for an increase in ombitasvir-related adverse reactions if coadministration with lapatinib is necessary. Ombitasvir is a P-glycoprotein (P-gp) substrate and lapatinib is a P-gp inhibitor. (Moderate) Monitor for an increase in dasabuvir-related adverse reactions if coadministration with lapatinib is necessary. Dasabuvir is a P-glycoprotein (P-gp) substrate and lapatinib is a P-gp inhibitor. Increased plasma concentrations of dasabuvir may occur. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with lapatinib is necessary. Paritaprevir is a P-glycoprotein (P-gp) substrate and lapatinib is a P-gp inhibitor.
    Dasatinib: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with dasatinib. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. In vitro studies have shown that dasatinib has the potential to prolong the QT interval.
    Degarelix: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with degarelix. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Androgen deprivation therapy (i.e., degarelix) may also prolong the QT/QTc interval.
    Delavirdine: (Major) Avoid coadministration of lapatinib with delavirdine due to increased plasma concentrations of lapatinib. If concomitant use is unavoidable, decrease the dose of lapatinib to 500 mg PO once daily. If delavirdine is discontinued, increase lapatinib to the indicated dose after a washout period of approximately 1 week. Lapatinib is a CYP3A4 substrate and delavirdine 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.
    Desflurane: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of lapatinib with halogenated anesthetics is necessary; correct electrolyte abnormalities prior to treatment. Halogenated anesthetics can 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 with lapatinib.
    Desipramine: (Minor) Monitor for evidence of QT prolongation if lapatinib is administered with tricyclic antidepressants. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Deutetrabenazine: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with deutetrabenazine. For patients taking a deutetrabenazine dosage more than 24 mg/day and lapatinib, assess the QTc interval before and after increasing the dosage of either medication. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Clinically relevant QTc prolongation may occur with deutetrabenazine.
    Dexamethasone: (Major) Avoid coadministration of lapatinib with dexamethasone due to decreased plasma concentrations of lapatinib. If concomitant use is unavoidable, gradually titrate the dose of lapatinib from 1,250 mg per day to 4,500 mg per day in patients receiving concomitant capecitabine (HER2-positive metastatic breast cancer), and from 1,500 mg per day to 5,500 mg per day in patients receiving concomitant aromatase inhibitor therapy (HR-positive, HER2-positive breast cancer) based on tolerability. If dexamethasone is discontinued, reduce lapatinib to the indicated dose. Lapatinib is a CYP3A4 substrate and dexamethasone is a CYP3A4 inducer. Concomitant use with a strong CYP3A4 inducer decreased lapatinib exposure by 72%.
    Dextromethorphan; Promethazine: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with promethazine. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
    Dextromethorphan; Quinidine: (Major) Monitor for an increase in treatment-related adverse reactions if coadministration of lapatinib with quinidine is necessary; also monitor ECGs for QT prolongation and monitor electrolytes. Correct any electrolyte abnormalities prior to treatment. Lapatinib is a P-glycoprotein (P-gp) substrate/inhibitor that has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have also been reported in postmarketing experience. Quinidine is also a P-gp substrate/inhibitor that is also associated with QT prolongation and TdP. Increased plasma concentrations of lapatinib are likely when administered with P-gp inhibitors.
    Digoxin: (Moderate) Increase monitoring of serum digoxin concentrations and watch for potential signs and symptoms of clinical toxicity when starting, adjusting, or discontinuing lapatinib; if the digoxin serum concentration is greater than 1.2 ng/mL, the digoxin dose should be reduced by half. Digoxin is a P-glycoprotein (P-gp) substrate with a narrow therapeutic index and lapatinib is a P-gp inhibitor. The systemic exposure of oral digoxin increased by approximately 2.8-fold following administration with lapatinib.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Consider a reduced dose of dihydrocodeine with frequent monitoring for respiratory depression and sedation if concurrent use of lapatinib is necessary. If lapatinib is discontinued, consider increasing the dihydrocodeine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. 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 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.
    Dihydroergotamine: (Moderate) Use caution if coadministration of lapatinib, a weak CYP3A4 inhibitor, with dihydroergotamine, a CYP3A4 substrate, is necessary, as the systemic exposure of dihydroergotamine may be increased resulting in an increase in dihydroergotamine-related adverse reactions including the risk for vasospasm leading to cerebral ischemia and/or ischemia of the extremities; adjust the dose of dihydroergotamine if necessary.
    Diltiazem: (Moderate) Monitor blood pressure and heart rate if coadministration of diltiazem with lapatinib is necessary. Diltiazem is a CYP3A4 substrate and lapatinib is a weak CYP3A4 inhibitor.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of lapatinib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like lapatinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If lapatinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Disopyramide: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of lapatinib with disopyramide is necessary; also monitor for an increase in disopyramide-related adverse reactions. Correct electrolyte abnormalities prior to treatment. Disopyramide is a CYP3A4 substrate that is associated with QT prolongation and torsade de pointes (TdP). Lapatinib is a weak CYP3A4 inhibitor that has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Concomitant use may increase plasma concentrations of disopyramide. Specific drug interaction studies have not been done for disopyramide; however, cases of life-threatening interactions have been reported when coadministered with moderate and strong CYP3A4 inhibitors. Coadministration of disopyramide with CYP3A4 inhibitors could result in a potentially fatal interaction.
    Dofetilide: (Major) Coadministration of dofetilide and lapatinib is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and TdP have been reported in postmarketing experience with lapatinib.
    Dolasetron: (Moderate) Administer dolasetron with caution in combination with lapatinib as concurrent use may increase the risk of QT prolongation. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram.
    Dolutegravir; Rilpivirine: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with rilpivirine. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Donepezil: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with donepezil. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy.
    Donepezil; Memantine: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with donepezil. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy.
    Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with lapatinib is necessary. Tenofovir is a P-glycoprotein (P-gp) substrate and lapatinib is a P-gp inhibitor. Increased plasma concentrations of tenofovir may occur.
    Doxepin: (Minor) Monitor for evidence of QT prolongation if lapatinib is administered with tricyclic antidepressants. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    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) Monitor for an increase in dronabinol-related adverse reactions if coadministration with lapatinib is necessary. Dronabinol is a CYP3A4 substrate and lapatinib is a weak CYP3A4 inhibitor.
    Dronedarone: (Severe) Because of the potential for torsade de pointes (TdP), use of lapatinib with dronedarone is contraindicated. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and TdP have been reported in postmarketing experience with lapatinib. Dronedarone administration is also associated with a dose-related increase in the QTc interval. 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) Droperidol should not be used in combination with any drug known to have potential to prolong the QT interval, such as lapatinib. If coadministration cannot be avoided, use extreme caution; initiate droperidol at a low dose and increase the dose as needed to achieve the desired effect. Monitor ECGs for QT prolongation and monitor electrolytes; 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 with lapatinib. Droperidol administration is also associated with an established risk for QT prolongation and TdP; some cases have occurred in patients with no known risk factors for QT prolongation and some cases have been fatal.
    Edoxaban: (Moderate) If coadministered with lapatinib, a P-gp inhibitor, dosage reduction of edoxaban, a P-gp substrate, may be necessary for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism (PE). An edoxaban dose reduction to 30 mg PO once daily is recommended by the manufacturer for use with certain P-gp inhibitors; however, because use of concomitant P-gp inhibitors was limited to only certain drugs that inhibit P-gp in DVT/PE clinical trials, clinicians should use professional judgment and guide edoxaban dose adjustments based on patient response if coadministered with lapatinib. Based on clinical experience in patients with non-valvular atrial fibrillation no dose reduction is recommended for concomitant use of lapatinib. Increased concentrations of edoxaban may occur during concomitant use of lapatinib; monitor for increased adverse effects of edoxaban.
    Efavirenz: (Moderate) Consider alternatives to efavirenz when coadministering with lapatinib as concurrent use may increase the risk of QT prolongation; increased efavirenz exposure is also possible. QTc prolongation has been observed with the use of efavirenz. Prolongation of the QTc interval has been observed with the use of efavirenz, a CYP3A4 substrate. Lapatinib is a weak CYP3A4 inhibitor that has also been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Consider alternatives to efavirenz when coadministering with lapatinib as concurrent use may increase the risk of QT prolongation; increased efavirenz exposure is also possible. QTc prolongation has been observed with the use of efavirenz. Prolongation of the QTc interval has been observed with the use of efavirenz, a CYP3A4 substrate. Lapatinib is a weak CYP3A4 inhibitor that has also been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with lapatinib is necessary. Tenofovir is a P-glycoprotein (P-gp) substrate and lapatinib is a P-gp inhibitor. Increased plasma concentrations of tenofovir may occur.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Consider alternatives to efavirenz when coadministering with lapatinib as concurrent use may increase the risk of QT prolongation; increased efavirenz exposure is also possible. QTc prolongation has been observed with the use of efavirenz. Prolongation of the QTc interval has been observed with the use of efavirenz, a CYP3A4 substrate. Lapatinib is a weak CYP3A4 inhibitor that has also been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with lapatinib is necessary. Tenofovir is a P-glycoprotein (P-gp) substrate and lapatinib is a P-gp inhibitor. Increased plasma concentrations of tenofovir may occur.
    Elagolix: (Moderate) Monitor for an increase in lapatinib-related adverse reactions if coadministration with elagolix is necessary. Lapatinib is a P-glycoprotein (P-gp) substrate and elagolix is a P-gp inhibitor. Increased plasma concentrations of lapatinib are likely.
    Elagolix; Estradiol; Norethindrone acetate: (Moderate) Monitor for an increase in lapatinib-related adverse reactions if coadministration with elagolix is necessary. Lapatinib is a P-glycoprotein (P-gp) substrate and elagolix is a P-gp inhibitor. Increased plasma concentrations of lapatinib are likely.
    Elexacaftor; tezacaftor; ivacaftor: (Moderate) Monitor for an increase in lapatinib-related adverse reactions if coadministration with ivacaftor is necessary. Lapatinib is a P-glycoprotein (P-gp) substrate and ivacaftor is a P-gp inhibitor. Increased plasma concentrations of lapatinib are likely.
    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. Monitor for QT prolongation and torsade de pointes (TdP). Eliglustat is a CYP3A and CYP2D6 substrate that is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations. Lapatinib is a weak CYP3A4 inhibitor that has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and TdP have been reported in postmarketing experience with lapatinib. 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.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid coadministration of lapatinib with cobicistat due to increased plasma concentrations of lapatinib. If concomitant use is unavoidable, decrease the dose of lapatinib to 500 mg PO once daily. If cobicistat is discontinued, increase lapatinib to the indicated dose after a washout period of approximately 1 week. Lapatinib is a CYP3A4 substrate and cobicistat 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.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of lapatinib with cobicistat due to increased plasma concentrations of lapatinib. If concomitant use is unavoidable, decrease the dose of lapatinib to 500 mg PO once daily. If cobicistat is discontinued, increase lapatinib to the indicated dose after a washout period of approximately 1 week. Lapatinib is a CYP3A4 substrate and cobicistat 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. (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with lapatinib is necessary. Tenofovir is a P-glycoprotein (P-gp) substrate and lapatinib is a P-gp inhibitor. Increased plasma concentrations of tenofovir may occur.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with rilpivirine. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with lapatinib is necessary. Tenofovir is a P-glycoprotein (P-gp) substrate and lapatinib is a P-gp inhibitor. Increased plasma concentrations of tenofovir may occur. (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with rilpivirine. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Emtricitabine; Tenofovir disoproxil fumarate: (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with lapatinib is necessary. Tenofovir is a P-glycoprotein (P-gp) substrate and lapatinib is a P-gp inhibitor. Increased plasma concentrations of tenofovir may occur.
    Enalapril; Felodipine: (Moderate) Concurrent use of felodipine and lapatinib should be approached with caution and conservative dosing of felodipine due to the potential for significant increases in felodipine exposure. Monitor for evidence of increased felodipine effects including decreased blood pressure and increased heart rate. Felodipine is a sensitive CYP3A4 substrate and lapatinib is a weak CYP3A4 inhibitor. Concurrent use of another weak CYP3A4 inhibitor increased felodipine AUC and Cmax by approximately 50%.
    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) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of lapatinib with halogenated anesthetics is necessary; correct electrolyte abnormalities prior to treatment. Halogenated anesthetics can 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 with lapatinib.
    Entrectinib: (Major) Avoid coadministration of entrectinib with lapatinib due to the risk of QT prolongation. If coadministration is necessary, monitor for evidence of QT prolongation during treatment. Entrectinib has been associated with QT prolongation. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
    Enzalutamide: (Major) Avoid coadministration of lapatinib with enzalutamide due to decreased plasma concentrations of lapatinib. If concomitant use is unavoidable, gradually titrate the dose of lapatinib from 1,250 mg per day to 4,500 mg per day in patients receiving concomitant capecitabine (HER2-positive metastatic breast cancer), and from 1,500 mg per day to 5,500 mg per day in patients receiving concomitant aromatase inhibitor therapy (HR-positive, HER2-positive breast cancer) based on tolerability. If enzalutamide is discontinued, reduce lapatinib to the indicated dose. Lapatinib is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Concomitant use with another strong CYP3A4 inducer decreased lapatinib exposure by 72%.
    Ergotamine: (Moderate) Use caution if coadministration of lapatinib, a weak CYP3A4 inhibitor, with ergotamine, a CYP3A4 substrate, is necessary, as the systemic exposure of ergotamine may be increased resulting in an increase in ergotamine-related adverse reactions including the risk for vasospasm leading to cerebral ischemia and/or ischemia of the extremities; adjust the dose of ergotamine if necessary.
    Eribulin: (Major) Closely monitor ECGs for QT prolongation and monitor electrolytes if coadministration of lapatinib with eribulin 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 with lapatinib. Eribulin has also been associated with QT prolongation.
    Erythromycin: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of lapatinib with erythromycin 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 with lapatinib. Erythromycin is also associated with QT prolongation and TdP.
    Erythromycin; Sulfisoxazole: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of lapatinib with erythromycin 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 with lapatinib. Erythromycin is also associated with QT prolongation and TdP.
    Escitalopram: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with escitalopram. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Escitalopram has also been associated with a risk of QT prolongation and TdP.
    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.
    Etravirine: (Moderate) Monitor for an increase in lapatinib-related adverse reactions if coadministration with etravirine is necessary. Lapatinib is a P-glycoprotein (P-gp) substrate and etravirine is a P-gp inhibitor. Increased plasma concentrations of lapatinib are likely.
    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: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with ezogabine. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Ezogabine has also been associated with QT prolongation.
    Felodipine: (Moderate) Concurrent use of felodipine and lapatinib should be approached with caution and conservative dosing of felodipine due to the potential for significant increases in felodipine exposure. Monitor for evidence of increased felodipine effects including decreased blood pressure and increased heart rate. Felodipine is a sensitive CYP3A4 substrate and lapatinib is a weak CYP3A4 inhibitor. Concurrent use of another weak CYP3A4 inhibitor increased felodipine AUC and Cmax by approximately 50%.
    Fentanyl: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of lapatinib is necessary. If lapatinib is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like lapatinib can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If lapatinib is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
    Fingolimod: (Moderate) Exercise caution when administering fingolimod concomitantly with lapatinib as concurrent use may increase the risk of QT prolongation. 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. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
    Flecainide: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of lapatinib with flecainide 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 with lapatinib. Flecainide is a Class IC antiarrhythmic associated with a possible risk for QT prolongation and/or torsade 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 that have the potential for QT prolongation may have an increased risk of developing proarrhythmias.
    Flibanserin: (Moderate) Monitor for an increase in treatment-related adverse reactions, including hypotension, syncope, and somnolence, if coadministration of lapatinib with flibanserin is necessary. Lapatinib is a P-glycoprotein (P-gp) substrate and weak CYP3A4 inhibitor. Flibanserin is a P-gp inhibitor and CYP3A4 substrate. Increased plasma concentrations of lapatinib are likely when administered with P-gp inhibitors. The concomitant use of flibanserin and multiple weak CYP3A4 inhibitors, including lapatinib, may increase flibanserin concentrations.
    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 is a moderate CYP3A4 inhibitor that has been associated with QT prolongation and rare cases of TdP. Lapatinib is a CYP3A4 substrate that has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and TdP have been reported in postmarketing experience with lapatinib. Coadministration may result in elevated plasma concentrations of lapatinib, causing an increased risk for adverse events such as QT prolongation.
    Fluoxetine: (Moderate) Monitor for evidence of QT prolongation if coadministration of lapatinib with fluoxetine is necessary. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Prolongation of the QT interval and TdP have been reported in patients treated with fluoxetine.
    Fluoxetine; Olanzapine: (Moderate) Monitor for evidence of QT prolongation if coadministration of lapatinib with fluoxetine is necessary. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Prolongation of the QT interval and TdP have been reported in patients treated with fluoxetine. (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with olanzapine. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Fluphenazine: (Minor) Monitor for evidence of QT prolongation if lapatinib is administered with fluphenazine. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Fluphenazine is also associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Fluvoxamine: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with fluvoxamine. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. QT prolongation and TdP have also been reported during fluvoxamine post-marketing use.
    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: (Major) Avoid coadministration of lapatinib with fosamprenavir due to increased plasma concentrations of lapatinib. If concomitant use is unavoidable, decrease the dose of lapatinib to 500 mg PO once daily. If fosamprenavir is discontinued, increase lapatinib to the indicated dose after a washout period of approximately 1 week. Lapatinib is a CYP3A4 substrate and fosamprenavir 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.
    Foscarnet: (Major) Avoid coadministration of foscarnet with lapatinib due to the risk of QT prolongation and torsade de pointes (TdP). Both QT prolongation and TdP have been reported during postmarketing use of foscarnet. Lapatinib has also been associated with concentration-dependent QT prolongation; ventricular arrhythmias and TdP have been reported in postmarketing experience with lapatinib.
    Fosphenytoin: (Major) Avoid coadministration of lapatinib with fosphenytoin due to decreased plasma concentrations of lapatinib. If concomitant use is unavoidable, gradually titrate the dose of lapatinib from 1,250 mg per day to 4,500 mg per day in patients receiving concomitant capecitabine (HER2-positive metastatic breast cancer), and from 1,500 mg per day to 5,500 mg per day in patients receiving concomitant aromatase inhibitor therapy (HR-positive, HER2-positive breast cancer) based on tolerability. If fosphenytoin is discontinued, reduce lapatinib to the indicated dose. Lapatinib is a CYP3A4 substrate and fosphenytoin is a strong CYP3A4 inducer. Concomitant use with another strong CYP3A4 inducer decreased lapatinib exposure by 72%.
    Fostamatinib: (Moderate) Monitor for an increase in lapatinib-related adverse reactions if coadministration with fostamatinib is necessary. Lapatinib is a P-glycoprotein (P-gp) substrate and fostamatinib is a P-gp inhibitor. Increased plasma concentrations of lapatinib are likely.
    Fostemsavir: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with fostemsavir. Lapatinib has been associated with dose-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Supratherapeutic doses of fostemsavir (2,400 mg twice daily, four times the recommended daily dose) have been shown to cause QT prolongation. Fostemsavir causes dose-dependent QT prolongation.
    Gemifloxacin: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with gemifloxacin. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Gemifloxacin may prolong the QT interval in some patients. The maximal change in the QTc interval occurs approximately 5 to 10 hours following oral administration of gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of the drug; 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) Monitor ECGs for QT prolongation and monitor electrolytes at baseline and throughout treatment if coadministration of lapatinib with gemtuzumab 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 with lapatinib. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin.
    Gilteritinib: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of lapatinib with gilteritinib 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. Gilteritinib has been associated with QT prolongation. Coadministration has the potential for additive effects.
    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) Monitor for an increase in treatment-related adverse reactions if coadministration of lapatinib with glecaprevir is necessary. Both drugs are P-glycoprotein (P-gp) substrates and inhibitors. Increased plasma concentrations of lapatinib are likely. Exposure to glecaprevir may also occur. (Moderate) Monitor for an increase in treatment-related adverse reactions if coadministration with lapatinib is necessary. Both drugs are P-glycoprotein (P-gp) substrates and inhibitors. Increased plasma concentrations of lapatinib are likely when administered with P-gp inhibitors. Exposure to pibrentasvir may also increase.
    Glimepiride; Rosiglitazone: (Moderate) Monitor blood sugar more frequently if coadministration of rosiglitazone with lapatinib is necessary. Rosiglitazone is a CYP2C8 substrate and lapatinib is a weak CYP2C8 inhibitor. Coadministration may increase exposure to rosiglitazone resulting in hypoglycemia.
    Goserelin: (Moderate) Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving lapatinib as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy (i.e., goserelin) may prolong the 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 with lapatinib.
    Granisetron: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with goserelin; correct electrolyte abnormalities prior to treatment. Granisetron has been associated with QT prolongation. Lapatinib has also been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
    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) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of lapatinib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like lapatinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If lapatinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of lapatinib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like lapatinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If lapatinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Halogenated Anesthetics: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of lapatinib with halogenated anesthetics is necessary; correct electrolyte abnormalities prior to treatment. Halogenated anesthetics can 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 with lapatinib.
    Haloperidol: (Moderate) Monitor for evidence of QT prolongation and an increase in haloperidol-related adverse reactions if administered with lapatinib. Haloperidol is a CYP3A4 substrate that has been associated QT prolongation and torsade de pointes (TdP) during treatment; excessive doses (particularly in the overdose setting) or IV administration may be associated with a higher risk. Lapatinib is a weak CYP3A4 inhibitor that has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and TdP have been reported in postmarketing experience with lapatinib. In clinical trials, mild to moderately increased haloperidol concentrations have been reported when haloperidol was given concomitantly with CYP3A4 inhibitors.
    Halothane: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of lapatinib with halogenated anesthetics is necessary; correct electrolyte abnormalities prior to treatment. Halogenated anesthetics can 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 with lapatinib.
    Histrelin: (Moderate) Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving lapatinib as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy (i.e., histrelin) may prolong the 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 with lapatinib.
    Homatropine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of lapatinib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like lapatinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If lapatinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of lapatinib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like lapatinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If lapatinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Ibuprofen: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of lapatinib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like lapatinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If lapatinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of lapatinib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like lapatinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If lapatinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of lapatinib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like lapatinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If lapatinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of lapatinib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like lapatinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If lapatinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of lapatinib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like lapatinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If lapatinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydroxychloroquine: (Major) Avoid coadministration of lapatinib and hydroxychloroquine due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Hydroxychloroquine prolongs 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 with lapatinib.
    Hydroxyzine: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with hydroxyzine as concurrent use may increase the risk of QT prolongation. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Postmarketing data indicate that hydroxyzine causes QT prolongation and TdP.
    Ibrutinib: (Moderate) Monitor for an increase in lapatinib-related adverse reactions if coadministration with ibrutinib is necessary. Lapatinib is a P-glycoprotein (P-gp) substrate and ibrutinib is a P-gp inhibitor. Increased plasma concentrations of lapatinib are likely.
    Ibuprofen; 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.
    Ibutilide: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of lapatinib with ibutilide 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 with lapatinib. Ibutilide administration can also cause QT prolongation and torsade 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 coadministration of lapatinib with idelalisib due to increased plasma concentrations of lapatinib. If concomitant use is unavoidable, decrease the dose of lapatinib to 500 mg PO once daily. If idelalisib is discontinued, increase lapatinib to the indicated dose after a washout period of approximately 1 week. Lapatinib is a CYP3A4 substrate and idelalisib 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.
    Iloperidone: (Major) Avoid coadministration of iloperidone with lapatinib due to the risk of QT prolongation. Iloperidone has been associated with QT prolongation. Lapatinib has also been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
    Imipramine: (Minor) Monitor for evidence of QT prolongation if lapatinib is administered with tricyclic antidepressants. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Indinavir: (Major) Avoid coadministration of lapatinib with indinavir due to increased plasma concentrations of lapatinib; exposure to indinavir may also increase. If concomitant use is unavoidable, decrease the dose of lapatinib to 500 mg PO once daily. If indinavir is discontinued, increase lapatinib to the indicated dose after a washout period of approximately 1 week. Lapatinib is a CYP3A4 substrate, weak CYP3A4 inhibitor, and P-glycoprotein (P-gp) inhibitor. Indinavir is a strong CYP3A4 inhibitor, a sensitive CYP3A4 substrate, and a P-gp substrate. 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.
    Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab with lapatinib due to the potential for additive QT prolongation and torsade de pointes (TdP). If coadministration is unavoidable, obtain ECGs prior to the start of treatment and periodically during treatment; also monitor electrolytes. Correct any electrolyte abnormalities prior to treatment. Inotuzumab has been associated with QT interval prolongation. Lapatinib has also been associated with concentration-dependent QT prolongation; ventricular arrhythmias and TdP have been reported in postmarketing experience with lapatinib.
    Isavuconazonium: (Moderate) Monitor for an increase in lapatinib-related adverse reactions if coadministration with isavuconazonium is necessary. Lapatinib is a P-glycoprotein (P-gp) substrate and isavuconazonium is a P-gp inhibitor. Increased plasma concentrations of lapatinib are likely.
    Isoflurane: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of lapatinib with halogenated anesthetics is necessary; correct electrolyte abnormalities prior to treatment. Halogenated anesthetics can 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 with lapatinib.
    Isradipine: (Moderate) Monitor blood pressure if coadministration of isradipine with lapatinib is necessary. Isradipine is a CYP3A4 substrate and lapatinib is a CYP3A4 inhibitor.
    Istradefylline: (Moderate) Monitor for an increase in lapatinib-related adverse reactions if coadministration with istradefylline is necessary. Lapatinib is a P-gp substrate and istradefylline is a P-gp inhibitor. Increased plasma concentrations of lapatinib are likely.
    Itraconazole: (Major) Avoid administration of lapatinib during and for 2 weeks after discontinuation of itraconazole therapy. If concurrent use is unavoidable, decrease the dose of lapatinib to 500 mg PO once daily. Monitor for an increase in lapatinib-related adverse reactions and for evidence of QT prolongation. If itraconazole is discontinued, increase lapatinib to the indicated dose after a washout period of approximately 1 week. Lapatinib is a CYP3A4 substrate that has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have also been reported in postmarketing experience. itraconazole is a strong CYP3A4 inhibitor that has also been associated with prolongation of the QT interval. 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.
    Ivacaftor: (Moderate) Monitor for an increase in lapatinib-related adverse reactions if coadministration with ivacaftor is necessary. Lapatinib is a P-glycoprotein (P-gp) substrate and ivacaftor is a P-gp inhibitor. Increased plasma concentrations of lapatinib are likely.
    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: (Moderate) Frequently monitor peripheral blood counts between cycles of ixabepilone, and for other acute ixabepilone-related adverse reactions if coadministration with lapatinib is necessary; consider the use of an alternative agent to lapatinib that does not inhibit CYP3A4. Ixabepilone is a CYP3A4 substrate and lapatinib is a weak CYP3A4 inhibitor. The effect of weak CYP3A4 inhibitors on exposure to ixabepilone has not been studied.
    Ketoconazole: (Major) Avoid coadministration of lapatinib with ketoconazole due to increased plasma concentrations of lapatinib; QT prolongation may also occur. If concomitant use is unavoidable, decrease the dose of lapatinib to 500 mg PO once daily. Monitor for evidence of QT prolongation and torsade de pointes (TdP). If ketoconazole is discontinued, increase lapatinib to the indicated dose after a washout period of approximately 1 week. Lapatinib is a CYP3A4 substrate that has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and TdP have also been reported in postmarketing experience. Ketoconazole is a strong CYP3A4 inhibitor that has also been associated with QT prolongation. Concomitant use with ketoconazole increased lapatinib exposure by 3.6-fold and increased the half-life of lapatinib by 1.7-fold.
    Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with lapatinib is necessary. Tenofovir is a P-glycoprotein (P-gp) substrate and lapatinib is a P-gp inhibitor. Increased plasma concentrations of tenofovir may occur.
    Ledipasvir; Sofosbuvir: (Moderate) Monitor for an increase in lapatinib-related adverse reactions if coadministration with ledipasvir is necessary. Lapatinib is a P-glycoprotein (P-gp) substrate and ledipasvir is a P-gp inhibitor. Increased plasma concentrations of lapatinib are likely.
    Lefamulin: (Moderate) Monitor for lefamulin-related adverse effects if oral lefamulin is administered with lapatinib as concurrent use may increase exposure from lefamulin tablets; an interaction is not expected with intravenous lefamulin. Lefamulin is a CYP3A4 and P-gp substrate and lapatinib is a P-gp inhibitor.
    Lemborexant: (Major) Limit the dose of lemborexant to a maximum of 5 mg PO once daily if coadministered with lapatinib as concurrent use may increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A4 substrate; lapatinib is a weak CYP3A4 inhibitor. Coadministration of lemborexant with a weak CYP3A4 inhibitor is predicted to increase lemborexant exposure by less than 2-fold.
    Lenvatinib: (Major) Avoid coadministration of lenvatinib with lapatinib due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Lapatinib has also been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
    Leuprolide: (Moderate) Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving lapatinib as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy (i.e., leuprolide) may prolong the 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 with lapatinib.
    Leuprolide; Norethindrone: (Moderate) Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving lapatinib as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy (i.e., leuprolide) may prolong the 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 with lapatinib.
    Levofloxacin: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with levofloxacin. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Levofloxacin has also been associated with a risk of QT prolongation and TdP. Although extremely rare, TdP has been reported during postmarketing surveillance of levofloxacin.
    Lidocaine: (Major) Monitor for lidocaine toxicity if coadministration with lapatinib is necessary. Concomitant use of systemic lidocaine and lapatinib may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Lidocaine is a CYP3A4 substrate and lapatinib is a weak CYP3A4 inhibitor.
    Lidocaine; Prilocaine: (Major) Monitor for lidocaine toxicity if coadministration with lapatinib is necessary. Concomitant use of systemic lidocaine and lapatinib may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Lidocaine is a CYP3A4 substrate and lapatinib is a weak CYP3A4 inhibitor.
    Lithium: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with lithium. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Lithium has also been associated with QT prolongation.
    Lofexidine: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of lapatinib with lofexidine is necessary; correct electrolyte abnormalities prior to treatment. Lofexidine prolongs 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 with lapatinib.
    Lomitapide: (Major) Decrease the dose of lomitapide by one-half not to exceed 30 mg/day PO if coadministration with lapatinib is necessary; also monitor for an increase in lapatinib-related adverse reactions. Concomitant use may significantly increase the serum concentration of lomitapide. Lapatinib is a P-glycoprotein (P-gp) substrate and a weak CYP3A4 inhibitor. Lomitapide is a P-gp inhibitor and a CYP3A4 substrate. The exposure to lomitapide is increased by approximately 2-fold in the presence of weak CYP3A4 inhibitors. Increased plasma concentrations of lapatinib are likely when administered with P-gp inhibitors.
    Long-acting beta-agonists: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with long-acting beta-agonists. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists, such as formoterol, as compared to short-acting beta-agonists.
    Loperamide: (Moderate) Monitor for an increase in loperamide-related adverse reactions, including CNS effects (e.g., syncope) and cardiac effects (e.g., ventricular tachycardia, QT prolongation, torsade de pointes (TdP)) if coadministration with lapatinib is necessary. Loperamide is a P-glycoprotein (P-gp) and CYP3A4 substrate that, at high doses, has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, TdP, and cardiac arrest. Lapatinib is a P-gp inhibitor and a weak CYP3A4 inhibitor that has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and TdP have been reported in postmarketing experience with lapatinib. Coadministration with other P-gp inhibitors increased loperamide plasma concentrations by 2-fold to 3-fold.
    Loperamide; Simethicone: (Moderate) Monitor for an increase in loperamide-related adverse reactions, including CNS effects (e.g., syncope) and cardiac effects (e.g., ventricular tachycardia, QT prolongation, torsade de pointes (TdP)) if coadministration with lapatinib is necessary. Loperamide is a P-glycoprotein (P-gp) and CYP3A4 substrate that, at high doses, has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, TdP, and cardiac arrest. Lapatinib is a P-gp inhibitor and a weak CYP3A4 inhibitor that has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and TdP have been reported in postmarketing experience with lapatinib. Coadministration with other P-gp inhibitors increased loperamide plasma concentrations by 2-fold to 3-fold.
    Lopinavir; Ritonavir: (Major) Avoid coadministration of lapatinib with ritonavir due to increased plasma concentrations of lapatinib. If concomitant use is unavoidable, decrease the dose of lapatinib to 500 mg PO once daily. If ritonavir is discontinued, increase lapatinib to the indicated dose after a washout period of approximately 1 week. Lapatinib is a CYP3A4 substrate and ritonavir 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. (Major) Avoid coadministration of lopinavir with lapatinib due to the potential for additive QT prolongation. If use together is necessary, obtain a baseline ECG to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Lopinavir is associated with QT prolongation. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of lapatinib with lumacaftor; ivacaftor due to decreased plasma concentrations of lapatinib. If concomitant use is unavoidable, gradually titrate the dose of lapatinib from 1,250 mg per day to 4,500 mg per day in patients receiving concomitant capecitabine (HER2-positive metastatic breast cancer), and from 1,500 mg per day to 5,500 mg per day in patients receiving concomitant aromatase inhibitor therapy (HR-positive, HER2-positive breast cancer) based on tolerability. If lumacaftor; ivacaftor is discontinued, reduce lapatinib to the indicated dose. Lapatinib is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Concomitant use with another strong CYP3A4 inducer decreased lapatinib exposure by 72%. (Moderate) Monitor for an increase in lapatinib-related adverse reactions if coadministration with ivacaftor is necessary. Lapatinib is a P-glycoprotein (P-gp) substrate and ivacaftor is a P-gp inhibitor. Increased plasma concentrations of lapatinib are likely.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of lapatinib with lumacaftor; ivacaftor due to decreased plasma concentrations of lapatinib. If concomitant use is unavoidable, gradually titrate the dose of lapatinib from 1,250 mg per day to 4,500 mg per day in patients receiving concomitant capecitabine (HER2-positive metastatic breast cancer), and from 1,500 mg per day to 5,500 mg per day in patients receiving concomitant aromatase inhibitor therapy (HR-positive, HER2-positive breast cancer) based on tolerability. If lumacaftor; ivacaftor is discontinued, reduce lapatinib to the indicated dose. Lapatinib is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Concomitant use with another strong CYP3A4 inducer decreased lapatinib exposure by 72%.
    Macimorelin: (Major) Avoid concurrent administration of macimorelin with lapatinib due to the risk of QT prolongation and torsade de pointes (TdP). Sufficient washout time of drugs that are known to prolong the QT interval, such as lapatinib, prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Lapatinib has also been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
    Maprotiline: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with maprotiline. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Maprotiline has also 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 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.
    Maraviroc: (Moderate) Monitor for an increase in maraviroc-related adverse reactions if coadministration with lapatinib is necessary. Maraviroc is a P-glycoprotein (P-gp) substrate and lapatinib is a P-gp inhibitor. Concomitant use may increase maraviroc exposure.
    Mefloquine: (Moderate) Monitor for evidence of QT prolongation and torsade de pointes (TdP) when coadministering lapatinib with mefloquine. Also, monitor for treatment-related adverse reactions. Lapatinib is a P-glycoprotein (P-gp) substrate/inhibitor as well as a weak CYP3A4 inhibitor, that has been associated with concentration-dependent QT prolongation. Ventricular arrhythmias and TdP have been reported in postmarketing experience with lapatinib. Mefloquine is also a P-gp substrate/inhibitor, as well as a CYP3A4 substrate. There is evidence that the use of halofantrine after mefloquine causes a 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. Increased plasma concentrations of lapatinib are likely when administered with P-gp inhibitors.
    Meperidine; Promethazine: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with promethazine. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
    Metformin; Rosiglitazone: (Moderate) Monitor blood sugar more frequently if coadministration of rosiglitazone with lapatinib is necessary. Rosiglitazone is a CYP2C8 substrate and lapatinib is a weak CYP2C8 inhibitor. Coadministration may increase exposure to rosiglitazone resulting in hypoglycemia.
    Methadone: (Major) Carefully assess treatment risks versus benefits if coadministration of methadone with lapatinib is necessary due to the risk of QT prolongation and increased methadone exposure. Monitor ECGs for QT prolongation and monitor electrolytes if coadministration is necessary; correct electrolyte abnormalities prior to treatment. Consider a reduced dose of methadone with frequent monitoring for respiratory depression and sedation. If lapatinib is discontinued, methadone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to methadone; consider increasing the methadone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Methadone is a CYP3A4 substrate, and coadministration with weak CYP3A4 inhibitors like lapatinib can increase methadone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of methadone. Methadone is also associated with an increased risk for QT prolongation and torsade de pointes (TdP), especially at higher doses (greater than 200 mg/day but averaging approximately 400 mg/day in adult patients). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. Lapatinib has also been associated with concentration-dependent QT prolongation; ventricular arrhythmias and TdP have been reported in postmarketing experience with lapatinib.
    Metronidazole: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with metronidazole. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Potential QT prolongation has been reported in limited case reports with metronidazole.
    Midazolam: (Moderate) Monitor for an increase in midazolam-related adverse reactions, including sedation and respiratory depression, if coadministration with lapatinib is necessary. Midazolam is a sensitive CYP3A4 substrate and lapatinib is a weak CYP3A4 inhibitor. Following coadministration of lapatinib and midazolam, the 24-hour systemic exposure (AUC) of orally administered midazolam increased by 45%, while the 24-hour AUC of IV midazolam increased by 22%.
    Midostaurin: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of lapatinib with midostaurin is necessary; correct electrolyte abnormalities prior to treatment. Prolongation of the QT interval was reported in patients who received midostaurin in clinical trials. Lapatinib has also been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
    Mifepristone: (Major) Avoid coadministration of lapatinib with mifepristone due to increased plasma concentrations of lapatinib; QT prolongation may also occur. If concomitant use is unavoidable, decrease the dose of lapatinib to 500 mg PO once daily; use the lowest effective dose of mifepristone to reduce the risk of QT prolongation. Monitor ECGs for QT prolongation and monitor electrolytes; correct any electrolyte abnormalities prior to treatment. If mifepristone is discontinued, increase lapatinib to the indicated dose after a washout period of approximately 1 week. Lapatinib is a CYP3A4 substrate that has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have also been reported in postmarketing experience. Mifepristone is a strong CYP3A4 inhibitor that has also been associated with dose-dependent prolongation of the QT interval. 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. The clinical significance of this interaction with the short-term use of mifepristone for termination of pregnancy is unknown.
    Mirtazapine: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with mirtazapine. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Mirtazapine has also been associated with dose-dependent prolongation of the QT interval. TdP has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Mitotane: (Major) Avoid coadministration of lapatinib with mitotane due to decreased plasma concentrations of lapatinib. If concomitant use is unavoidable, gradually titrate the dose of lapatinib from 1,250 mg per day to 4,500 mg per day in patients receiving concomitant capecitabine (HER2-positive metastatic breast cancer), and from 1,500 mg per day to 5,500 mg per day in patients receiving concomitant aromatase inhibitor therapy (HR-positive, HER2-positive breast cancer) based on tolerability. If mitotane is discontinued, reduce lapatinib to the indicated dose. Lapatinib is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Concomitant use with another strong CYP3A4 inducer decreased lapatinib exposure by 72%.
    Morphine: (Moderate) Monitor for an increase in morphine-related adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death, if coadministration with lapatinib is necessary; decrease the dose of morphine as clinically appropriate. Morphine is a P-glycoprotein (P-gp) substrate and lapatinib is a P-gp inhibitor. The concomitant use of P-gp inhibitors can increase the exposure to morphine by about 2-fold.
    Morphine; Naltrexone: (Moderate) Monitor for an increase in morphine-related adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death, if coadministration with lapatinib is necessary; decrease the dose of morphine as clinically appropriate. Morphine is a P-glycoprotein (P-gp) substrate and lapatinib is a P-gp inhibitor. The concomitant use of P-gp inhibitors can increase the exposure to morphine by about 2-fold.
    Moxifloxacin: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of lapatinib with moxifloxacin 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 with lapatinib. Quinolones have also been associated with a risk of QT prolongation; although extremely rare, TdP has been reported during postmarketing surveillance of moxifloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Naldemedine: (Moderate) Monitor for potential naldemedine-related adverse reactions if coadministered with lapatinib. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a P-gp substrate; lapatinib is a P-gp inhibitor.
    Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for an increase in nab-paclitaxel-related adverse reactions if coadministration of nab-paclitaxel with lapatinib is necessary due to the risk of increased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP2C8 substrate and lapatinib is a weak CYP2C8 inhibitor. In vitro, the metabolism of paclitaxel to 6-alpha-hydroxypaclitaxel was inhibited by another inhibitor of CYP2C8.
    Nefazodone: (Major) Avoid coadministration of lapatinib with nefazodone due to increased plasma concentrations of lapatinib. If concomitant use is unavoidable, decrease the dose of lapatinib to 500 mg PO once daily. If nefazodone is discontinued, increase lapatinib to the indicated dose after a washout period of approximately 1 week. Lapatinib is a CYP3A4 substrate and nefazodone 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.
    Nelfinavir: (Major) Avoid coadministration of lapatinib with nelfinavir due to increased plasma concentrations of lapatinib. If concomitant use is unavoidable, decrease the dose of lapatinib to 500 mg PO once daily. If nelfinavir is discontinued, increase lapatinib to the indicated dose after a washout period of approximately 1 week. Lapatinib is a CYP3A4 substrate and nelfinavir 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.
    Neratinib: (Moderate) Monitor for an increase in lapatinib-related adverse reactions if coadministration with neratinib is necessary. Lapatinib is a P-glycoprotein (P-gp) substrate and neratinib is a P-gp inhibitor. Increased plasma concentrations of lapatinib are likely.
    Nilotinib: (Major) Avoid administration of nilotinib with lapatinib due to the risk of QT prolongation. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy. Lapatinib has also been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
    Nimodipine: (Moderate) Monitor blood pressure if coadministration of nimodipine with lapatinib is necessary; a reduction of the nimodipine dose may be necessary. Nimodipine is a CYP3A4 substrate and lapatinib is a weak CYP3A4 inhibitor. Coadministration with another weak CYP3A4 inhibitor increased mean peak nimodipine plasma concentrations by 50% and increased the mean AUC by 90%.
    Nintedanib: (Moderate) Monitor for an increase in nintedanib-related adverse reactions if coadministration with lapatinib is necessary. Nintedanib is a substrate of P-glycoprotein (P-gp) and, to a minor extent, CYP3A4. Lapatinib is a P-gp inhibitor as well as a weak CYP3A4 inhibitor. Coadministration with a dual P-gp and strong CYP3A4 inhibitor increased nintedanib exposure by 60%.
    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.
    Nortriptyline: (Minor) Monitor for evidence of QT prolongation if lapatinib is administered with tricyclic antidepressants. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Octreotide: (Moderate) Use octreotide with caution in combination with lapatinib. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. 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: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with ofloxacin as concurrent use may increase the risk of QT prolongation. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Quinolones have been associated with a risk of QT prolongation and TdP. Although extremely rare, TdP has been reported during postmarketing surveillance of ofloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Olanzapine: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with olanzapine. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of lapatinib with ritonavir due to increased plasma concentrations of lapatinib. If concomitant use is unavoidable, decrease the dose of lapatinib to 500 mg PO once daily. If ritonavir is discontinued, increase lapatinib to the indicated dose after a washout period of approximately 1 week. Lapatinib is a CYP3A4 substrate and ritonavir 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. (Major) Monitor for an increase in ombitasvir-related adverse reactions if coadministration with lapatinib is necessary. Ombitasvir is a P-glycoprotein (P-gp) substrate and lapatinib is a P-gp inhibitor. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with lapatinib is necessary. Paritaprevir is a P-glycoprotein (P-gp) substrate and lapatinib is a P-gp inhibitor.
    Ondansetron: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of lapatinib with ondansetron 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 with lapatinib. Ondansetron has also been associated with a dose-related increase in the QT interval and postmarketing reports of TdP.
    Osilodrostat: (Moderate) Monitor ECGs in patients receiving osilodrostat with lapatinib. Osilodrostat is associated with dose-dependent QT prolongation. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
    Osimertinib: (Major) Avoid coadministration of lapatinib with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP); exposure to lapatinib may also increase. If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation may be necessary if QT prolongation occurs. Correct electrolyte abnormalities prior to treatment. 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 also been reported in postmarketing experience. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib, a P-gp inhibitor. Increased plasma concentrations of lapatinib are likely when administered with P-gp inhibitors.
    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.
    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.
    Ozanimod: (Major) In general, do not initiate ozanimod in patients taking lapatinib due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ozanimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and TdP have been reported in postmarketing experience with lapatinib.
    Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration with lapatinib is necessary. Paclitaxel is a CYP3A4 and P-glycoprotein (P-gp) substrate. Lapatinib is a weak CYP3A4 inhibitor as well as a P-gp inhibitor. The 24-hour systemic exposure (AUC) of paclitaxel was increased by 23% in cancer patients receiving concomitant lapatinib; this increase in paclitaxel exposure may have been underestimated from the in vivo evaluation due to study design limitations.
    Paliperidone: (Major) Avoid coadministration of paliperidone with lapatinib if possible due to the risk of QT prolongation. If concomitant administration is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct electrolyte abnormalities prior to treatment. Paliperidone has been associated with QT prolongation. Lapatinib has also been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
    Panobinostat: (Major) Coadministration of panobinostat with lapatinib is not recommended due to the risk of QT prolongation. Prolongation of the QT interval has been reported with panobinostat. Lapatinib has also been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
    Pasireotide: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with pasireotide. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. QT prolongation has occurred with pasireotide at therapeutic and supra-therapeutic doses.
    Pazopanib: (Major) Coadministration of pazopanib lapatinib is not advised due to the risk of QT prolongation; exposure to pazopanib may also increase. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct electrolyte abnormalities prior to treatment. Pazopanib is a P-glycoprotein (P-gp) substrate that has been reported to prolong the QT interval. Lapatinib is a P-gp inhibitor that has also been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
    Pentamidine: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of lapatinib with systemic pentamidine is necessary; correct electrolyte abnormalities prior to treatment. Systemic pentamidine has been associated with QT prolongation. Lapatinib has also been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
    Perphenazine: (Minor) Monitor for evidence of QT prolongation if lapatinib is administered with perphenazine. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Perphenazine is also associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Perphenazine; Amitriptyline: (Minor) Monitor for evidence of QT prolongation if lapatinib is administered with perphenazine. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Perphenazine is also associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation. (Minor) Monitor for evidence of QT prolongation if lapatinib is administered with tricyclic antidepressants. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Phenobarbital: (Major) Avoid coadministration of lapatinib with phenobarbital due to decreased plasma concentrations of lapatinib. If concomitant use is unavoidable, gradually titrate the dose of lapatinib from 1,250 mg per day to 4,500 mg per day in patients receiving concomitant capecitabine (HER2-positive metastatic breast cancer), and from 1,500 mg per day to 5,500 mg per day in patients receiving concomitant aromatase inhibitor therapy (HR-positive, HER2-positive breast cancer) based on tolerability. If phenobarbital is discontinued, reduce lapatinib to the indicated dose. Lapatinib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Concomitant use with another strong CYP3A4 inducer decreased lapatinib exposure by 72%.
    Phenylephrine; Promethazine: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with promethazine. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
    Phenytoin: (Major) Avoid coadministration of lapatinib with phenytoin due to decreased plasma concentrations of lapatinib. If concomitant use is unavoidable, gradually titrate the dose of lapatinib from 1,250 mg per day to 4,500 mg per day in patients receiving concomitant capecitabine (HER2-positive metastatic breast cancer), and from 1,500 mg per day to 5,500 mg per day in patients receiving concomitant aromatase inhibitor therapy (HR-positive, HER2-positive breast cancer) based on tolerability. If phenytoin is discontinued, reduce lapatinib to the indicated dose. Lapatinib is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Concomitant use with another strong CYP3A4 inducer decreased lapatinib exposure by 72%.
    Pimavanserin: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval such as lapatinib. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; 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 with lapatinib.
    Pimozide: (Severe) Because of the potential for torsade de pointes (TdP), use of lapatinib with pimozide is contraindicated. Pimozide is associated with a well-established risk of QT prolongation and TdP. Lapatinib has also been associated with concentration-dependent QT prolongation; ventricular arrhythmias and TdP have been reported in postmarketing experience with lapatinib.
    Pitolisant: (Major) Avoid coadministration of pitolisant with lapatinib as concurrent use may increase the risk of QT prolongation. If concomitant use is necessary, monitor for evidence of QT prolongation. Pitolisant prolongs 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 with lapatinib.
    Ponatinib: (Moderate) Monitor for an increase in lapatinib-related adverse reactions if coadministration with ponatinib is necessary. Lapatinib is a P-glycoprotein (P-gp) substrate and ponatinib is a P-gp inhibitor. Increased plasma concentrations of lapatinib are likely.
    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). Posaconazole is a strong CYP3A4 inhibitor as well as a P-glycoprotein (P-gp) substrate/inhibitor that has been associated with QT prolongation and torsade de pointes. Lapatinib is a CYP3A4 substrate and a P-gp substrate/inhibitor that has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
    Primaquine: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with primaquine. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Primaquine also has the potential for QT prolongation.
    Primidone: (Major) Avoid coadministration of lapatinib with primidone due to decreased plasma concentrations of lapatinib. If concomitant use is unavoidable, gradually titrate the dose of lapatinib from 1,250 mg per day to 4,500 mg per day in patients receiving concomitant capecitabine (HER2-positive metastatic breast cancer), and from 1,500 mg per day to 5,500 mg per day in patients receiving concomitant aromatase inhibitor therapy (HR-positive, HER2-positive breast cancer) based on tolerability. If primidone is discontinued, reduce lapatinib to the indicated dose. Lapatinib is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Concomitant use with another strong CYP3A4 inducer decreased lapatinib exposure by 72%.
    Procainamide: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of lapatinib with procainamide is necessary; correct electrolyte abnormalities prior to treatment. Procainamide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Lapatinib has also been associated with concentration-dependent QT prolongation; ventricular arrhythmias and TdP have been reported in postmarketing experience with lapatinib.
    Prochlorperazine: (Minor) Monitor for evidence of QT prolongation if lapatinib is administered with prochlorperazine. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Prochlorperazine is also associated with a possible risk for QT prolongation. Theoretically, prochlorperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Promethazine: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with promethazine. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
    Propafenone: (Major) Monitor for an increase in treatment-related adverse reactions if coadministration with propafenone is necessary; also monitor ECGs for QT prolongation and monitor electrolytes. Correct any electrolyte abnormalities prior to treatment. Because of its metabolism, coadministration of lapatinib with propafenone, and either CYP2D6 deficiency or CYP2D6 inhibition is potentially hazardous. Therefore, avoid simultaneous use of propafenone with both a CYP2D6 inhibitor and lapatinib. Lapatinib is a P-glycoprotein (P-gp) substrate and a weak CYP3A4 inhibitor that has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have also been reported in postmarketing experience. Propafenone is a P-gp inhibitor, CYP3A4 substrate, and Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval. Increased plasma concentrations of lapatinib are likely when administered with P-gp inhibitors. Drugs that inhibit CYP3A4 can be expected to cause increased plasma levels of propafenone, which may lead to cardiac arrhythmias and exaggerated beta-adrenergic blocking activity.
    Protriptyline: (Minor) Monitor for evidence of QT prolongation if lapatinib is administered with tricyclic antidepressants. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Quetiapine: (Major) Avoid coadministration of quetiapine with lapatinib due to the risk of QT prolongation. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Limited data, including some case reports, suggest that quetiapine may also be associated with a significant prolongation of the QTc interval in rare instances.
    Quinidine: (Major) Monitor for an increase in treatment-related adverse reactions if coadministration of lapatinib with quinidine is necessary; also monitor ECGs for QT prolongation and monitor electrolytes. Correct any electrolyte abnormalities prior to treatment. Lapatinib is a P-glycoprotein (P-gp) substrate/inhibitor that has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have also been reported in postmarketing experience. Quinidine is also a P-gp substrate/inhibitor that is also associated with QT prolongation and TdP. Increased plasma concentrations of lapatinib are likely when administered with P-gp inhibitors.
    Quinine: (Major) Avoid coadministration of quinine with lapatinib due to the risk of QT prolongation and torsade de pointes (TdP); exposure to both drugs may also increase. Lapatinib is a P-glycoprotein (P-gp) substrate/inhibitor as well as a CYP3A4 substrate/weak inhibitor. It has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and TdP have been reported in postmarketing experience with lapatinib. Quinine is also a P-gp substrate/inhibitor and CYP3A4 substrate, that has also been associated with QT prolongation and rare cases of TdP.
    Ranolazine: (Major) Monitor for an increase in treatment-related adverse reactions if coadministration with ranolazine is necessary. Lapatinib is a P-glycoprotein (P-gp) substrate/inhibitor that has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have also been reported in postmarketing experience. Ranolazine is also a P-gp substrate/inhibitor that is also associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Increased plasma concentrations of lapatinib are likely when administered with P-gp inhibitors.
    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) Avoid coadministration of lapatinib with rifamycins (rifampin, rifabutin, and rifapentine) due to decreased plasma concentrations of lapatinib. If concomitant use is unavoidable, gradually titrate the dose of lapatinib from 1,250 mg per day to 4,500 mg per day in patients receiving concomitant capecitabine (HER2-positive metastatic breast cancer), and from 1,500 mg per day to 5,500 mg per day in patients receiving concomitant aromatase inhibitor therapy (HR-positive, HER2-positive breast cancer) based on tolerability. If the rifamycin is discontinued, reduce lapatinib to the indicated dose. Lapatinib is a CYP3A4 substrate. Rifampin is a strong CYP3A4 inducer; rifabutin and rifapentine are also CYP3A4 inducers. Concomitant use with another strong CYP3A4 inducer decreased lapatinib exposure by 72%.
    Rifaximin: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with lapatinib is necessary. Rifaximin is a P-glycoprotein (P-gp) substrate and lapatinib is a P-gp inhibitor. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Coadministration with one P-gp inhibitor decreased the efflux ration of rifaximin by greater than 50%. Concomitant use with another P-gp inhibitor increased the Cmax and AUC of rifaximin by 83-fold and 124-fold.
    Rilpivirine: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with rilpivirine. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Rimegepant: (Major) Avoid coadministration of rimegepant with lapatinib; concurrent use may increase rimegepant exposure. Rimegepant is a substrate of P-gp and lapatinib is a P-gp inhibitor.
    Risperidone: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with risperidone. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Risperidone has 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 due to increased plasma concentrations of lapatinib. If concomitant use is unavoidable, decrease the dose of lapatinib to 500 mg PO once daily. If ritonavir is discontinued, increase lapatinib to the indicated dose after a washout period of approximately 1 week. Lapatinib is a CYP3A4 substrate and ritonavir 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.
    Rolapitant: (Moderate) Monitor for an increase in lapatinib-related adverse reactions if coadministration with rolapitant is necessary. Lapatinib is a P-glycoprotein (P-gp) substrate and rolapitant is a P-gp inhibitor. Increased plasma concentrations of lapatinib are likely.
    Romidepsin: (Major) Monitor for an increase in treatment-related adverse reactions if coadministration with romidepsin is necessary. Lapatinib is a P-glycoprotein (P-gp) substrate/inhibitor that has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have also been reported in postmarketing experience. Romidepsin is also a P-gp substrate/inhibitor that has been reported to prolong the QT interval. Increased plasma concentrations of both drugs are likely when administered with P-gp inhibitors.
    Rosiglitazone: (Moderate) Monitor blood sugar more frequently if coadministration of rosiglitazone with lapatinib is necessary. Rosiglitazone is a CYP2C8 substrate and lapatinib is a weak CYP2C8 inhibitor. Coadministration may increase exposure to rosiglitazone resulting in hypoglycemia.
    Sapropterin: (Moderate) Monitor for an increase in lapatinib-related adverse reactions if coadministration with lapatinib is necessary. Lapatinib is a P-glycoprotein (P-gp) substrate and lapatinib is a P-gp inhibitor. Increased plasma concentrations of lapatinib are likely.
    Saquinavir: (Severe) Coadministration of saquinavir with lapatinib is contraindicated due to the risk of QT prolongation and torsade de pointes (TdP); exposure to lapatinib may also increase. Saquinavir, boosted with ritonavir, is a strong CYP3A4 inhibitor that increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP. Lapatinib is a CYP3A4 substrate that has also been associated with concentration-dependent QT prolongation; ventricular arrhythmias and TdP have been reported in postmarketing experience with lapatinib.
    Sarecycline: (Moderate) Monitor for an increase in lapatinib-related adverse reactions if coadministration with sarecycline is necessary. Lapatinib is a P-glycoprotein (P-gp) substrate and sarecycline is a P-gp inhibitor. Increased plasma concentrations of lapatinib are likely.
    Selexipag: (Moderate) Consider a dose reduction of selexipag to once daily dosing as clinically appropriateif adverse reactions occur when administered with lapatinib. Increased exposure to the active metabolite of selexipag is possible. Selexipag is a CYP2C8 substrate. In vitro data predicts inhibition of CYP2C8 by lapatinib potentially resulting in clinically significant interactions.
    Selpercatinib: (Major) Monitor ECGs more frequently for QT prolongation if coadministration of selpercatinib with lapatinib is necessary due to the risk of additive QT prolongation. Concentration-dependent QT prolongation has been observed with selpercatinib therapy. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
    Sertraline: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with sertraline. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes have been reported in postmarketing experience with lapatinib. Sertraline's FDA-approved labeling recommends avoiding concomitant use with drugs known to prolong the QTc interval; however, the risk of sertraline-induced QT prolongation is generally considered to be low in clinical practice. Its effect on QTc interval is minimal (typically less than 5 msec), and the drug has been used safely in patients with cardiac disease (e.g., recent myocardial infarction, unstable angina, chronic heart failure).
    Sevoflurane: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of lapatinib with halogenated anesthetics is necessary; correct electrolyte abnormalities prior to treatment. Halogenated anesthetics can 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 with lapatinib.
    Short-acting beta-agonists: (Minor) Monitor for evidence of QT prolongation if lapatinib is administered with short-acting beta-agonists. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Simeprevir: (Major) Monitor for an increase in treatment-related adverse reactions if coadministration of simeprevir with lapatinib is necessary. Both drugs are P-glycoprotein (P-gp) substrates and inhibitors. Increased plasma concentrations of lapatinib are likely when administered with P-gp inhibitors. Concomitant use may also increase simeprevir exposure.
    Siponimod: (Major) In general, do not initiate treatment with siponimod in patients receiving lapatinib due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes have been reported in postmarketing experience with lapatinib.
    Sirolimus: (Moderate) Monitor for an increase in sirolimus-related adverse reactions if coadministration with lapatinib is necessary. Monitor sirolimus concentrations and adjust the dose as clinically appropriate. Sirolimus is a P-glycoprotein (P-gp) and CYP3A4 substrate. Llapatinib is a P-gp inhibitor and a weak CYP3A4 inhibitor.
    Sofosbuvir; Velpatasvir: (Moderate) Monitor for an increase in lapatinib-related adverse reactions if coadministration with velpatasvir is necessary. Lapatinib is a P-glycoprotein (P-gp) substrate and velpatasvir is a P-gp inhibitor. Increased plasma concentrations of lapatinib are likely.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Monitor for an increase in lapatinib-related adverse reactions if coadministration with velpatasvir is necessary. Lapatinib is a P-glycoprotein (P-gp) substrate and velpatasvir is a P-gp inhibitor. Increased plasma concentrations of lapatinib are likely. (Moderate) Monitor for an increase in lapatinib-related adverse reactions if coadministration with voxilaprevir is necessary. Lapatinib is a P-glycoprotein (P-gp) substrate and voxilaprevir is a P-gp inhibitor. Increased plasma concentrations of lapatinib are likely.
    Solifenacin: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with solifenacin. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Solifenacin has also been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported with postmarketing use, although causality was not determined. This should be taken into consideration when prescribing solifenacin to patients taking other drugs that are associated with QT prolongation.
    Sorafenib: (Major) Avoid coadministration of sorafenib with lapatinib due to the risk of additive QT prolongation; the risk of lapatinib-related adverse reactions may also increase. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is a P-glycoprotein (P-gp) inhibitor that has been associated with QTc prolongation. Lapatinib is a P-gp substrate that has also been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
    Sotalol: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of lapatinib with sotalol 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 with lapatinib. Sotalol administration is also associated with QT prolongation and TdP; proarrhythmic events should be anticipated after initiation of therapy and after each upward dosage adjustment.
    St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of lapatinib with St. Johns Wort due to decreased plasma concentrations of lapatinib. If concomitant use is unavoidable, gradually titrate the dose of lapatinib from 1,250 mg per day to 4,500 mg per day in patients receiving concomitant capecitabine (HER2-positive metastatic breast cancer), and from 1,500 mg per day to 5,500 mg per day in patients receiving concomitant aromatase inhibitor therapy (HR-positive, HER2-positive breast cancer) based on tolerability. If St. Johns Wort is discontinued, reduce lapatinib to the indicated dose. Lapatinib is a CYP3A4 substrate and St. Johns Wort is a strong CYP3A4 inducer. Concomitant use with another strong CYP3A4 inducer decreased lapatinib exposure by 72%.
    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.
    Sunitinib: (Moderate) Monitor for evidence of QT prolongation if sunitinib is administered with lapatinib. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Sunitinib can prolong the QT interval.
    Tacrolimus: (Major) Measure tacrolimus whole blood trough concentrations and adjust the dose as clinically appropriate if coadministration with lapatinib is necessary. Tacrolimus is a CYP3A4 substrate that can cause QT prolongation. Lapatinib is a weak CYP3A4 inhibitor that has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
    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: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with tamoxifen. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Tamoxifen has 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.
    Telavancin: (Moderate) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of lapatinib with telavancin is necessary; correct electrolyte abnormalities prior to treatment. Telavancin has been associated with QT prolongation. Lapatinib has also been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
    Telithromycin: (Major) Avoid coadministration of lapatinib with telithromycin due to increased plasma concentrations of lapatinib; QT prolongation may also occur. If concomitant use is unavoidable, decrease the dose of lapatinib to 500 mg PO once daily. If telithromycin is discontinued, increase lapatinib to the indicated dose after a washout period of approximately 1 week. Lapatinib is a CYP3A4 substrate that has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have also been reported in postmarketing experience. Telithromycin is a strong CYP3A4 inhibitor that is also associated with QT prolongation and torsade de pointes (TdP). 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.
    Temsirolimus: (Moderate) Monitor for an increase in treatment-related adverse reactions if coadministration of lapatinib with temsirolimus 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.
    Tenofovir, PMPA: (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with lapatinib is necessary. Tenofovir is a P-glycoprotein (P-gp) substrate and lapatinib is a P-gp inhibitor. Increased plasma concentrations of tenofovir may occur.
    Tetrabenazine: (Major) Avoid coadministration of tetrabenazine with lapatinib due to the risk of QT prolongation. Tetrabenazine causes a small increase in the corrected QT interval (QTc). Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
    Tezacaftor; Ivacaftor: (Moderate) Monitor for an increase in lapatinib-related adverse reactions if coadministration with ivacaftor is necessary. Lapatinib is a P-glycoprotein (P-gp) substrate and ivacaftor is a P-gp inhibitor. Increased plasma concentrations of lapatinib are likely.
    Thioridazine: (Severe) Because of the potential for torsade de pointes (TdP), use of lapatinib with thioridazine is contraindicated. Thioridazine is associated with a well-established risk of QT prolongation and TdP. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and TdP have been reported in postmarketing experience with lapatinib.
    Ticagrelor: (Moderate) Monitor for an increased risk of treatment-related adverse reactions including bleeding if coadministration of ticagrelor and lapatinib are necessary. Both drugs are P-glycoprotein (P-gp) substrates and inhibitors. Increased plasma concentrations of lapatinib are likely. Exposure to ticagrelor may also increase. Based on drug information data with cyclosporine, no dose adjustment is recommended by the manufacturer of ticagrelor.
    Tipranavir: (Major) Avoid coadministration of lapatinib with tipranavir due to increased plasma concentrations of lapatinib; exposure to tipranavir may also increase. If concomitant use is unavoidable, decrease the dose of lapatinib to 500 mg PO once daily. If tipranavir is discontinued, increase lapatinib to the indicated dose after a washout period of approximately 1 week. Lapatinib is a CYP3A4 substrate and a P-glycoprotein (P-gp) inhibitor. Tipranavir is a strong CYP3A4 inhibitor and a P-gp substrate. 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. Inhibitors of P-gp may increase plasma concentrations of tipranavir.
    Tolterodine: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with tolterodine. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
    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 due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct electrolyte abnormalities prior to treatment. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Lapatinib has also been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
    Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with lapatinib is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of lapatinib, a weak CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
    Trandolapril; Verapamil: (Major) Monitor blood pressure, heart rate, and monitor for an increase in lapatinib-related adverse reactions if coadministration of verapamil with lapatinib is necessary. Both drugs are P-glycoprotein (P-gp) substrates and inhibitors. Increased plasma concentrations of lapatinib are likely. Concomitant use may also increase verapamil exposure.
    Trazodone: (Major) Avoid coadministration of trazodone with lapatinib due to the risk of QT prolongation. Trazodone can prolong the QT/QTc interval at therapeutic doses; in addition, there are postmarketing reports of torsade de pointes (TdP). Lapatinib has also been associated with concentration-dependent QT prolongation; ventricular arrhythmias and TdP have been reported in postmarketing experience with lapatinib.
    Triclabendazole: (Moderate) Monitor ECGs in patients receiving triclabendazole with lapatinib. Transient prolongation of the mean QTc interval was noted on the ECG recordings in dogs administered triclabendazole. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
    Tricyclic antidepressants: (Minor) Monitor for evidence of QT prolongation if lapatinib is administered with tricyclic antidepressants. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Trifluoperazine: (Minor) Monitor for evidence of QT prolongation if lapatinib is administered with trifluoperazine. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Trifluoperazine is also associated with a possible risk for QT prolongation. Theoretically, trifluoperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Trimipramine: (Minor) Monitor for evidence of QT prolongation if lapatinib is administered with tricyclic antidepressants. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Triptorelin: (Moderate) Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving lapatinib as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy (i.e., triptorelin) may prolong the 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 with lapatinib.
    Tucatinib: (Major) Avoid coadministration of lapatinib with tucatinib due to increased plasma concentrations of lapatinib. If concomitant use is unavoidable, decrease the dose of lapatinib to 500 mg PO once daily. If tucatinib is discontinued, increase lapatinib to the indicated dose after a washout period of approximately 1 week. Lapatinib is a CYP3A4 and P-glycoprotein (P-gp) substrate and tucatinib is a strong CYP3A4 inhibitor and P-gp 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.
    Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with lapatinib. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A4 and P-gp substrate; lapatinib is a weak CYP3A4 inhibitor and a P-gp inhibitor.
    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 treatment. 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 been associated with concentration-dependent QT prolongation; ventricular arrhythmias and TdP have been reported in postmarketing experience with lapatinib.
    Vardenafil: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with vardenafil. Vardenafil is associated with QT prolongation at both therapeutic and supratherapeutic doses. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
    Vemurafenib: (Major) Monitor for an increase in lapatinib-related adverse reactions if coadministration with vemurafenib is necessary; also monitor ECGs for QT prolongation and monitor electrolytes. Correct any electrolyte abnormalities prior to treatment. 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 also been reported in postmarketing experience. Vemurafenib is a P-gp inhibitor that has been associated with QT prolongation. Increased plasma concentrations of lapatinib are likely when administered with P-gp inhibitors.
    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 coadministration with lapatinib is necessary; lapatinib exposure may also 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. Increased plasma concentrations of lapatinib are likely when administered with P-gp inhibitors.
    Venlafaxine: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with venlafaxine. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has reported with postmarketing use.
    Verapamil: (Major) Monitor blood pressure, heart rate, and monitor for an increase in lapatinib-related adverse reactions if coadministration of verapamil with lapatinib is necessary. Both drugs are P-glycoprotein (P-gp) substrates and inhibitors. Increased plasma concentrations of lapatinib are likely. Concomitant use may also increase verapamil exposure.
    Vincristine Liposomal: (Moderate) Monitor for an increase in vincristine-related adverse reactions if coadministration with lapatinib is necessary. Vincristine is a P-glycoprotein (P-gp) substrate and lapatinib is a P-gp inhibitor.
    Vincristine: (Moderate) Monitor for an increase in vincristine-related adverse reactions if coadministration with lapatinib is necessary. Vincristine is a P-glycoprotein (P-gp) substrate and lapatinib is a P-gp inhibitor.
    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.
    Voriconazole: (Major) Avoid coadministration of lapatinib with voriconazole due to increased plasma concentrations of lapatinib; QT prolongation may also occur. If concomitant use is unavoidable, decrease the dose of lapatinib to 500 mg PO once daily. If voriconazole is discontinued, increase lapatinib to the indicated dose after a washout period of approximately 1 week. Lapatinib is a CYP3A4 substrate that has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have also been reported in postmarketing experience. Voriconazole is a strong CYP3A4 inhibitor that has also been associated with QT prolongation and rare cases of TdP. 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.
    Vorinostat: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with vorinostat. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Vorinostat therapy is also associated with a risk of QT prolongation.
    Ziprasidone: (Major) Concomitant use of ziprasidone and lapatinib should be avoided due to a 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. Lapatinib has also been associated with concentration-dependent QT prolongation; ventricular arrhythmias and TdP have been reported in postmarketing experience with lapatinib.
    Zonisamide: (Moderate) Monitor for an increase in lapatinib-related adverse reactions if coadministration with zonisamide is necessary. Lapatinib is a P-glycoprotein (P-gp) substrate and zonisamide is a P-gp inhibitor. Increased plasma concentrations of lapatinib are likely.

    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.