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    Small Molecule Antineoplastic HER2/neu Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Oral kinase inhibitor targeting EGFR, HER2, and HER4
    Used for the extended adjuvant treatment of patients with early-stage HER2-positive breast cancer following adjuvant trastuzumab-based therapy, and for the treatment of metastatic HER2-positive breast cancer after at least 2 prior anti-HER2 based regimens in combination with capecitabine
    Antidiarrheal prophylaxis with loperamide recommended if starting at the maximum dosage; monitor for hepatotoxicity

    COMMON BRAND NAMES

    Nerlynx

    HOW SUPPLIED

    Nerlynx Oral Tab: 40mg

    DOSAGE & INDICATIONS

    For the treatment of breast cancer.
    For the extended adjuvant treatment of early-stage HER2-positive breast cancer, after completion of adjuvant trastuzumab-based therapy, as monotherapy.
    Oral dosage
    Adults

    240 mg PO once daily with food until disease recurrence or for up to 1 year. Alternatively, a 2-week dose escalation schedule may be given as follows: 120 mg PO once daily on days 1 to 7 (week 1), 160 mg PO once daily on days 8 to 14 (week 2), and 240 mg PO once daily starting on day 15 (week 3 and beyond). Coadministration of certain drugs may need to be avoided; review drug interactions. In patients starting neratinib at the maximum dosage of 240 mg/day, administer concomitant antidiarrheal prophylaxis with loperamide 4 mg PO three times daily on weeks 1 and 2 (days 1 to 14), then loperamide 4 mg PO twice daily on weeks 3 to 8 (days 15 to 56); beginning on day 57, give loperamide 4 mg PO as needed to achieve 1 to 2 bowel movements per day (maximum, 16 mg per day). Treatment with neratinib significantly improved the primary endpoint of 2-year invasive disease-free survival (iDFS) (94.2% vs. 91.9%) in a multicenter, randomized, double-blind, placebo-controlled clinical trial of patients with HER2-positive breast cancer after adjuvant treatment with trastuzumab (the ExteNET trial); the median time from the last adjuvant trastuzumab treatment to randomization was 4.4 months. After a median follow-up of 8 years, there was not a statistically significant difference in overall survival between arms; the estimated 5-year overall survival was 94.1% versus 93.3%, respectively.

    For the treatment of advanced or metastatic HER2-positive breast cancer in patients who have received 2 or more prior anti-HER2 based regimens in the metastatic setting, in combination with capecitabine.
    Oral dosage
    Adults

    240 mg PO once daily with food in combination with capecitabine (750 mg/m2 PO twice daily within 30 minutes after a meal on days 1 to 14 every 21 days) until disease progression or unacceptable toxicity. Alternatively, a 2-week neratinib dose escalation schedule may be given as follows: 120 mg PO once daily on days 1 to 7 (week 1), 160 mg PO once daily on days 8 to 14 (week 2), and 240 mg PO once daily starting on day 15 (week 3 and beyond). Coadministration of certain drugs may need to be avoided; review drug interactions. In patients starting neratinib at the maximum dosage of 240 mg/day, administer concomitant antidiarrheal prophylaxis with loperamide 4 mg PO three times daily on weeks 1 and 2 (days 1 to 14), then loperamide 4 mg PO twice daily on weeks 3 to 8 (days 15 to 56); beginning on day 57, give loperamide 4 mg PO as needed to achieve 1 to 2 bowel movements per day (maximum, 16 mg per day). Treatment with neratinib plus capecitabine significantly improved median progression-free survival (PFS) (5.6 months vs. 5.5 months) compared with lapatinib plus capecitabine in patients with metastatic HER2-positive breast cancer who had received at least 2 prior anti-HER2 based regimens in the metastatic setting in a randomized, open-label clinical trial (the NALA study). Rates of PFS were more durable in the neratinib plus capecitabine arm at 12 months (29% vs. 15%) and 24 months (12% vs. 3%). The objective response rate was 32.8% in the neratinib arm for a median duration of 8.5 months compared with 26.7% in the lapatinib arm for a median duration of 5.6 months. The median overall survival was 21 months versus 18.7 months, respectively.

    MAXIMUM DOSAGE

    Adults

    240 mg PO once daily.

    Geriatric

    240 mg PO once daily.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Baseline Hepatic Impairment:
    Mild to moderate hepatic impairment (Child-Pugh A or B): No dose adjustments are recommended.
    Severe hepatic impairment (Child-Pugh C): Reduce the starting dose of neratinib to 80 mg once daily.
     
    Treatment-Related Hepatotoxicity:
    Grade 3 elevations in ALT or AST (5 to 20 times the upper limit of normal (ULN)) or bilirubin (3 to 10 times ULN): Hold neratinib therapy and evaluate alternative causes. For the first occurrence, if liver function tests resolve to less than or equal to grade 1 (ALT less than or equal to 3 times ULN or bilirubin less than or equal to 1.5 times ULN) in three weeks or less, resume neratinib treatment at the next lower dose level. Discontinue neratinib treatment if hepatotoxicity does not recover to grade 1 or less, if hepatotoxicity results in a treatment delay of more than 3 weeks, or if grade 3 ALT, AST, or bilirubin recurs despite one dose reduction.
    Grade 4 elevations in ALT or AST (greater than 20 times ULN) or bilirubin (greater than 10 times ULN): Permanently discontinue neratinib treatment. Evaluate alternative causes of elevated liver function tests.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Emetic Risk
    Minimal/Low
    Administer prn antiemetics as necessary.

    Oral Administration

    Neratinib tablets should be taken with food at approximately the same time every day.
    Swallow tablets whole; do not chew, crush, or split.
    If a dose is missed, do not replace the missed dose. Resume neratinib with the next scheduled daily dose.
    Administer antidiarrheal prophylaxis during the first 56 days of treatment in patients who start therapy at the maximum dosage of 240 mg/day. Loperamide should be taken as directed below. Additional antidiarrheal agents may be required to manage patients with loperamide-refractory diarrhea.
    Weeks 1 to 2 (days 1 to 14): Take loperamide 4 mg PO three times daily.
    Weeks 3 to 8 (days 15 to 56): Take loperamide 4 mg PO twice daily.
    Weeks 9 (day 57) and beyond: Take loperamide 4 mg as needed (maximum, 16 mg per day); titrate to achieve 1 to 2 bowel movements per day.

    STORAGE

    Nerlynx:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Diarrhea

    Severe diarrhea and sequelae such as dehydration, hypotension, and renal failure have been reported with neratinib therapy. Using a 2-week neratinib dose escalation schedule may delay the onset, shorten the duration, and reduce the incidence of severe diarrhea. Additionally, antidiarrheal prophylaxis has been shown to lower the incidence and severity of diarrhea. In patients starting neratinib at the maximum dosage of 240 mg/day, prophylaxis with loperamide should begin with the first dose of neratinib and continue for the first 56 days of treatment; after day 56, titrate the dose of loperamide to achieve 1 to 2 bowel movements per day. Monitor patients for diarrhea and treat with additional antidiarrheals as needed. Treat severe diarrhea with additional antidiarrheals, fluids, and electrolytes as clinically indicated; an interruption of therapy or dose reduction may be necessary. Additionally, monitor liver function tests (including fractionated bilirubin and prothrombin time) if grade 3 diarrhea requiring IV fluid treatment occurs. Perform stool cultures as clinically indicated to exclude infectious causes of grade 3 or 4 diarrhea or diarrhea of any grade with complicating features.

    Hepatic disease, hepatotoxicity

    Use neratinib with caution in patients with pre-existing hepatic disease; a dose reduction is required for patients with severe (Child-Pugh C) hepatic impairment at baseline. Neratinib has been associated with hepatotoxicity in clinical trials, characterized by increased liver enzymes. Monitor liver function tests (LFTs) (e.g., total bilirubin, AST, ALT, and alkaline phosphatase) prior to starting therapy, every month for the first 3 months of treatment and then every 3 months and as clinically indicated thereafter. Additionally, monitor LFTs (including fractionated bilirubin and prothrombin time) in patients experiencing grade 3 diarrhea or with any signs of hepatotoxicity, including fatigue, nausea, vomiting, right upper quadrant tenderness, fever, rash, or eosinophilia.

    Geriatric

    Monitor geriatric patients (greater than or equal to 65 years; n = 172) more closely for neratinib-related toxicities. The incidence of serious neratinib-related adverse reactions was increased in these patients, occurring in 9.9% of patients age 65 and older compared with 7% of patients younger than age 65. The most common serious adverse reactions reported in patients older than 65 years included vomiting, diarrhea, renal failure, and dehydration. There was also a higher frequency of discontinuations of therapy due to adverse reactions in the geriatric age group compared to the younger age group (44.8% vs. 25.2%).

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during neratinib treatment and for at least 1 month after the last dose. Although there are no adequately controlled studies in pregnant women, neratinib 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 neratinib should be apprised of the potential hazard to the fetus. In animal reproduction studies, administration to pregnant rabbits during organogenesis caused abortions, embryofetal death, and fetal abnormalities (domed head, dilation of brain ventricles and ventricular septal defect, misshapen anterior fontanelles, enlarged anterior and/or posterior fontanelles) at maternal AUCs approximately 0.2 times those achieved in patients receiving the recommended dose. Neratinib did not cause embryonic toxicity in rats at doses up to 0.5 to 0.6 times the maximum recommended dose on a mg/m2 basis.

    Contraception requirements, infertility, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during neratinib treatment. Neratinib can be teratogenic if taken by the mother during pregnancy. Females should avoid pregnancy and use effective contraception during and for at least 1 month after treatment with neratinib. Males with female partners of reproductive potential should avoid pregnancy and use effective contraception during and for at least 3 months after the last dose of neratinib. Females of reproductive potential should undergo pregnancy testing prior to initiation of neratinib. Women who become pregnant while receiving neratinib should be apprised of the potential hazard to the fetus. Although there are no data regarding the effect of neratinib on human fertility, female fertility was not affected in animal studies. Male infertility was observed in dogs (tubular hypoplasia of the testes) at exposures approximately 0.4 times the AUC in patients at the recommended dose, but was not observed in rats at a similar level of exposure.

    Breast-feeding

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

    ADVERSE REACTIONS

    Severe

    diarrhea / Early / 13.0-40.1
    vomiting / Early / 3.0-3.0
    nausea / Early / 2.0-2.0
    fatigue / Early / 2.0-2.0
    abdominal pain / Early / 2.0-2.0
    elevated hepatic enzymes / Delayed / 0.7-1.7
    dehydration / Delayed / 0-1.0
    rash / Early / 0.6-0.6
    stomatitis / Delayed / 0.6-0.6
    dyspepsia / Early / 0.4-0.4
    renal failure (unspecified) / Delayed / 0-0.4
    infection / Delayed / 0.1-0.4
    anorexia / Delayed / 0.2-0.2
    muscle cramps / Delayed / 0.1-0.1
    weight loss / Delayed / 0.1-0.1
    hepatotoxicity / Delayed / Incidence not known

    Moderate

    hypotension / Rapid / Incidence not known
    eosinophilia / Delayed / Incidence not known
    hyperbilirubinemia / Delayed / Incidence not known
    dysuria / Early / Incidence not known
    constipation / Delayed / Incidence not known
    glossitis / Early / Incidence not known
    oral ulceration / Delayed / Incidence not known

    Mild

    xerosis / Delayed / 6.0-6.0
    epistaxis / Delayed / 5.0-5.0
    fever / Early / Incidence not known
    nail discoloration / Delayed / Incidence not known
    acneiform rash / Delayed / Incidence not known
    maculopapular rash / Early / Incidence not known
    asthenia / Delayed / Incidence not known
    malaise / Early / Incidence not known
    arthralgia / Delayed / Incidence not known
    back pain / Delayed / Incidence not known
    influenza / Delayed / Incidence not known
    cheilitis / Delayed / Incidence not known
    xerostomia / Early / Incidence not known
    dizziness / Early / Incidence not known

    DRUG INTERACTIONS

    Abacavir; Dolutegravir; Lamivudine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with neratinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-glycoprotein (P-gp) substrate and neratinib is a P-gp inhibitor.
    Adagrasib: (Major) Avoid concomitant use of adagrasib with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A may also increase neratinib concentrations.
    Afatinib: (Moderate) If the concomitant use of neratinib 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 neratinib. 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 neratinib 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.
    Aluminum Hydroxide: (Major) Administer neratinib at least 3 hours after administration of antacids if concomitant use is necessary due to decreased absorption and systemic exposure of neratinib; the solubility of neratinib decreases with increasing pH of the GI tract. The efficacy of neratinib may be decreased.
    Aluminum Hydroxide; Magnesium Carbonate: (Major) Administer neratinib at least 3 hours after administration of antacids if concomitant use is necessary due to decreased absorption and systemic exposure of neratinib; the solubility of neratinib decreases with increasing pH of the GI tract. The efficacy of neratinib may be decreased.
    Aluminum Hydroxide; Magnesium Hydroxide: (Major) Administer neratinib at least 3 hours after administration of antacids if concomitant use is necessary due to decreased absorption and systemic exposure of neratinib; the solubility of neratinib decreases with increasing pH of the GI tract. The efficacy of neratinib may be decreased.
    Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Major) Administer neratinib at least 3 hours after administration of antacids if concomitant use is necessary due to decreased absorption and systemic exposure of neratinib; the solubility of neratinib decreases with increasing pH of the GI tract. The efficacy of neratinib may be decreased.
    Aluminum Hydroxide; Magnesium Trisilicate: (Major) Administer neratinib at least 3 hours after administration of antacids if concomitant use is necessary due to decreased absorption and systemic exposure of neratinib; the solubility of neratinib decreases with increasing pH of the GI tract. The efficacy of neratinib may be decreased.
    Amiodarone: (Major) Avoid concomitant use of amiodarone with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and amiodarone is a dual moderate CYP3A4/P-glycoprotein (P-gp) inhibitor. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that another dual moderate CYP3A4/P-gp inhibitor may increase neratinib exposure by 299%.
    Amlodipine; Atorvastatin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with neratinib is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp substrate; neratinib is a P-gp inhibitor.
    Amobarbital: (Major) Avoid concomitant use of amobarbital with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and amobarbital is a moderate CYP3A4 inducer. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that another moderate CYP3A4 inducer may decrease neratinib exposure by 52%.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid concomitant use of clarithromycin with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations. (Major) Avoid concomitant use of neratinib with proton pump inhibitors due to decreased absorption and systemic exposure of neratinib; the solubility of neratinib decreases with increasing pH of the GI tract. Concomitant use with lansoprazole decreased neratinib exposure by 65%.
    Antacids: (Major) Administer neratinib at least 3 hours after administration of antacids if concomitant use is necessary due to decreased absorption and systemic exposure of neratinib; the solubility of neratinib decreases with increasing pH of the GI tract. The efficacy of neratinib may be decreased.
    Apalutamide: (Major) Avoid concomitant use of apalutamide with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased neratinib exposure by 87%, while exposure to active metabolites M6 and M7 were reduced by 37% to 49%.
    Aprepitant, Fosaprepitant: (Major) Avoid concomitant use of aprepitant with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and aprepitant is a moderate CYP3A4 inhibitor. The effect of moderate CYP3A4 inhibition on neratinib concentrations has not been studied; however, coadministration with a strong CYP3A4 inhibitor increased neratinib exposure by 481%. Because of the significant impact on neratinib exposure from strong CYP3A4 inhibition, the potential impact on neratinib safety from concomitant use with moderate CYP3A4 inhibitors should be considered as they may also significantly increase neratinib exposure.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Avoid concomitant use of butalbital with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and butalbital is a moderate CYP3A4 inducer. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that another moderate CYP3A4 inducer may decrease neratinib exposure by 52%.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Avoid concomitant use of butalbital with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and butalbital is a moderate CYP3A4 inducer. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that another moderate CYP3A4 inducer may decrease neratinib exposure by 52%.
    Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Major) Administer neratinib at least 3 hours after administration of sodium bicarbonate if concomitant use is necessary due to decreased absorption and systemic exposure of neratinib; the solubility of neratinib decreases with increasing pH of the GI tract.
    Aspirin, ASA; Omeprazole: (Major) Avoid concomitant use of neratinib with proton pump inhibitors due to decreased absorption and systemic exposure of neratinib; the solubility of neratinib decreases with increasing pH of the GI tract. Concomitant use with lansoprazole decreased neratinib exposure by 65%.
    Atazanavir: (Major) Avoid concomitant use of atazanavir with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and atazanavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations.
    Atazanavir; Cobicistat: (Major) Avoid concomitant use of atazanavir with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and atazanavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations. (Major) Avoid concomitant use of cobicistat with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations.
    Atorvastatin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with neratinib is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp substrate; neratinib is a P-gp inhibitor.
    Atorvastatin; Ezetimibe: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with neratinib is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp substrate; neratinib is a P-gp inhibitor.
    Berotralstat: (Major) Avoid concomitant use of berotralstat with neratinib due to an increased risk of neratinib-related toxicity. The exposure of berotralstat may also be increased. If combination use is unavoidable, reduce the dose of berotralstat to 110 mg once daily and monitor patients closely for toxicity. Neratinib is a CYP3A4 substrate and P-gp inhibitor and berotralstat is a dual moderate CYP3A4/P-glycoprotein (P-gp) inhibitor. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that another dual moderate CYP3A4/P-gp inhibitor may increase neratinib exposure by 299%.
    Betrixaban: (Major) Avoid betrixaban use in patients with severe renal impairment receiving neratinib. Reduce betrixaban dosage to 80 mg PO once followed by 40 mg PO once daily in all other patients receiving neratinib. 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-glycoprotein (P-gp) substrate; neratinib is a P-gp inhibitor. Coadministration of other P-gp inhibitors increased betrixaban exposure by 2 to 3-fold.
    Bexarotene: (Major) Avoid concomitant use of bexarotene with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and bexarotene is a moderate CYP3A4 inducer. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that another moderate CYP3A4 inducer may decrease neratinib exposure by 52%.
    Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with neratinib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-glycoprotein (P-gp) substrate and neratinib is a P-gp inhibitor.
    Bosentan: (Major) Avoid concomitant use of bosentan with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that another moderate CYP3A4 inducer may decrease neratinib exposure by 52%.
    Butabarbital: (Major) Avoid concomitant use of butabarbital with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and butabarbital is a moderate CYP3A4 inducer. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that another moderate CYP3A4 inducer may decrease neratinib exposure by 52%.
    Butalbital; Acetaminophen: (Major) Avoid concomitant use of butalbital with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and butalbital is a moderate CYP3A4 inducer. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that another moderate CYP3A4 inducer may decrease neratinib exposure by 52%.
    Butalbital; Acetaminophen; Caffeine: (Major) Avoid concomitant use of butalbital with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and butalbital is a moderate CYP3A4 inducer. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that another moderate CYP3A4 inducer may decrease neratinib exposure by 52%.
    Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Avoid concomitant use of butalbital with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and butalbital is a moderate CYP3A4 inducer. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that another moderate CYP3A4 inducer may decrease neratinib exposure by 52%.
    Calcium Carbonate: (Major) Administer neratinib at least 3 hours after administration of calcium carbonate if concomitant use is necessary due to decreased absorption and systemic exposure of neratinib; the solubility of neratinib decreases with increasing pH of the GI tract.
    Calcium Carbonate; Famotidine; Magnesium Hydroxide: (Major) Administer neratinib at least 3 hours after administration of calcium carbonate if concomitant use is necessary due to decreased absorption and systemic exposure of neratinib; the solubility of neratinib decreases with increasing pH of the GI tract. (Major) Take neratinib at least 2 hours before the next dose of an H2-blocker or 10 hours after the last dose of an H2-blocker due to decreased absorption and systemic exposure of neratinib; the solubility of neratinib decreases with increasing pH of the GI tract. The Cmax and AUC of neratinib were reduced by 57% and 48%, respectively, when administered 2 hours after a daily dose of ranitidine 300 mg. The Cmax and AUC of neratinib were reduced by 44% and 32%, respectively, when administered 2 hours before ranitidine 150 mg twice daily (given approximately 12 hours apart).
    Calcium Carbonate; Magnesium Hydroxide: (Major) Administer neratinib at least 3 hours after administration of calcium carbonate if concomitant use is necessary due to decreased absorption and systemic exposure of neratinib; the solubility of neratinib decreases with increasing pH of the GI tract.
    Calcium Carbonate; Magnesium Hydroxide; Simethicone: (Major) Administer neratinib at least 3 hours after administration of calcium carbonate if concomitant use is necessary due to decreased absorption and systemic exposure of neratinib; the solubility of neratinib decreases with increasing pH of the GI tract.
    Calcium Carbonate; Risedronate: (Major) Administer neratinib at least 3 hours after administration of calcium carbonate if concomitant use is necessary due to decreased absorption and systemic exposure of neratinib; the solubility of neratinib decreases with increasing pH of the GI tract.
    Calcium Carbonate; Simethicone: (Major) Administer neratinib at least 3 hours after administration of calcium carbonate if concomitant use is necessary due to decreased absorption and systemic exposure of neratinib; the solubility of neratinib decreases with increasing pH of the GI tract.
    Calcium; Vitamin D: (Major) Administer neratinib at least 3 hours after administration of calcium carbonate if concomitant use is necessary due to decreased absorption and systemic exposure of neratinib; the solubility of neratinib decreases with increasing pH of the GI tract.
    Carbamazepine: (Major) Avoid concomitant use of carbamazepine with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and carbamazepine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased neratinib exposure by 87%, while exposure to active metabolites M6 and M7 were reduced by 37% to 49%. Concomitant use with other strong inducers of CYP3A4 may also decrease neratinib concentrations.
    Cenobamate: (Major) Avoid concomitant use of cenobamate with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that another moderate CYP3A4 inducer may decrease neratinib exposure by 52%.
    Ceritinib: (Major) Avoid concomitant use of ceritinib with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations.
    Chloramphenicol: (Major) Avoid concomitant use of chloramphenicol with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and chloramphenicol is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations.
    Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
    Cimetidine: (Major) Take neratinib at least 2 hours before the next dose of an H2-blocker or 10 hours after the last dose of an H2-blocker due to decreased absorption and systemic exposure of neratinib; the solubility of neratinib decreases with increasing pH of the GI tract. The Cmax and AUC of neratinib were reduced by 57% and 48%, respectively, when administered 2 hours after a daily dose of ranitidine 300 mg. The Cmax and AUC of neratinib were reduced by 44% and 32%, respectively, when administered 2 hours before ranitidine 150 mg twice daily (given approximately 12 hours apart).
    Ciprofloxacin: (Major) Avoid concomitant use of ciprofloxacin with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and ciprofloxacin is a moderate CYP3A4 inhibitor. The effect of moderate CYP3A4 inhibition on neratinib concentrations has not been studied; however, coadministration with a strong CYP3A4 inhibitor increased neratinib exposure by 481%. Because of the significant impact on neratinib exposure from strong CYP3A4 inhibition, the potential impact on neratinib safety from concomitant use with moderate CYP3A4 inhibitors should be considered as they may also significantly increase neratinib exposure.
    Clarithromycin: (Major) Avoid concomitant use of clarithromycin with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations.
    Cobicistat: (Major) Avoid concomitant use of cobicistat with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations.
    Cobimetinib: (Moderate) Monitor for an increase in cobimetinib-related adverse reactions if coadministration with neratinib is necessary. In vitro, cobimetinib is a P-glycoprotein (P-gp) substrate; drugs that inhibit P-gp may increase cobimetinib concentrations. Neratinib is a P-gp inhibitor.
    Colchicine: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and neratinib 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. Neratinib can inhibit colchicine's metabolism via P-glycoprotein (P-gp), 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 a P-gp inhibitor like neratinib 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 concomitant use of conivaptan with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A substrate and conivaptan is a dual moderate CYP3A/P-gp inhibitor. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that another dual moderate CYP3A/P-gp inhibitor may increase neratinib exposure by 299%.
    Crizotinib: (Major) Avoid concomitant use of crizotinib with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor. The effect of moderate CYP3A4 inhibition on neratinib concentrations has not been studied; however, coadministration with a strong CYP3A4 inhibitor increased neratinib exposure by 481%. Because of the significant impact on neratinib exposure from strong CYP3A4 inhibition, the potential impact on neratinib safety from concomitant use with moderate CYP3A4 inhibitors should be considered as they may also significantly increase neratinib exposure.
    Cyclosporine: (Major) Avoid concomitant use of cyclosporine with neratinib due to an increased risk of neratinib-related toxicity; cyclosporine exposure may also increase. Neratinib is a CYP3A4 substrate and cyclosporine is a dual moderate CYP3A4/P-glycoprotein (P-gp) inhibitor. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that another dual moderate CYP3A4/P-gp inhibitor may increase neratinib exposure by 299%.
    Dabigatran: (Moderate) Monitor for an increase in dabigatran-related adverse reactions if coadministration with neratinib is necessary in patients with creatinine clearance (CrCl) greater than 50 mL/minute. Avoid coadministration 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 in patients with CrCl less than 30 mL/minute in patients with non-valvular atrial fibrillation. Serum concentrations of dabigatran are expected to be higher in patients with renal impairment compared to patients with normal renal function. Dabigatran is a P-glycoprotein (P-gp) substrate and neratinib is a P-gp inhibitor.
    Dabrafenib: (Major) Avoid concomitant use of dabrafenib with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and dabrafenib is a moderate CYP3A4 inducer. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that another moderate CYP3A4 inducer may decrease neratinib exposure by 52%.
    Danazol: (Major) Avoid concomitant use of danazol with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and danazol is a moderate CYP3A4 inhibitor. The effect of moderate CYP3A4 inhibition on neratinib concentrations has not been studied; however, coadministration with a strong CYP3A4 inhibitor increased neratinib exposure by 481%. Because of the significant impact on neratinib exposure from strong CYP3A4 inhibition, the potential impact on neratinib safety from concomitant use with moderate CYP3A4 inhibitors should be considered as they may also significantly increase neratinib exposure.
    Darunavir: (Major) Avoid concomitant use of darunavir with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations.
    Darunavir; Cobicistat: (Major) Avoid concomitant use of cobicistat with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations. (Major) Avoid concomitant use of darunavir with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid concomitant use of cobicistat with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations. (Major) Avoid concomitant use of darunavir with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations. (Moderate) Coadministration of tenofovir alafenamide with neratinib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-glycoprotein (P-gp) substrate and neratinib is a P-gp inhibitor.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid concomitant use of ritonavir with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations. (Moderate) Monitor for an increase in ombitasvir-related adverse reactions if coadministration with neratinib is necessary. Concurrent use may increase ombitasvir exposure. Ombitasvir is a P-glycoprotein (P-gp) substrate and neratinib is a P-gp inhibitor. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with neratinib is necessary. Paritaprevir is a P-glycoprotein (P-gp) substrate. Neratinib is a P-gp inhibitor. (Moderate) Monitor for increased dasabuvir-related adverse reactions, including QT prolongation, if coadministered with neratinib. Concurrent use may increase dasabuvir exposure. Dasabuvir is a P-glycoprotein (P-gp) substrate and neratinib is a P-gp inhibitor.
    Deferasirox: (Major) Avoid concomitant use of deferasirox with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and deferasirox is a moderate CYP3A4 inducer. The effect of moderate CYP3A4 induction on neratinib concentrations has not been studied; however, coadministration with a strong CYP3A4 inducer decreased neratinib exposure by 87% and decreased exposure to active metabolites M6 and M7 by 37% to 49%. Because of the significant impact on neratinib exposure from strong CYP3A4 induction, the potential impact on neratinib efficacy from concomitant use with moderate CYP3A4 inducers should be considered as they may also significantly decrease neratinib exposure.
    Delavirdine: (Major) Avoid concomitant use of delavirdine with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and delavirdine is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations.
    Dexamethasone: (Major) Avoid concomitant use dexamethasone with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and dexamethasone is a moderate CYP3A4 inducer. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that another moderate CYP3A4 inducer may decrease neratinib exposure by 52%.
    Dexlansoprazole: (Major) Avoid concomitant use of neratinib with proton pump inhibitors due to decreased absorption and systemic exposure of neratinib; the solubility of neratinib decreases with increasing pH of the GI tract. Concomitant use with lansoprazole decreased neratinib exposure by 65%.
    Digoxin: (Moderate) Increase monitoring of serum digoxin concentrations and watch for potential signs and symptoms of clinical toxicity when starting, adjusting, or discontinuing neratinib. Concurrent use may increase digoxin exposure. Digoxin is a P-glycoprotein (P-gp) substrate with a narrow therapeutic index and neratinib is a P-gp inhibitor. Coadministration with neratinib increased the mean Cmax and AUC of digoxin by 54% and 32%, respectively.
    Diltiazem: (Major) Avoid concomitant use of diltiazem with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and diltiazem is a moderate CYP3A4 inhibitor. The effect of moderate CYP3A4 inhibition on neratinib concentrations has not been studied; however, coadministration with a strong CYP3A4 inhibitor increased neratinib exposure by 481%. Because of the significant impact on neratinib exposure from strong CYP3A4 inhibition, the potential impact on neratinib safety from concomitant use with moderate CYP3A4 inhibitors should be considered as they may also significantly increase neratinib exposure.
    Dolutegravir: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with neratinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-glycoprotein (P-gp) substrate and neratinib is a P-gp inhibitor.
    Dolutegravir; Lamivudine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with neratinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-glycoprotein (P-gp) substrate and neratinib is a P-gp inhibitor.
    Dolutegravir; Rilpivirine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with neratinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-glycoprotein (P-gp) substrate and neratinib is a P-gp inhibitor.
    Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with neratinib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-glycoprotein (P-gp) substrate and neratinib is a P-gp inhibitor.
    Doxorubicin Liposomal: (Major) Avoid coadministration of neratinib with doxorubicin due to the risk for increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Neratinib is a P-glycoprotein (P-gp) inhibitor and doxorubicin is a P-gp substrate. Concurrent use of P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    Doxorubicin: (Major) Avoid coadministration of neratinib with doxorubicin due to the risk for increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Neratinib is a P-glycoprotein (P-gp) inhibitor and doxorubicin is a P-gp substrate. Concurrent use of P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    Dronedarone: (Major) Avoid concomitant use of dronedarone with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and dronedarone is a dual moderate CYP3A4/P-glycoprotein (P-gp) inhibitor. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that another dual moderate CYP3A4/P-gp inhibitor may increase neratinib exposure by 299%.
    Duvelisib: (Major) Avoid concomitant use of duvelisib with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and duvelisib is a moderate CYP3A4 inhibitor. The effect of moderate CYP3A4 inhibition on neratinib concentrations has not been studied; however, coadministration with a strong CYP3A4 inhibitor increased neratinib exposure by 481%. Because of the significant impact on neratinib exposure from strong CYP3A4 inhibition, the potential impact on neratinib safety from concomitant use with moderate CYP3A4 inhibitors should be considered as they may also significantly increase neratinib exposure.
    Edoxaban: (Major) If coadministered with neratinib, 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 neratinib. Based on clinical experience in patients with non-valvular atrial fibrillation no dose reduction is recommended for concomitant use of neratinib. Increased concentrations of edoxaban may occur during concomitant use of neratinib; monitor for increased adverse effects of edoxaban.
    Efavirenz: (Major) Avoid concomitant use of efavirenz with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that efavirenz may decrease neratinib exposure by 52%.
    Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid concomitant use of efavirenz with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that efavirenz may decrease neratinib exposure by 52%. (Moderate) Coadministration of tenofovir disoproxil fumarate with neratinib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-glycoprotein (P-gp) substrate and neratinib is a P-gp inhibitor.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Avoid concomitant use of efavirenz with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that efavirenz may decrease neratinib exposure by 52%. (Moderate) Coadministration of tenofovir disoproxil fumarate with neratinib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-glycoprotein (P-gp) substrate and neratinib is a P-gp inhibitor.
    Elagolix: (Major) Avoid concomitant use of elagolix with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and elagolix is a moderate CYP3A4 inducer. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that another moderate CYP3A4 inducer may decrease neratinib exposure by 52%.
    Elagolix; Estradiol; Norethindrone acetate: (Major) Avoid concomitant use of elagolix with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and elagolix is a moderate CYP3A4 inducer. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that another moderate CYP3A4 inducer may decrease neratinib exposure by 52%.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid concomitant use of cobicistat with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations. (Moderate) Coadministration of tenofovir alafenamide with neratinib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-glycoprotein (P-gp) substrate and neratinib is a P-gp inhibitor.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid concomitant use of cobicistat with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations. (Moderate) Coadministration of tenofovir disoproxil fumarate with neratinib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-glycoprotein (P-gp) substrate and neratinib is a P-gp inhibitor.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Coadministration of tenofovir alafenamide with neratinib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-glycoprotein (P-gp) substrate and neratinib is a P-gp inhibitor.
    Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with neratinib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-glycoprotein (P-gp) substrate and neratinib is a P-gp inhibitor.
    Emtricitabine; Tenofovir alafenamide: (Moderate) Coadministration of tenofovir alafenamide with neratinib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-glycoprotein (P-gp) substrate and neratinib is a P-gp inhibitor.
    Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with neratinib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-glycoprotein (P-gp) substrate and neratinib is a P-gp inhibitor.
    Enzalutamide: (Major) Avoid concomitant use of enzalutamide with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased neratinib exposure by 87%, while exposure to active metabolites M6 and M7 were reduced by 37% to 49%. Concomitant use with other strong inducers of CYP3A4 may also decrease neratinib concentrations.
    Erythromycin: (Major) Avoid concomitant use of erythromycin with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and erythromycin is a dual moderate CYP3A4/P-glycoprotein (P-gp) inhibitor. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that another dual moderate CYP3A4/P-gp inhibitor may increase neratinib exposure by 299%.
    Eslicarbazepine: (Major) Avoid concomitant use of eslicarbazepine with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and eslicarbazepine is a moderate CYP3A4 inducer. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that another moderate CYP3A4 inducer may decrease neratinib exposure by 52%.
    Esomeprazole: (Major) Avoid concomitant use of neratinib with proton pump inhibitors due to decreased absorption and systemic exposure of neratinib; the solubility of neratinib decreases with increasing pH of the GI tract. Concomitant use with lansoprazole decreased neratinib exposure by 65%.
    Etravirine: (Major) Avoid concomitant use of etravirine with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and etravirine is a moderate CYP3A4 inducer. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that another moderate CYP3A4 inducer may decrease neratinib exposure by 52%.
    Everolimus: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with neratinib is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate and neratinib is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
    Ezetimibe; Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with neratinib is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-glycoprotein (P-gp) substrate; neratinib is a P-gp inhibitor.
    Famotidine: (Major) Take neratinib at least 2 hours before the next dose of an H2-blocker or 10 hours after the last dose of an H2-blocker due to decreased absorption and systemic exposure of neratinib; the solubility of neratinib decreases with increasing pH of the GI tract. The Cmax and AUC of neratinib were reduced by 57% and 48%, respectively, when administered 2 hours after a daily dose of ranitidine 300 mg. The Cmax and AUC of neratinib were reduced by 44% and 32%, respectively, when administered 2 hours before ranitidine 150 mg twice daily (given approximately 12 hours apart).
    Fedratinib: (Major) Avoid concomitant use of fedratinib with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and fedratinib is a moderate CYP3A4 inhibitor. The effect of moderate CYP3A4 inhibition on neratinib concentrations has not been studied; however, coadministration with a strong CYP3A4 inhibitor increased neratinib exposure by 481%. Because of the significant impact on neratinib exposure from strong CYP3A4 inhibition, the potential impact on neratinib safety from concomitant use with moderate CYP3A4 inhibitors should be considered as they may also significantly increase neratinib exposure.
    Fluconazole: (Major) Avoid concomitant use of fluconazole with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and fluconazole is a moderate CYP3A4 inhibitor. The effect of moderate CYP3A4 inhibition on neratinib concentrations has not been studied; however, coadministration with a strong CYP3A4 inhibitor increased neratinib exposure by 481%. Because of the significant impact on neratinib exposure from strong CYP3A4 inhibition, the potential impact on neratinib safety from concomitant use with moderate CYP3A4 inhibitors should be considered as they may also significantly increase neratinib exposure.
    Fluvoxamine: (Major) Avoid concomitant use of fluvoxamine with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and fluvoxamine is a moderate CYP3A4 inhibitor. Coadministration of neratinib with a strong CYP3A4 inhibitor increased neratinib exposure by 481%; concomitant use with moderate inhibitors of CYP3A4 may also increase neratinib concentrations.
    Fosamprenavir: (Major) Avoid concomitant use of fosamprenavir with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and fosamprenavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations.
    Fosphenytoin: (Major) Avoid concomitant use of fosphenytoin with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and fosphenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased neratinib exposure by 87%, while exposure to active metabolites M6 and M7 were reduced by 37% to 49%. Concomitant use with other strong inducers of CYP3A4 may also decrease neratinib concentrations.
    Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and neratinib as coadministration may increase serum concentrations of glecaprevir and increase the risk of adverse effects. Glecaprevir is a substrate of P-glycoprotein (P-gp); neratinib is a P-gp inhibitor. (Moderate) Caution is advised with the coadministration of pibrentasvir and neratinib as coadministration may increase serum concentrations of pibrentasvir and increase the risk of adverse effects. Pibrentasvir is a substrate of P-glycoprotein (P-gp); neratinib is an inhibitor of P-gp.
    Grapefruit juice: (Major) Have patients avoid grapefruit or grapefruit juice during neratinib treatment due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and grapefruit juice is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 481%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations.
    H2-blockers: (Major) Take neratinib at least 2 hours before the next dose of an H2-blocker or 10 hours after the last dose of an H2-blocker due to decreased absorption and systemic exposure of neratinib; the solubility of neratinib decreases with increasing pH of the GI tract. The Cmax and AUC of neratinib were reduced by 57% and 48%, respectively, when administered 2 hours after a daily dose of ranitidine 300 mg. The Cmax and AUC of neratinib were reduced by 44% and 32%, respectively, when administered 2 hours before ranitidine 150 mg twice daily (given approximately 12 hours apart).
    Ibuprofen; Famotidine: (Major) Take neratinib at least 2 hours before the next dose of an H2-blocker or 10 hours after the last dose of an H2-blocker due to decreased absorption and systemic exposure of neratinib; the solubility of neratinib decreases with increasing pH of the GI tract. The Cmax and AUC of neratinib were reduced by 57% and 48%, respectively, when administered 2 hours after a daily dose of ranitidine 300 mg. The Cmax and AUC of neratinib were reduced by 44% and 32%, respectively, when administered 2 hours before ranitidine 150 mg twice daily (given approximately 12 hours apart).
    Idelalisib: (Major) Avoid concomitant use of idelalisib with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and idelalisib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations.
    Imatinib: (Major) Avoid concomitant use of imatinib with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and imatinib is a moderate CYP3A4 inhibitor. The effect of moderate CYP3A4 inhibition on neratinib concentrations has not been studied; however, coadministration with a strong CYP3A4 inhibitor increased neratinib exposure by 481%. Because of the significant impact on neratinib exposure from strong CYP3A4 inhibition, the potential impact on neratinib safety from concomitant use with moderate CYP3A4 inhibitors should be considered as they may also significantly increase neratinib exposure.
    Indinavir: (Major) Avoid concomitant use of indinavir with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and indinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations.
    Isavuconazonium: (Major) Avoid concomitant use of isavuconazonium with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and isavuconazonium is a dual moderate CYP3A4/P-glycoprotein (P-gp) inhibitor. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that another dual moderate CYP3A4/P-gp inhibitor may increase neratinib exposure by 299%.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid concomitant use of rifampin with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased neratinib exposure by 87%, while exposure to active metabolites M6 and M7 were reduced by 37% to 49%.
    Isoniazid, INH; Rifampin: (Major) Avoid concomitant use of rifampin with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased neratinib exposure by 87%, while exposure to active metabolites M6 and M7 were reduced by 37% to 49%.
    Itraconazole: (Major) Avoid concomitant use of itraconazole with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and itraconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations.
    Ketoconazole: (Major) Avoid concomitant use of ketoconazole with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased neratinib exposure by 381%.
    Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with neratinib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-glycoprotein (P-gp) substrate and neratinib is a P-gp inhibitor.
    Lansoprazole: (Major) Avoid concomitant use of neratinib with proton pump inhibitors due to decreased absorption and systemic exposure of neratinib; the solubility of neratinib decreases with increasing pH of the GI tract. Concomitant use with lansoprazole decreased neratinib exposure by 65%.
    Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid concomitant use of clarithromycin with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations. (Major) Avoid concomitant use of neratinib with proton pump inhibitors due to decreased absorption and systemic exposure of neratinib; the solubility of neratinib decreases with increasing pH of the GI tract. Concomitant use with lansoprazole decreased neratinib exposure by 65%.
    Lansoprazole; Naproxen: (Major) Avoid concomitant use of neratinib with proton pump inhibitors due to decreased absorption and systemic exposure of neratinib; the solubility of neratinib decreases with increasing pH of the GI tract. Concomitant use with lansoprazole decreased neratinib exposure by 65%.
    Lapatinib: (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.
    Lefamulin: (Major) Avoid coadministration of neratinib with oral lefamulin unless the benefits outweigh the risks as concurrent use may increase lefamulin exposure and adverse effects; neratinib may be administered with intravenous lefamulin. Lefamulin is a P-gp substrate and neratinib is a P-gp inhibitor.
    Lenacapavir: (Major) Avoid concomitant use of lenacapavir with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A substrate and lenacapavir is a dual moderate CYP3A/P-gp inhibitor. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that another dual moderate CYP3A/P-gp inhibitor may increase neratinib exposure by 299%.
    Letermovir: (Major) Avoid concomitant use of letermovir with neratinib in patients who are also receiving treatment with cyclosporine due to an increased risk of neratinib-related toxicity; an interaction is not expected in patients tatking letermovir without cyclosporine. Neratinib is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations.
    Levoketoconazole: (Major) Avoid concomitant use of ketoconazole with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased neratinib exposure by 381%.
    Lonafarnib: (Major) Avoid concomitant use of lonafarnib with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations.
    Loperamide: (Moderate) Monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest), if coadministered with neratinib. Concurrent use may increase loperamide exposure. Loperamide is a P-gp substrate and neratinib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased loperamide plasma concentrations by 2- to 3-fold.
    Loperamide; Simethicone: (Moderate) Monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest), if coadministered with neratinib. Concurrent use may increase loperamide exposure. Loperamide is a P-gp substrate and neratinib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased loperamide plasma concentrations by 2- to 3-fold.
    Lopinavir; Ritonavir: (Major) Avoid concomitant use of ritonavir with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations.
    Lorlatinib: (Major) Avoid concomitant use of lorlatinib with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that another moderate CYP3A4 inducer may decrease neratinib exposure by 52%.
    Lovastatin: (Moderate) Monitor for an increase in lovastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with neratinib is necessary. Concomitant use may increase lovastatin exposure. Lovastatin is a substrate of P-gp; neratinib is an inhibitor of P-gp.
    Lovastatin; Niacin: (Moderate) Monitor for an increase in lovastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with neratinib is necessary. Concomitant use may increase lovastatin exposure. Lovastatin is a substrate of P-gp; neratinib is an inhibitor of P-gp.
    Lumacaftor; Ivacaftor: (Major) Avoid concomitant use of lumacaftor; ivacaftor with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased neratinib exposure by 87%, while exposure to active metabolites M6 and M7 were reduced by 37% to 49%. Concomitant use with other strong inducers of CYP3A4 may also decrease neratinib concentrations.
    Lumacaftor; Ivacaftor: (Major) Avoid concomitant use of lumacaftor; ivacaftor with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased neratinib exposure by 87%, while exposure to active metabolites M6 and M7 were reduced by 37% to 49%. Concomitant use with other strong inducers of CYP3A4 may also decrease neratinib concentrations.
    Magnesium Hydroxide: (Major) Administer neratinib at least 3 hours after administration of antacids if concomitant use is necessary due to decreased absorption and systemic exposure of neratinib; the solubility of neratinib decreases with increasing pH of the GI tract. The efficacy of neratinib may be decreased.
    Maraviroc: (Moderate) Monitor for an increase in maraviroc-related adverse reactions if coadministration with neratinib is necessary. Concurrent use may increase the plasma concentrations of maraviroc. Maraviroc is a P-glycoprotein (P-gp) substrate; neratinib is a P-gp inhibitor.
    Mavacamten: (Major) Avoid concomitant use of mavacamten with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A substrate and mavacamten is a moderate CYP3A inducer. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that another moderate CYP3A inducer may decrease neratinib exposure by 52%.
    Mefloquine: (Moderate) Use mefloquine with caution if coadministration with neratinib is necessary as concurrent use may increase mefloquine exposure and mefloquine-related adverse events. Mefloquine is a P-glycoprotein (P-gp) substrate and neratinib is a P-gp inhibitor.
    Methohexital: (Major) Avoid concomitant use of methohexital with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and methohexital is a moderate CYP3A4 inducer. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that another moderate CYP3A4 inducer may decrease neratinib exposure by 52%.
    Mifepristone: (Major) Avoid concomitant use of mifepristone with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and mifepristone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations. The clinical significance of this interaction with the short-term use of mifepristone for termination of pregnancy is unknown.
    Mitotane: (Major) Avoid concomitant use of mitotane with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased neratinib exposure by 87%, while exposure to active metabolites M6 and M7 were reduced by 37% to 49%. Concomitant use with other strong inducers of CYP3A4 may also decrease neratinib concentrations.
    Modafinil: (Major) Avoid concomitant use of modafinil with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and modafinil is a moderate CYP3A4 inducer. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that another moderate CYP3A4 inducer may decrease neratinib exposure by 52%.
    Morphine: (Moderate) Monitor for an increase in morphine-related adverse reactions including hypotension, sedation, and respiratory depression if coadministration with neratinib is necessary. Decrease the dose of morphine as necessary. Morphine is a P-glycoprotein (P-gp) substrate. Neratinib is a P-gp inhibitor. Concomitant use of P-gp inhibitors can increase morphine exposure by approximately 2-fold.
    Morphine; Naltrexone: (Moderate) Monitor for an increase in morphine-related adverse reactions including hypotension, sedation, and respiratory depression if coadministration with neratinib is necessary. Decrease the dose of morphine as necessary. Morphine is a P-glycoprotein (P-gp) substrate. Neratinib is a P-gp inhibitor. Concomitant use of P-gp inhibitors can increase morphine exposure by approximately 2-fold.
    Nafcillin: (Major) Avoid concomitant use of nafcillin with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that another moderate CYP3A4 inducer may decrease neratinib exposure by 52%.
    Naldemedine: (Moderate) Monitor for potential naldemedine-related adverse reactions if coadministered with neratinib. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a P-gp substrate; neratinib is a P-gp inhibitor.
    Nanoparticle Albumin-Bound Sirolimus: (Major) Avoid coadministration of sirolimus with neratinib as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp substrate and neratinib is a P-gp inhibitor.
    Naproxen; Esomeprazole: (Major) Avoid concomitant use of neratinib with proton pump inhibitors due to decreased absorption and systemic exposure of neratinib; the solubility of neratinib decreases with increasing pH of the GI tract. Concomitant use with lansoprazole decreased neratinib exposure by 65%.
    Nefazodone: (Major) Avoid concomitant use of nefazodone with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations.
    Nelfinavir: (Major) Avoid concomitant use of nelfinavir with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and nelfinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations.
    Netupitant, Fosnetupitant; Palonosetron: (Major) Avoid concomitant use of netupitant with neratinib due to an increased risk of neratinib-related toxicity; if possible, allow a washout period of one week after the last dose of netupitant prior to beginning therapy with neratinib. Neratinib is a CYP3A4 substrate; netupitant significantly inhibits CYP3A4 for at least 4 days after a single dose. The effect of moderate CYP3A4 inhibition on neratinib concentrations has not been studied; however, coadministration with a strong CYP3A4 inhibitor increased neratinib exposure by 481%. Because of the significant impact on neratinib exposure from strong CYP3A4 inhibition, the potential impact on neratinib safety from concomitant use with moderate CYP3A4 inhibitors should be considered as they may also significantly increase neratinib exposure.
    Niacin; Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with neratinib is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-glycoprotein (P-gp) substrate; neratinib is a P-gp inhibitor.
    Nilotinib: (Major) Avoid concomitant use of nilotinib with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and nilotinib is a moderate CYP3A4 inhibitor. The effect of moderate CYP3A4 inhibition on neratinib concentrations has not been studied; however, coadministration with a strong CYP3A4 inhibitor increased neratinib exposure by 481%. Because of the significant impact on neratinib exposure from strong CYP3A4 inhibition, the potential impact on neratinib safety from concomitant use with moderate CYP3A4 inhibitors should be considered as they may also significantly increase neratinib exposure.
    Nirmatrelvir; Ritonavir: (Major) Avoid concomitant use of ritonavir with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations.
    Nizatidine: (Major) Take neratinib at least 2 hours before the next dose of an H2-blocker or 10 hours after the last dose of an H2-blocker due to decreased absorption and systemic exposure of neratinib; the solubility of neratinib decreases with increasing pH of the GI tract. The Cmax and AUC of neratinib were reduced by 57% and 48%, respectively, when administered 2 hours after a daily dose of ranitidine 300 mg. The Cmax and AUC of neratinib were reduced by 44% and 32%, respectively, when administered 2 hours before ranitidine 150 mg twice daily (given approximately 12 hours apart).
    Octreotide: (Major) Avoid concomitant use of octreotide with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate. Somatostatin analogs, such as octreotide, decrease growth hormone secretion which in turn may inhibit CYP3A4. The effect of moderate CYP3A4 inhibition on neratinib concentrations has not been studied; however, coadministration with a strong CYP3A4 inhibitor increased neratinib exposure by 481%. Because of the significant impact on neratinib exposure from strong CYP3A4 inhibition, the potential impact on neratinib safety from concomitant use with moderate CYP3A4 inhibitors should be considered as they may also significantly increase neratinib exposure.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid concomitant use of ritonavir with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations. (Moderate) Monitor for an increase in ombitasvir-related adverse reactions if coadministration with neratinib is necessary. Concurrent use may increase ombitasvir exposure. Ombitasvir is a P-glycoprotein (P-gp) substrate and neratinib is a P-gp inhibitor. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with neratinib is necessary. Paritaprevir is a P-glycoprotein (P-gp) substrate. Neratinib is a P-gp inhibitor.
    Omeprazole: (Major) Avoid concomitant use of neratinib with proton pump inhibitors due to decreased absorption and systemic exposure of neratinib; the solubility of neratinib decreases with increasing pH of the GI tract. Concomitant use with lansoprazole decreased neratinib exposure by 65%.
    Omeprazole; Amoxicillin; Rifabutin: (Major) Avoid concomitant use of neratinib with proton pump inhibitors due to decreased absorption and systemic exposure of neratinib; the solubility of neratinib decreases with increasing pH of the GI tract. Concomitant use with lansoprazole decreased neratinib exposure by 65%. (Major) Avoid concomitant use of rifabutin with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that another moderate CYP3A4 inducer may decrease neratinib exposure by 52%.
    Omeprazole; Sodium Bicarbonate: (Major) Administer neratinib at least 3 hours after administration of sodium bicarbonate if concomitant use is necessary due to decreased absorption and systemic exposure of neratinib; the solubility of neratinib decreases with increasing pH of the GI tract. (Major) Avoid concomitant use of neratinib with proton pump inhibitors due to decreased absorption and systemic exposure of neratinib; the solubility of neratinib decreases with increasing pH of the GI tract. Concomitant use with lansoprazole decreased neratinib exposure by 65%.
    Pantoprazole: (Major) Avoid concomitant use of neratinib with proton pump inhibitors due to decreased absorption and systemic exposure of neratinib; the solubility of neratinib decreases with increasing pH of the GI tract. Concomitant use with lansoprazole decreased neratinib exposure by 65%.
    Pazopanib: (Major) Avoid coadministration of pazopanib and neratinib due to the potential for increased pazopanib exposure. Pazopanib is a P-gp substrate; neratinib is a P-gp inhibitor. Consider selection of an alternative concomitant medication with no or minimal potential to inhibit P-gp.
    Pentobarbital: (Major) Avoid concomitant use of pentobarbital with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and pentobarbital is a moderate CYP3A4 inducer. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that another moderate CYP3A4 inducer may decrease neratinib exposure by 52%.
    Pexidartinib: (Major) Avoid concomitant use of pexidartinib with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and pexidartinib is a moderate CYP3A4 inducer. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that another moderate CYP3A4 inducer may decrease neratinib exposure by 52%.
    Phenobarbital: (Major) Avoid concomitant use of phenobarbital with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased neratinib exposure by 87%, while exposure to active metabolites M6 and M7 were reduced by 37% to 49%. Concomitant use with other strong inducers of CYP3A4 may also decrease neratinib concentrations.
    Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid concomitant use of phenobarbital with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased neratinib exposure by 87%, while exposure to active metabolites M6 and M7 were reduced by 37% to 49%. Concomitant use with other strong inducers of CYP3A4 may also decrease neratinib concentrations.
    Phenytoin: (Major) Avoid concomitant use of phenytoin with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased neratinib exposure by 87%, while exposure to active metabolites M6 and M7 were reduced by 37% to 49%. Concomitant use with other strong inducers of CYP3A4 may also decrease neratinib concentrations.
    Pitavastatin: (Moderate) Monitor for an increase in pitavastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with neratinib is necessary. Concomitant use may increase pitavastatin exposure. Pitavastatin is a P-glycoprotein (P-gp) substrate; neratinib is a P-gp inhibitor.
    Posaconazole: (Major) Avoid concomitant use of posaconazole with neratinib due to an increased risk of neratinib-related toxicity; posaconazole exposure may also increase. Neratinib is a CYP3A4 substrate and a P-glycoprotein (P-gp) inhibitor. Posaconazole is a strong CYP3A4 inhibitor and a P-gp substrate. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations.
    Primidone: (Major) Avoid concomitant use of primidone with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased neratinib exposure by 87%, while exposure to active metabolites M6 and M7 were reduced by 37% to 49%. Concomitant use with other strong inducers of CYP3A4 may also decrease neratinib concentrations.
    Probenecid; Colchicine: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and neratinib 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. Neratinib can inhibit colchicine's metabolism via P-glycoprotein (P-gp), 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 a P-gp inhibitor like neratinib 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.
    Proton pump inhibitors: (Major) Avoid concomitant use of neratinib with proton pump inhibitors due to decreased absorption and systemic exposure of neratinib; the solubility of neratinib decreases with increasing pH of the GI tract. Concomitant use with lansoprazole decreased neratinib exposure by 65%.
    Quinine: (Major) Avoid concomitant use of quinine with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and quinine is a moderate CYP3A4 inhibitor. The effect of moderate CYP3A4 inhibition on neratinib concentrations has not been studied; however, coadministration with a strong CYP3A4 inhibitor increased neratinib exposure by 481%. Because of the significant impact on neratinib exposure from strong CYP3A4 inhibition, the potential impact on neratinib safety from concomitant use with moderate CYP3A4 inhibitors should be considered as they may also significantly increase neratinib exposure.
    Rabeprazole: (Major) Avoid concomitant use of neratinib with proton pump inhibitors due to decreased absorption and systemic exposure of neratinib; the solubility of neratinib decreases with increasing pH of the GI tract. Concomitant use with lansoprazole decreased neratinib exposure by 65%.
    Ranitidine: (Major) Take neratinib at least 2 hours before the next dose of an H2-blocker or 10 hours after the last dose of an H2-blocker due to decreased absorption and systemic exposure of neratinib; the solubility of neratinib decreases with increasing pH of the GI tract. The Cmax and AUC of neratinib were reduced by 57% and 48%, respectively, when administered 2 hours after a daily dose of ranitidine 300 mg. The Cmax and AUC of neratinib were reduced by 44% and 32%, respectively, when administered 2 hours before ranitidine 150 mg twice daily (given approximately 12 hours apart).
    Ranolazine: (Moderate) Monitor for an increase in ranolazine-related adverse reactions if coadministration with neratinib is necessary and titrate the dose of ranolazine based on clinical response. Concomitant use may increase ranolazine exposure. Ranolazine is a P-glycoprotein (P-gp) substrate. Neratinib is a P-gp inhibitor.
    Relugolix: (Major) Avoid concomitant use of relugolix and oral neratinib. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is unavoidable, administer neratinib at least 6 hours after relugolix and monitor for adverse reactions. Relugolix is a P-glycoprotein (P-gp) substrate and neratinib is a P-gp inhibitor.
    Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid concomitant use of relugolix and oral neratinib. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is unavoidable, administer neratinib at least 6 hours after relugolix and monitor for adverse reactions. Relugolix is a P-glycoprotein (P-gp) substrate and neratinib is a P-gp inhibitor.
    Ribociclib: (Major) Avoid concomitant use of ribociclib with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations.
    Ribociclib; Letrozole: (Major) Avoid concomitant use of ribociclib with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations.
    Rifabutin: (Major) Avoid concomitant use of rifabutin with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that another moderate CYP3A4 inducer may decrease neratinib exposure by 52%.
    Rifampin: (Major) Avoid concomitant use of rifampin with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased neratinib exposure by 87%, while exposure to active metabolites M6 and M7 were reduced by 37% to 49%.
    Rifapentine: (Major) Avoid concomitant use of rifapentine with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased neratinib exposure by 87%, while exposure to active metabolites M6 and M7 were reduced by 37% to 49%. Concomitant use with other strong inducers of CYP3A4 may also decrease neratinib concentrations.
    Rifaximin: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with neratinib is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and neratinib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.
    Rimegepant: (Major) Avoid a second dose of rimegepant within 48 hours if coadministered with neratinib; concurrent use may increase rimegepant exposure. Rimegepant is a P-gp substrate and neratinib is a P-gp inhibitor.
    Ritonavir: (Major) Avoid concomitant use of ritonavir with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations.
    Saquinavir: (Major) Avoid concomitant use of saquinavir with neratinib due to an increased risk of neratinib-related toxicity; saquinavir exposure may also increase. Neratinib is a CYP3A4 substrate and a P-gycoprotein (P-gp) inhibitor. Saquinavir is a strong CYP3A4 inhibitor and a P-gp substrate. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations.
    SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
    Secobarbital: (Major) Avoid concomitant use of secobarbital with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and secobarbital is a moderate CYP3A4 inducer. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that another moderate CYP3A4 inducer may decrease neratinib exposure by 52%.
    Simeprevir: (Moderate) Monitor for an increase in simeprevir-related adverse reactions if coadministration with neratinib is necessary. Simeprevir is a P-glycoprotein (P-gp) substrate. Neratinib may inhibit the transport of P-gp substrates.
    Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with neratinib is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-glycoprotein (P-gp) substrate; neratinib is a P-gp inhibitor.
    Simvastatin; Sitagliptin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with neratinib is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-glycoprotein (P-gp) substrate; neratinib is a P-gp inhibitor.
    Sirolimus: (Major) Avoid coadministration of sirolimus with neratinib as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp substrate and neratinib is a P-gp inhibitor.
    Sodium Bicarbonate: (Major) Administer neratinib at least 3 hours after administration of sodium bicarbonate if concomitant use is necessary due to decreased absorption and systemic exposure of neratinib; the solubility of neratinib decreases with increasing pH of the GI tract.
    Sotorasib: (Major) Avoid concomitant use of sotorasib with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that a moderate CYP3A4 inducer may decrease neratinib exposure by 52%.
    St. John's Wort, Hypericum perforatum: (Major) Avoid concomitant use of St. Johns Wort with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and St. Johns Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased neratinib exposure by 87%, while exposure to active metabolites M6 and M7 were reduced by 37% to 49%. Concomitant use with other strong inducers of CYP3A4 may also decrease neratinib concentrations.
    Talazoparib: (Moderate) Monitor for an increase in talazoparib-related adverse reactions if coadministration with neratinib is necessary. Talazoparib is a P-glycoprotein (P-gp) substrate and neratinib is a P-gp inhibitor. Coadministration with other P-gp inhibitors increased talazoparib exposure by 8% to 45%.
    Telithromycin: (Major) Avoid concomitant use of telithromycin with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and telithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations.
    Temsirolimus: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with neratinib is necessary. Temsirolimus is a P-glycoprotein (P-gp) substrate and neratinib is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of temsirolimus.
    Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with neratinib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-glycoprotein (P-gp) substrate and neratinib is a P-gp inhibitor.
    Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with neratinib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-glycoprotein (P-gp) substrate and neratinib is a P-gp inhibitor.
    Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with neratinib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-glycoprotein (P-gp) substrate and neratinib is a P-gp inhibitor.
    Ticagrelor: (Moderate) Monitor for increased bleeding if ticagrelor is coadministered with neratinib as concurrent use may increase the exposure of ticagrelor. Ticagrelor is a P-glycoprotein (P-gp) substrate and neratinib is a P-gp inhibitor.
    Tipranavir: (Major) Avoid concomitant use of tipranavir with neratinib due to an increased risk of neratinib-related toxicity; tipranavir exposure may also increase. Neratinib is a CYP3A4 substrate and a P-glycoprotein (P-gp) inhibitor. Tipranavir is a strong CYP3A4 inhibitor and a P-gp substrate. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations.
    Topotecan: (Major) Avoid coadministration of neratinib with oral topotecan due to increased topotecan exposure; neratinib may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and neratinib 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.
    Trandolapril; Verapamil: (Major) Avoid concomitant use of verapamil with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and verapamil is a dual moderate CYP3A4/P-glycoprotein (P-gp) inhibitor. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that verapamil may increase neratinib exposure by 299%.
    Tucatinib: (Major) Avoid concomitant use of tucatinib with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations.
    Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with neratinib. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a substrate of the P-gp drug transporter; neratinib is a P-gp inhibitor.
    Venetoclax: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with neratinib due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of neratinib. Venetoclax is a P-glycoprotein (P-gp) substrate; neratinib is a P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Verapamil: (Major) Avoid concomitant use of verapamil with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and verapamil is a dual moderate CYP3A4/P-glycoprotein (P-gp) inhibitor. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that verapamil may increase neratinib exposure by 299%.
    Vincristine Liposomal: (Moderate) Monitor for vincristine-related adverse reactions if coadministration of neratinib is necessary as concurrent use may increase vincristine exposure. Vincristine is a P-glycoprotein (P-gp) substrate and neratinib is a P-gp inhibitor.
    Vincristine: (Moderate) Monitor for vincristine-related adverse reactions if coadministration of neratinib is necessary as concurrent use may increase vincristine exposure. Vincristine is a P-glycoprotein (P-gp) substrate and neratinib is a P-gp inhibitor.
    Vonoprazan; Amoxicillin: (Major) Avoid concomitant use of neratinib and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of neratinib reducing its efficacy.
    Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid concomitant use of clarithromycin with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations. (Major) Avoid concomitant use of neratinib and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of neratinib reducing its efficacy.
    Voriconazole: (Major) Avoid concomitant use of voriconazole with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations.

    PREGNANCY AND LACTATION

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during neratinib treatment and for at least 1 month after the last dose. Although there are no adequately controlled studies in pregnant women, neratinib 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 neratinib should be apprised of the potential hazard to the fetus. In animal reproduction studies, administration to pregnant rabbits during organogenesis caused abortions, embryofetal death, and fetal abnormalities (domed head, dilation of brain ventricles and ventricular septal defect, misshapen anterior fontanelles, enlarged anterior and/or posterior fontanelles) at maternal AUCs approximately 0.2 times those achieved in patients receiving the recommended dose. Neratinib did not cause embryonic toxicity in rats at doses up to 0.5 to 0.6 times the maximum recommended dose on a mg/m2 basis.

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

    MECHANISM OF ACTION

    Neratinib is an irreversible intracellular inhibitor of the epidermal growth factor receptor (EGFR) and the human epidermal receptor type 2 (HER2), and HER4. It is a member of the 4-anilino quinolidine class of protein kinase inhibitors. In vitro, neratinib reduces EGFR and HER2 autophosphorylation, downstream MAPK and AKT signaling pathways, and has shown antitumor activity in EGFR and/or HER2 expressing carcinoma cell lines. Active metabolites M3, M6, M7, and M11 also inhibit the activity of EGFR, HER2, and HER4 in vitro. In vivo, oral administration of neratinib inhibited tumor growth in mouse xenograft models with tumor cell lines expressing HER2 and EGFR.

    PHARMACOKINETICS

    Neratinib is administered orally. In vitro protein binding in human plasma is greater than 99% and independent of concentration. It is predominantly bound to human serum albumin and human alpha-1 acid glycoprotein. After multiple doses of neratinib, the mean apparent volume of distribution at steady-state was 6,433 L (CV, 19%). The mean plasma half-life of neratinib after 7 days was 14.6 hours (CV, 38%), while the mean elimination ranged from 7 to 17 hours following a single dose. The mean plasma half-life of active metabolites M3, M6, and M7 were 21.6 hours (CV, 77%), 13.8 hours (CV, 50%), and 10.4 hours (CV, 33%), respectively. The mean clearance after the first dose and at steady-state were 216 (CV, 34%) and 281 (CV, 40%) L/hour, respectively. Fecal excretion accounted for 97% of a radiolabeled dose, while urinary excretion accounted for 1.1% of the dose; 61% was recovered in 96 hours and 98% was recovered after 10 days.
     
    Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP3A4, P-glycoprotein (P-gp)
    Neratinib is metabolized primarily in the liver by CYP3A4, and to a lesser extent by flavin-containing monooxygenase (FMO), to four active metabolites, M3, M6, M7, and M11. Neratinib should be avoided with strong and moderate CYP3A4 inhibitors and inducers, as its exposure is expected to be significantly impacted. Coadministration with ketoconazole, a strong CYP3A4 inhibitor, increased the Cmax and AUC of neratinib by 221% and 381%, respectively. Simulations using PBPK models suggested that a moderate dual CYP3A4/P-gp inhibitor may increase the Cmax and AUC of neratinib by 203% and 299%, respectively, while a moderate CYP3A4 inhibitor alone may increase the Cmax and AUC of neratinib by 30% and 68%, respectively. Coadministration with rifampin, a strong CYP3A4 inducer, decreased neratinib exposure by 76% and 87%, respectively; the AUC of M6 and M7 were also reduced by 37% to 49% compared to neratinib administered alone. Simulations using PBPK models suggested that a moderate CYP3A4 inducer may decrease the Cmax and AUC of neratinib by 36% and 52%, respectively. Neratinib may also inhibit P-gp. Coadministration with digoxin, a P-gp substrate, increased the mean digoxin Cmax and AUC by 54% and 32%, respectively. Caution and monitoring is advised with other P-gp substrates.

    Oral Route

    Neratinib exhibits nonlinear pharmacokinetics, with less than dose proportional increases of exposure with increases in dose over the range of 40 mg to 400 mg. The three active metabolites, M3, M6, and M7, reach peak concentrations between 2 to 8 hours after oral administration. At steady state, neratinib represents the most prominent component in plasma, with these metabolites comprising 15%, 33%, and 22% of the systemic neratinib exposure (AUC), respectively; another active metabolite, M11, constitutes 4% of neratinib exposure.
     
    The Cmax and AUC of neratinib after a single 240-mg dose to healthy volunteers were increased by 70% (90% CI, 1.1- to 2.7-fold) and 120% (90% CI, 1.4- to 3.5-fold), respectively, when administered with a high-fat meal (55% fat, 31% carbohydrate, and 14% protein). A standard breakfast (50% carbohydrate, 35% fat, and 15% protein) increased the Cmax and AUC of neratinib by 20% (90% CI, 0.97- to 1.42-fold) and 10% (90% CI, 1.02- to 1.24-fold), respectively. Neratinib should be administered with food.
     
    Neratinib solubility decreases with increasing pH. Gastric acid reducing agents may decrease neratinib exposure. Concomitant use with proton pump inhibitors should be avoided, while coadministration with antacids should be separated by 3 hours. Coadministration with lansoprazole decreased the Cmax and AUC of neratinib by 71% and 65%, respectively. Coadministration with ranitidine (300 mg once) administered 2 hours before neratinib decreased the neratinib Cmax and AUC by 57% and 48%, respectively. Coadministration with ranitidine (150 mg twice daily) administered 2 hours after neratinib, the neratinib Cmax and AUC were reduced by 44% and 32%, respectively.