Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

tablet

  • 40mg (equivalent to 48.31mg neratinib maleate)

Breast Cancer

Early-stage breast cancer

  • Indicated for the extended adjuvant treatment of early-stage HER2-overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy
  • 240 mg (6 tablets) PO qDay continuously for 1 yr
  • Consider a two-week dose escalation instead of starting at the 240-mg daily dose to minimize severe diarrhea if not using antidiarrheal prophylaxis

Advanced or metastatic breast cancer

  • Indicated in combination with capecitabine for advanced or metastatic HER2-positive breast cancer in adults who have received ≥2 prior anti-HER2 based regimens in the metastatic setting
  • Consider a two-week dose escalation instead of starting at the 240-mg daily dose to minimize severe diarrhea if not using antidiarrheal prophylaxis
  • Each cycle is 21 days
  • Days 1-21: 240 mg PO qDay PLUS
  • Days 1-14: Capecitabine 750 mg/m2 PO BID
  • Continue until disease progression or unacceptable toxicities
  • Dose escalation regimen
    • Days 1 to 7: 120 mg PO qDay
    • Days 8 to 14: 160 mg PO qDay
    • Day 15 and thereafter: 240 mg PO qDay; continue for up to 1 year
    • If diarrhea occurs, treat with antidiarrheal medications, fluids, and electrolytes as clinically warranted

Dosage Modifications

Dose adjustments for adverse reactions and general toxicities

  • Monotherapy
    • First dose reduction: 200 mg/day
    • Second dose reduction: 160 mg/day
    • Third dose reduction: 120 mg/day
  • In combination with capecitabine
    • First dose reduction: 160 mg/day
    • Second dose reduction: 120 mg/day
  • Additional clinical situations may result in dose adjustments as clinically indicated (eg, intolerable toxicities, persistent grade 2 adverse reactions)
  • Discontinue if patient fails to recover to grade 0-1 from treatment-related toxicity, for toxicities that result in a treatment delay >3 weeks, or if unable to tolerate 120 mg/day
  • Grade 3: Hold until recovery to Grade ≤1 or baseline within 3 weeks of stopping treatment, then resume at the next lower dose level
  • Grade 4: Discontinue permanently

Diarrhea

  • Severity
    • Grade 1 diarrhea (increase of <4 stools/day over baseline)
    • Grade 2 diarrhea (increase of 4-6 stools/day over baseline) lasting <5 days
    • Grade 3 diarrhea (increase of ≥7 stools/day over baseline, incontinence, hospitalization indicated, limiting self-care activities of daily living) lasting <2 days
    • Grade 4 diarrhea (life-threatening consequences; urgent intervention indicated)
  • Dosage modifications for Grade 1-3 diarrhea
    • Adjust antidiarrheal treatment
    • Diet modifications
    • Maintain fluid intake of ~2 L to avoid dehydration
    • Once resolves to Grade ≤1 or baseline, start loperamide 4 mg with each subsequent administration
    • In combination with capecitabine: Continue at full doses
  • Dosage modifications for any grade with complicated features, Grade 2 diarrhea ≥5 days, or Grade 3 diarrhea ≥2 days (monotherapy only)
    • Interrupt treatment
    • Diet modifications
    • Maintain fluid intake of ~2 L to avoid dehydration
    • If diarrhea resolves to Grade ≤1 in <1 week, then resume at the same dose
    • If diarrhea resolves to Grade ≤1 in ≥1 week, then resume at reduced dose
    • Once resolves to Grade ≤1 or baseline, start loperamide 4 mg with each subsequent administration
  • Grade 4 diarrhea or Grade ≥2 diarrhea at 120 mg/day (monotherapy only)
    • Permanently discontinue
  • Dosage modifications for persisting and intolerable Grade 2 diarrhea ≥5 days, or Grade 3 diarrhea ≥2 days, or Grade 4 diarrhea (in combination with capecitabine)
    • Adjust antidiarrheal treatment
    • Hold neratinib and capecitabine until recovery to Grade ≤1 or baseline
    • Maintain fluid intake of ~2 L/day intravenously, if needed
    • If recovery occurs ≤1 week after withholding, resume same doses of neratinib and capecitabine
    • If recovery occurs within 1-3 weeks after withholding, reduce neratinib dose to 160 mg and maintain the same dose of capecitabine
    • If event occurs a second time and neratinib dose has not already been decreased, reduce dose to 160 mg (maintain the same dose of capecitabine); reduce capecitabine dose to 550 mg/m2 BID if neratinib dose was already reduced (maintain the same neratinib dose )
    • If subsequent events occur, reduce neratinib dose or capecitabine to the next lower dose level in an alternate fashion (eg, reduce capecitabine to 375 mg/m2 BID if neratinib was previously reduced, or reduce neratinib to 120 mg if capecitabine was previously reduced)
    • Once the event resolved to Grade ≤1 or baseline, start loperamide 4 mg

Hepatoxicity

  • Patients who experience Grade ≥3 diarrhea requiring IV fluid treatment or any signs or symptoms of hepatotoxicity, should be evaluated for changes in liver function tests; fractionated bilirubin and prothrombin time should also be collected during hepatotoxicity evaluation
  • Grade 3 ALT (>5-20x ULN) or Grade 3 bilirubin (>3-10x ULN)
    • Hold until recovery to Grade ≤1 and evaluate alternative causes
    • Resume at next lower dose level if recovery Grade ≤1 within 3 wk
    • Permanently discontinue if Grade 3 ALT or bilirubin reoccurs despite 1 dose reduction
  • Grade 4 ALT (>20x ULN), OR Grade 4 bilirubin (>10x ULN)
    • Permanently discontinue
    • Evaluate alternative causes

Coadministration with gastric acid reducing agents

  • Proton pump inhibitor (PPI): Avoid concomitant use
  • H2-antagonists: Avoid concomitant use
  • Antacids: Separate dose by 3 hr after antacids

Renal impairment

No clinical significant effect on pharmacokinetics

Hepatic impairment

  • Mild-moderate (Child-Pugh A or B): No dose modifications required
  • Severe (Child-Pugh C): Reduce starting dose to 80 mg

Breast Cancer with Brain Metastases (Orphan)

Orphan designation for patients with breast cancer who have brain metastases

Orphan sponsor

  • Puma Biotechnology Inc; 10880 Wilshire Blvd., Suite 2150; Los Angeles, California 90024

Dosing Considerations

Antidiarrheal prophylaxis

  • When not using dose escalation, administer loperamide prophylaxis during the first 2 cycles (56 days) of treatment and initiate with the first neratinib dose
  • Titrate dose to 1-2 bowels/day
  • Weeks 1-2 (days 1-14): 4 mg PO TID
  • Weeks 3-8 (days 15-56): 4 mg PO BID
  • Weeks 9-52 (days 57-365): 4 mg PO PRN; not to exceed 16 mg/day
  • If diarrhea occurs despite prophylaxis, treat with additional antidiarrheals, fluids and electrolytes as clinically indicated
  • Dose interruptions and reductions may also be required to manage diarrhea

Safety and efficacy not established

Next:

Interactions

Interaction Checker

and neratinib

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              Serious - Use Alternative (94)

              • abametapir

                abametapir will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. For 2 weeks after abametapir application, avoid taking drugs that are CYP3A4 substrates. If not feasible, avoid use of abametapir.

              • amiodarone

                amiodarone will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inhibitors.

              • amobarbital

                amobarbital will decrease the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inducers.

              • aprepitant

                aprepitant will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inhibitors.

              • armodafinil

                armodafinil will decrease the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inducers.

              • atazanavir

                atazanavir will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inhibitors.

              • bicalutamide

                bicalutamide will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inhibitors.

              • bosentan

                bosentan will decrease the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inducers.

              • brigatinib

                brigatinib will decrease the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inducers.

              • butabarbital

                butabarbital will decrease the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inducers.

              • butalbital

                butalbital will decrease the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inducers.

              • carbamazepine

                carbamazepine will decrease the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inducers.

              • cimetidine

                cimetidine will decrease the level or effect of neratinib by increasing gastric pH. Applies only to oral form of both agents. Avoid or Use Alternate Drug.

              • clarithromycin

                clarithromycin will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inhibitors.

              • clobazam

                clobazam will decrease the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inducers.

              • clozapine

                clozapine will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inhibitors.

              • cobicistat

                cobicistat will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inhibitors.

              • colchicine

                neratinib increases levels of colchicine by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. Avoid use of colchicine with P-gp inhibitors. If coadministration is necessary, decrease colchicine dose or frequency as recommended in prescribing information. Use of any colchicine product in conjunction with P-gp inhibitors is contraindicated in patients with renal or hepatic impairment. .

              • conivaptan

                conivaptan will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inhibitors.

              • crizotinib

                crizotinib will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inhibitors

              • cyclosporine

                cyclosporine will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inhibitors.

                cyclosporine will increase the level or effect of neratinib by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. Cyclosporine (CYP3A4 and P-gp inhibitor) may increase level or effect of neratinib (a CYP3A4 and P-gp substrate).

              • dabrafenib

                dabrafenib will decrease the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inducers.

              • darunavir

                darunavir will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inhibitors.

              • desipramine

                desipramine will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inhibitors.

              • dexamethasone

                dexamethasone will decrease the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inducers.

              • dexlansoprazole

                dexlansoprazole will decrease the level or effect of neratinib by increasing gastric pH. Applies only to oral form of both agents. Avoid or Use Alternate Drug.

              • diltiazem

                diltiazem will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inhibitors.

              • doxycycline

                doxycycline will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inhibitors.

              • dronedarone

                dronedarone will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inhibitors.

              • efavirenz

                efavirenz will decrease the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inducers.

              • enzalutamide

                enzalutamide will decrease the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inducers.

              • erythromycin base

                erythromycin base will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inhibitors.

              • erythromycin ethylsuccinate

                erythromycin ethylsuccinate will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inhibitors.

              • erythromycin lactobionate

                erythromycin lactobionate will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inhibitors.

              • erythromycin stearate

                erythromycin stearate will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inhibitors.

              • eslicarbazepine acetate

                eslicarbazepine acetate will decrease the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inducers.

              • esomeprazole

                esomeprazole will decrease the level or effect of neratinib by increasing gastric pH. Applies only to oral form of both agents. Avoid or Use Alternate Drug.

              • etravirine

                etravirine will decrease the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inducers.

              • famotidine

                famotidine will decrease the level or effect of neratinib by increasing gastric pH. Applies only to oral form of both agents. Avoid or Use Alternate Drug.

              • fluconazole

                fluconazole will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inhibitors.

              • fluvoxamine

                fluvoxamine will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • fosamprenavir

                fosamprenavir will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inhibitors.

              • fosphenytoin

                fosphenytoin will decrease the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inducers.

              • grapefruit

                grapefruit will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inhibitors.

              • haloperidol

                haloperidol will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inhibitors.

              • ibuprofen/famotidine

                ibuprofen/famotidine will decrease the level or effect of neratinib by increasing gastric pH. Applies only to oral form of both agents. Avoid or Use Alternate Drug.

              • idelalisib

                idelalisib will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inhibitors.

              • imatinib

                imatinib will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inhibitors.

              • indinavir

                indinavir will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inhibitors.

              • isoniazid

                isoniazid will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inhibitors.

              • itraconazole

                itraconazole will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inhibitors.

              • ketoconazole

                ketoconazole will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inhibitors.

              • lansoprazole

                lansoprazole will decrease the level or effect of neratinib by increasing gastric pH. Applies only to oral form of both agents. Avoid or Use Alternate Drug.

              • lapatinib

                lapatinib will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inhibitors.

              • lopinavir

                lopinavir will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inhibitors.

              • lumacaftor/ivacaftor

                lumacaftor/ivacaftor will decrease the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inducers.

              • metronidazole

                metronidazole will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inhibitors.

              • mitotane

                mitotane will decrease the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inducers.

              • modafinil

                modafinil will decrease the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inducers.

              • nafcillin

                nafcillin will decrease the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inducers.

              • nefazodone

                nefazodone will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inhibitors.

              • nelfinavir

                nelfinavir will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inhibitors.

              • netupitant/palonosetron

                netupitant/palonosetron will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inhibitors.

              • nevirapine

                nevirapine will decrease the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inducers.

              • nicardipine

                nicardipine will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inhibitors.

              • nizatidine

                nizatidine will decrease the level or effect of neratinib by increasing gastric pH. Applies only to oral form of both agents. Avoid or Use Alternate Drug.

              • ombitasvir/paritaprevir/ritonavir & dasabuvir

                ombitasvir/paritaprevir/ritonavir & dasabuvir will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inhibitors.

              • omeprazole

                omeprazole will decrease the level or effect of neratinib by increasing gastric pH. Applies only to oral form of both agents. Avoid or Use Alternate Drug.

              • oxcarbazepine

                oxcarbazepine will decrease the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inducers.

              • palifermin

                palifermin increases toxicity of neratinib by Other (see comment). Avoid or Use Alternate Drug. Comment: Palifermin should not be administered within 24 hr before, during infusion of, or within 24 hr after administration of antineoplastic agents. Coadministration of palifermin within 24 hr of chemotherapy resulted in increased severity and duration of oral mucositis.

              • pantoprazole

                pantoprazole will decrease the level or effect of neratinib by increasing gastric pH. Applies only to oral form of both agents. Avoid or Use Alternate Drug.

              • pentobarbital

                pentobarbital will decrease the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inducers.

              • phenobarbital

                phenobarbital will decrease the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inducers.

              • phenytoin

                phenytoin will decrease the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inducers.

              • posaconazole

                posaconazole will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inhibitors.

              • primidone

                primidone will decrease the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inducers.

              • quinupristin/dalfopristin

                quinupristin/dalfopristin will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inhibitors.

              • rabeprazole

                rabeprazole will decrease the level or effect of neratinib by increasing gastric pH. Applies only to oral form of both agents. Avoid or Use Alternate Drug.

              • ribociclib

                ribociclib will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inhibitors.

              • rifabutin

                rifabutin will decrease the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inducers.

              • rifampin

                rifampin will decrease the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inducers.

              • rifapentine

                rifapentine will decrease the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inducers.

              • rimegepant

                neratinib will increase the level or effect of rimegepant by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug.

              • ritonavir

                ritonavir will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inhibitors.

              • saquinavir

                saquinavir will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inhibitors.

              • schisandra

                schisandra will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inhibitors.

              • secobarbital

                secobarbital will decrease the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inducers.

              • sertraline

                sertraline will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inhibitors.

              • sofosbuvir/velpatasvir

                sofosbuvir/velpatasvir will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inhibitors.

              • St John's Wort

                St John's Wort will decrease the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inducers.

              • tetracycline

                tetracycline will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inhibitors.

              • tipranavir

                tipranavir will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inhibitors.

              • verapamil

                verapamil will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inhibitors.

              • voriconazole

                voriconazole will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inhibitors.

              Monitor Closely (14)

              • aluminum hydroxide

                aluminum hydroxide will decrease the level or effect of neratinib by increasing gastric pH. Applies only to oral form of both agents. Modify Therapy/Monitor Closely. Separate antacid and neratinib dosing by 3 hr.

              • aspirin/citric acid/sodium bicarbonate

                aspirin/citric acid/sodium bicarbonate will decrease the level or effect of neratinib by increasing gastric pH. Applies only to oral form of both agents. Modify Therapy/Monitor Closely. Separate antacid and neratinib dosing by 3 hr.

              • berotralstat

                neratinib increases levels of berotralstat by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. Reduced berotralstat dose to 110 mg/day when coadministered with P-gp inhibitors.

              • calcium carbonate

                calcium carbonate will decrease the level or effect of neratinib by increasing gastric pH. Applies only to oral form of both agents. Modify Therapy/Monitor Closely. Separate antacid and neratinib dosing by 3 hr.

              • clonidine

                neratinib increases levels of clonidine by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Neratinib inhibits P-gp transport. Caution if coadministered with a P-gp substrate with a narrow therapeutic index.

              • dabigatran

                neratinib increases levels of dabigatran by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Neratinib inhibits P-gp transport. Caution if coadministered with a P-gp substrate with a narrow therapeutic index.

              • dengue vaccine

                neratinib decreases effects of dengue vaccine by immunosuppressive effects; risk of infection. Use Caution/Monitor. Immunosuppressive therapies (eg, irradiation, antimetabolites, alkylating agents, cytotoxic drugs, corticosteroids [greater than physiologic doses]) may reduce immune response to dengue vaccine.

              • digoxin

                neratinib increases levels of digoxin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Neratinib inhibits P-gp transport. Caution if coadministered with a P-gp substrate with a narrow therapeutic index.

              • duvelisib

                duvelisib will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Coadministration with duvelisib increases AUC of a sensitive CYP3A4 substrate which may increase the risk of toxicities of these drugs. Consider reducing the dose of the sensitive CYP3A4 substrate and monitor for signs of toxicities of the coadministered sensitive CYP3A substrate.

                neratinib will increase the level or effect of duvelisib by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • fexofenadine

                neratinib increases levels of fexofenadine by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Neratinib inhibits P-gp transport. Caution if coadministered with a P-gp substrate with a narrow therapeutic index.

              • magnesium oxide

                magnesium oxide will decrease the level or effect of neratinib by increasing gastric pH. Applies only to oral form of both agents. Modify Therapy/Monitor Closely. Separate antacid and neratinib dosing by 3 hr.

              • siponimod

                siponimod and neratinib both increase immunosuppressive effects; risk of infection. Use Caution/Monitor. Caution if coadministered because of additive immunosuppressive effects during such therapy and in the weeks following administration. When switching from drugs with prolonged immune effects, consider the half-life and mode of action of these drugs to avoid unintended additive immunosuppressive effects.

              • sodium zirconium cyclosilicate

                sodium zirconium cyclosilicate will decrease the level or effect of neratinib by increasing gastric pH. Applies only to oral form of both agents. Modify Therapy/Monitor Closely. Check specific recommendations for drugs that exhibit pH-dependent solubility that may affect their systemic exposure and efficacy. In general, administer drugs at least 2 hr before or after sodium zirconium cyclosilicate.

              • talazoparib

                neratinib will increase the level or effect of talazoparib by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Talazoparib is a P-glycoprotein (P-gp) substrate; coadministration with P-gp inhibitors may increase talazoparib systemic exposure.

              Minor (0)

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                Adverse Effects

                >10%

                All grades

                • Diarrhea (95%)
                • Nausea (43%)
                • Abdominal pain (36%)
                • Fatigue (27%)
                • Vomiting (26%)
                • Rash (18%)
                • Stomatitis (14%)
                • Decreased appetite (12%)
                • Muscle spasms (11%)

                Grade 3-4

                • Diarrhea (40%)

                1-10%

                All grades

                • Dyspepsia (10%)
                • ALT increased (9%)
                • Nail disorder (8%)
                • AST increased (7%)
                • Dry skin (6%)
                • Abdominal distension (5%)
                • Urinary tract infection (5%)
                • Decreased (5%)
                • Epistaxis (5%)
                • Dehydration (4%)
                • Dry mouth (3%)
                • Skin fissures (2%)

                Grade 3-4

                • Vomiting (3%)
                • Nausea (2%)
                • Abdominal pain (2%)
                • Fatigue (2%)
                • ALT increased (1%)

                <1%

                Grade 3-4

                • Dehydration (0.9%)
                • Stomatitis (0.6%)
                • Rash (0.3%)
                • AST increased (0.5%)
                • Dyspepsia (0.4%)
                • Abdominal distension (0.3%)
                • Nail disorder (0.3%)
                • Decreased appetite (0.2%)
                • Skin fissures (0.1%)
                • Dry mouth (0.1%)
                • Urinary tract infection (0.1%)
                • Decreased weight (0.1%)
                • Muscle spasms (0.1%)
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                Warnings

                Contraindications

                None

                Cautions

                No clinically relevant effect on the QTc intervals

                Hepatoxicity reported with therapy; monitor liver function test at baseline, once monthly for the first 3 months, followed by q3 months while on treatment and as clinically indicated; discontinue and do not restart therapy if patients experience severe changes in liver function tests

                Animal studies have shown therapy can severely affect organ growth and maturation during early postnatal development; safety and effectiveness in pediatric patients not established

                Can cause fetal harm when administered to a pregnant woman

                Diarrhea

                • Severe diarrhea and sequelae (eg, dehydration, hypotension, renal failure) occurred
                • Diarrhea was reported in in patients treated neratinib plus capecitabine in NALA, a randomized placebo-controlled trial in the metastatic breast cancer setting who were required to receive anti-diarrheal prophylaxis in the first cycle
                • Antidiarrheal prophylaxis has been shown to lower the incidence and severity of diarrhea
                • Consider adding other agents to loperamide as clinically indicated
                • Alternatively, consider a 2-week dose escalation approach prior to initiation of treatment regimen for diarrhea management
                • Median time to first onset of Grade ≥3 diarrhea was 45 days (range, 15-132) and the median cumulative duration of Grade ≥3 diarrhea was 2.5 days (range, 1-6)
                • Monitor for diarrhea and treat with additional antidiarrheals as needed
                • When severe diarrhea with dehydration occurs, administer fluid and electrolytes as needed, interrupt therapy, and reduce subsequent doses
                • Perform stool cultures as clinically indicated to exclude infectious causes of Grade 3 or 4 diarrhea or diarrhea of any grade with complicating features (dehydration, fever, neutropenia)

                Drug interaction overview

                • Neratinib is a CYP3A4 substrate and inhibits P-glycoprotein (P-gp) transporters
                • P-gp substrates
                  • Coadministration with digoxin, a P-gp substrate, increased digoxin concentrations
                  • Increased concentrations of digoxin may lead to increased risk of adverse reactions including cardiac toxicity
                  • Caution if using concomitant P-gp substrates; monitor substrate for necessary dosage adjustments
                • Strong and moderate CYP3A4 inhibitors
                  • Coadministration with strong CYP3A4 inhibitors (eg, ketoconazole, ritonavir, clarithromycin, grapefruit juice) may increase neratinib serum levels
                  • Avoid coadministration
                • Strong and moderate CYP3A4 inducers
                  • CYP3A4 inducers (eg, rifampin, carbamazepine) decrease neratinib serum levels
                  • Avoid coadministration
                • Drugs that increase gastric pH
                  • Concomitant use of neratinib with a PPI (eg, lansoprazole) decreased neratinib Cmax by 71% and AUC by 65%, which may reduce efficacy
                  • Avoid concomitant use with drugs that raise gastric pH (ie, PPIs, H2-receptor antagonists)
                  • Consider short-acting antacids in place of PPIs and H2-receptor antagonists
                  • Separate antacid and neratinib dosing by 3 hr
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                Pregnancy

                Pregnancy

                Based on findings from animal studies and its mechanism of action, can cause fetal harm when administered to pregnant women

                Females of reproductive potential should have a pregnancy test before starting treatment

                If used during pregnancy, or becomes pregnant while taking drug, advise of the potential hazard to fetus

                Animal studies

                • Administration to pregnant rabbits during organogenesis caused abortions, embryofetal death, and fetal abnormalities in rabbits at maternal AUCs ~0.2 times the AUC in patients receiving the recommended dose

                Contraception

                • Females of reproductive potential: Use effective contraception during treatment and for at least 1 month after last dose
                • Males with females of reproductive potential: Use effective contraception during treatment and for 3 months after the last dose

                Lactation

                Unknown if distributed in human breast milk

                Owing to the potential for serious adverse reactions in breastfed infants, advise lactating women not to breastfeed while taking neratinib and for at least 1 month after the last dose

                Pregnancy Categories

                A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

                B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

                C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

                D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

                X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

                NA: Information not available.

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                Pharmacology

                Mechanism of Action

                Irreversible tyrosine kinase inhibitor (TKI) that blocks signal transduction through the epidermal growth factor receptors (EGFRs), human epidermal growth factor receptor 2 (HER2), and HER4

                In vitro, inhibition reduces EGFR and HER2 autophosphorylation, subsequently inhibits signal transduction pathways, and demonstrates antitumor activity in overexpressed EGFR and/or HER2 carcinoma cells; neratinib human metabolites (M3, M6, M7, and M11) inhibit EGFR, HER2, and HER4 activity

                Absorption

                Peak plasma time: 2-8 hr (active metabolites M3, M6, and M7)

                Systemic absorption increased with food

                Peak plasma concentration: 1.7-fold (high fat); 1.2-fold (standard breakfast)

                AUC: 2.2-fold (high fat); AUC: 1.1-fold (standard breakfast)

                Distribution

                Vd: 6433 L (steady-state)

                Protein bound (in vitro): >99%

                Metabolism

                Primarily metabolized by CYP3A4 and, to a lesser extent, flavin-containing monooxygenase (FMO)

                Metabolites (active): M3, M6, M7, and M11

                Elimination

                Half-life: 7-17 hr (single dose)

                Half-life: 21.6 hr (M3 metabolite); 13.8 hr (M6 metabolite); 10.4 hr (M7 metabolite)

                Excretion: Feces (97.1%) and urine (1.13%)

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                Administration

                Oral Administration

                Take with food at approximately the same time each day

                Swallow tablet whole; do not chew, crush, or split

                Missed dose: Do not replace missed dose; resume taking with the next scheduled daily dose

                Storage

                Store at room temperature, 20-25°C (68-77°F); excursions permitted to 15-30°C (59–86°F)

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                Images

                BRAND FORM. UNIT PRICE PILL IMAGE
                Nerlynx oral
                -
                40 mg tablet

                Copyright © 2010 First DataBank, Inc.

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                Patient Handout

                A Patient Handout is not currently available for this monograph.
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                Formulary

                FormularyPatient Discounts

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                To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.

                Adding plans allows you to:

                • View the formulary and any restrictions for each plan.
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                • Compare formulary status to other drugs in the same class.
                • Access your plan list on any device – mobile or desktop.

                The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

                Tier Description
                1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
                2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
                3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
                4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
                5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
                6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
                NC NOT COVERED – Drugs that are not covered by the plan.
                Code Definition
                PA Prior Authorization
                Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
                QL Quantity Limits
                Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
                ST Step Therapy
                Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
                OR Other Restrictions
                Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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                Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.