Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

tablet

  • 40mg (equivalent to 48.31mg neratinib maleate)

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 with food continuously for 1 yr

Also see Administration for information on antidiarrheal prophylaxis

Dosage Modifications

Hepatic impairment

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

Dose adjustments for adverse reactions and general toxicities

  • First dose reduction: 200 mg/day
  • Second dose reduction: 160 mg/day
  • Third 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 drug until recovery to ≤grade 1 or baseline within 3 weeks of stopping treatment, then resume at the next lower dose level
  • Grad 4: Discontinue permanently

Severity of diarrhea

  • Grade 1 diarrhea (increase of <4 stools per 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
  • Dosing modifications for Grades 1, 2, or 3
    • 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
  • Dose modifications for any grade with complicated features, grade 2 diarrhea ≥5 days, or grade 3 diarrhea ≥2 days
    • Interrupt neratinib treatment
    • Diet modifications
    • Maintain fluid intake of ~2 L to avoid dehydration
    • If diarrhea resolves to grade 0-1 in <1 week, then resume treatment at the same dose
    • If diarrhea resolves to grade 0-1 in ≥1 week, then resume treatment at reduced dose
    • Once resolves to ≤grade 1 or baseline, start loperamide 4 mg with each subsequent administration
  • Grade 4 diarrhea
    • Permanently discontinue
  • Diarrhea ≥grade 2 at 120 mg/day
    • Permanently discontinue

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 (>5-20 x ULN) or grade 3 bilirubin (>3-10 x ULN)
    • Hold drug until recovery to ≤grade 1 and evaluate alternative causes
    • Resume at next lower dose level if recovery to ≤grade 1 within 3 wk
    • Permanently discontinue if grade 3 ALT or bilirubin reoccurs despite 1 dose reduction
  • Grade 4 ALT (>20 x ULN), OR Grade 4 bilirubin (>10 x 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

Safety and efficacy not established

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Interactions

Interaction Checker

and neratinib

No Results

     activity indicator 
    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            Adverse Effects

            >10%

            Diarrhea, all grades (95%)

            Nausea (43%)

            Diarrhea, grade 3 (40%)

            Abdominal pain (36%)

            Fatigue (27%)

            Vomiting (26%)

            Rash (18%)

            Stomatitis (14%)

            Decreased appetite (12%)

            Muscle spasms (11%)

            1-10%

            Dyspepsia (10%)

            Increased ALT (9%)

            Nail disorder (8%)

            Increased AST (7%)

            Dry skin (6%)

            Abdominal distension (5%)

            Epistaxis (5%)

            Urinary tract infection (5%)

            Weight decreased (5%)

            Dehydration (4%)

            Dry mouth (3%)

            Skin fissures (2%)

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            Warnings

            Contraindications

            None

            Cautions

            Aggressively manage diarrhea occurring despite recommended prophylaxis with additional antidiarrheals, fluids, and electrolytes as clinically indicated; withhold therapy in patients experiencing severe and/or persistent diarrhea; permanently discontinue in patients experiencing grade 4 diarrhea or grade ≥2 diarrhea that occurs after maximal dose reduction (see Dosage Modifications; loperamide may lower the incidence and severity of diarrhea (see Oral Administration)

            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 (see Pregnancy and Lactation)

            Interaction overview

            • (See Drug Interactions)
            • Neratinib is a CYP3A4 substrate and inhibits P-glycoprotein (P-gp) transporters CYP3A4 inducers (eg, rifampin, carbamazepine) decrease neratinib serum levels
            • Coadministration with strong CYP3A4 inhibitors (eg, ketoconazole, ritonavir, clarithromycin, grapefruit juice) may increase neratinib serum levels
            • Caution if using concomitant P-gp substrates; monitor substrate for necessary dosage adjustments
            • 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 prior to starting treatment

            If drug used during pregnancy, or if patient becomes pregnant while taking drug, patient should be apprised of potential hazard to fetus

            Animal studies

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

            Contraception

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

            Lactation

            Unknown if distributed in human breast milk

            Because of 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

            Antidiarrheal prophylaxis

            • Antidiarrheal prophylaxis is recommended during the first 2 cycles (56 days) of treatment and should be initiated with the first dose
            • Loperamide prophylaxis dose
              • Weeks 1-2: 4 mg PO TID
              • Weeks 3-8: 4 mg PO BID
              • Weeks 9-52: 4 mg PO prn; not to exceed 16 mg/day
              • May also require dose interruption and reduction and additional antidiarrheal agents may be required to manage diarrhea in patients with loperamide-refractory diarrhea (also see Dosage Modifications)

            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

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            Formulary

            FormularyPatient Discounts

            Adding plans allows you to compare formulary status to other drugs in the same class.

            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.