Dosing & Uses
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
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
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%)
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
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.
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%)
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)
Images
Patient Handout
Formulary
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