Dosing & Uses
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
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
- 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
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
Safety and efficacy not established
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
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%)
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 during treatment
- 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
- Initiate antidiarrheal prophylaxis with loperamide along with the first dose of neratinib and continue during the first 56 days of treatment; after day 56 titrate dose to achieve 1-2 bowel movements per day and not to exceed 16 mg loperamide per day
- Consider adding other agents to loperamide as clinically indicated
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
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.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
- Recommended during the first 2 cycles (56 days) of treatment and initiate with the first dose
- Titrate dose to 1-2 bowels/day
-
Loperamide prophylaxis dose
- 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
- 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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Patient Handout
Formulary
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