neratinib (Rx)

>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%)

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)

Drug interaction overview H4

• 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

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 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

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.

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%)

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)