Neratinib

Severe diarrhea, which may result in dehydration, hypotension, and renal failure has been observed commonly with neratinib treatment. Almost all patients receiving neratinib in a clinical trial experienced diarrhea; the majority developed diarrhea during the first month of treatment. The median time to onset of grade 3 or higher diarrhea was 8 days (range: 1 day to 350 days); the median cumulative duration of toxicity was 5 days (range: 1 day to 139 days). Antidiarrheal prophylaxis with loperamide has been shown to lower the incidence and severity of diarrhea and is recommended during the first 2 cycles of therapy (begin with the first dose of neratinib). Monitor closely for diarrhea and subsequent complications; additional antidiarrheals may be necessary. Administer fluid and electrolytes as needed; stool cultures may be needed to exclude infectious etiologies for diarrhea. Diarrhea may require therapy interruption and dosage reductions and/or discontinuation. Nausea, vomiting, abdominal pain, and stomatitis have also been reported. ·

Hepatotoxicity characterized by elevated liver enzymes has been reported with neratinib therapy. ALT and AST elevations have been observed, and have led to treatment discontinuation in some patients. Monitor liver function tests (ALT, AST, total bilirubin, and alkaline phosphatase) prior to treatment initiation, monthly for the first 3 months, then every 3 months thereafter and as clinically indicated. Assess liver function tests in patients with grade 3 or higher diarrhea requiring IV fluids or in those with signs/symptoms of hepatotoxicity (worsening fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or eosinophilia). May require therapy interruption, dose reduction, or permanent discontinuation. Disease related concerns:

Use with caution in patients with hepatic impairment; neratinib clearance may be reduced in patients with severe hepatic dysfunction. Dose reduction is required in patients with preexisting severe (Child-Pugh class C) hepatic impairment. Concurrent drug therapy issues:

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Concomitant use of neratinib with drugs that affect gastric pH may result in decreased neratinib exposure and reduced efficacy; avoid concomitant use with proton pump inhibitors and H2-receptor antagonists. If antacid administration is necessary, administer neratinib 3 hours after the antacid. Special populations:

The incidence of serious adverse reactions and treatment discontinuation was higher in patients 65 years and older (compared to patients younger than 65 years) in a clinical trial. The most commonly reported serious adverse reactions in elderly patients included vomiting, diarrhea, renal failure, and dehydration.