Neratinib Maleate

Neratinib maleate has the following uses:

Neratinib maleate is a kinase inhibitor indicated for extended adjuvant treatment following adjuvant trastuzumab-based therapy for early stage HER2-overexpressed/amplified breast cancer.1

Contraindications

None.1

Warnings/Precautions

Diarrhea

Severe diarrhea and sequelae, such as dehydration, hypotension, and renal failure, have been reported during treatment with neratinib maleate. Diarrhea was reported in 95% of neratinib maleate-treated patients in ExteNET, a randomized placebo controlled trial. In the neratinib maleate arm, Grade 3 diarrhea occurred in 40% and Grade 4 diarrhea occurred in 0.1% of patients. The majority of patients (93%) had diarrhea in the first month of treatment, the median time to first onset of Grade ≥ 3 diarrhea was 8 days (range, 1-350), and the median cumulative duration of Grade ≥ 3 diarrhea was 5 days (range, 1-139).1

Antidiarrheal prophylaxis with loperamide has been shown to lower the incidence and severity of diarrhea. Instruct patients to initiate antidiarrheal prophylaxis with loperamide along with the first dose of neratinib maleate and continue during the first two cycles (56 days) of treatment.1

Monitor patients for diarrhea and treat with additional antidiarrheals as needed. When severe diarrhea with dehydration occurs, administer fluid and electrolytes as needed, interrupt neratinib maleate, and reduce subsequent doses. Perform stool cultures as clinically indicated to exclude infectious causes of Grade 3 or 4 diarrhea or diarrhea of any grade with complicating features (dehydration, fever, neutropenia).1

Hepatotoxicity

Neratinib maleate has been associated with hepatotoxicity characterized by increased liver enzymes. In ExteNET, 9.7% of patients experienced an alanine aminotransferase (ALT) increase ≥ 2 x ULN, 5.1% of patients experienced an aspartate aminotransferase (AST) increase ≥ 2 x ULN, and 1.7% of patients experienced an AST or ALT elevation > 5 x ULN (≥ Grade 3). Hepatotoxicity or increases in liver transaminases led to drug discontinuation in 1.7% of neratinib maleate-treated patients.1

Total bilirubin, AST, ALT, and alkaline phosphatase should be measured prior to starting treatment with neratinib maleate monthly for the first 3 months of treatment, then every 3 months while on treatment and as clinically indicated. These tests should also be performed in patients experiencing Grade 3 diarrhea or any signs or symptoms of hepatotoxicity, such as worsening of fatigue, nausea, vomiting, right upper quadrant tenderness, fever, rash, or eosinophilia.1

Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, neratinib maleate can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of neratinib 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. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for at least 1 month after the last dose.1

Specific Populations

Based on findings from animal studies and the mechanism of action, neratinib maleate can cause fetal harm when administered to a pregnant woman. There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of neratinib to pregnant rabbits during organogenesis resulted in abortions, embryo-fetal death and fetal abnormalities in rabbits at maternal exposures (AUC) approximately 0.2 times exposures in patients at the recommended dose. Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies in the U.S. general population.1

In a fertility and early embryonic development study in female rats, neratinib was administered orally for 15 days before mating to Day 7 of pregnancy, which did not cause embryonic toxicity at doses up to 12 mg/kg/day in the presence of maternal toxicity. A dose of 12 mg/kg/day in rats is approximately 0.5 times the maximum recommended dose of 240 mg/day in patients on a mg/m2 basis. In an embryo-fetal development study in rats, pregnant animals received oral doses of neratinib up to 15 mg/kg/day during the period of organogenesis. No effects on embryo-fetal development or survival were observed. Maternal toxicity was evident at 15 mg/kg/day (approximately 0.6 times the AUC in patients receiving the maximum recommended dose of 240 mg/day). In an embryo-fetal development study in rabbits, pregnant animals received oral doses of neratinib up to 9 mg/kg/day during the period of organogenesis. Administration of neratinib at doses ≥ 6 mg/kg/day resulted in maternal toxicity, abortions and embryo-fetal death (increased resorptions). Neratinib administration resulted in increased incidence of fetal gross external (domed head), soft tissue (dilation of the brain ventricles and ventricular septal defect), and skeletal (misshapen anterior fontanelles and enlarged anterior and/or posterior fontanelles) abnormalities at ≥ 3 mg/kg/day. The AUC(0-t) at 6 mg/kg/day and 9 mg/kg/day in rabbits were approximately 0.5 and 0.8 times, respectively, the AUCs in patients receiving the maximum recommended dose of 240 mg/day. In a peri and postnatal development study in rats, oral administration of neratinib from gestation day 7 until lactation day 20 resulted in maternal toxicity at ≥ 10 mg/kg/day (approximately 0.4 times the maximum recommended dose of 240 mg/day in patients on a mg/m2 basis) including decreased body weights, body weight gains, and food consumption. Effects on long-term memory were observed in male offspring at maternal doses ≥ 5 mg/kg/day (approximately 0.2 times the maximum recommended dose of 240 mg/day in patients on a mg/m2 basis).1

No data are available regarding the presence of neratinib or its metabolites in human milk or its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in breastfed infants from neratinib maleate, advise lactating women not to breastfeed while taking neratinib maleate and for at least 1 month after the last dose.1

Based on animal studies, neratinib maleate can cause fetal harm when administered to a pregnant woman. Females of reproductive potential should have a pregnancy test prior to starting treatment with neratinib maleate.1

Based on animal studies, neratinib maleate can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with neratinib maleate and for at least 1 month after the last dose.1

Based on findings in animal reproduction studies, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of neratinib maleate.1

The safety and efficacy of neratinib maleate in pediatric patients have not been established.1

In the ExteNET trial, the mean age was 52 years in the neratinib maleate arm; 1236 patients were < 65 years, 172 patients were ≥ 65 years, of whom 25 patients were 75 years or older.1

There was a higher frequency of treatment discontinuations due to adverse reactions in the ≥ 65 years age group than in the < 65 years age group; in the neratinib maleate arm, the percentages were 44.8% compared with 25.2%, respectively, and in the placebo arm 6.4% and 5.3%, respectively.1

The incidence of serious adverse reactions in the neratinib maleate arm vs. placebo arm was 7.0% vs. 5.7% (< 65 years-old) and 9.9% vs. 8.1% (≥ 65 years-old). The serious adverse reactions most frequently reported in the ≥ 65 years-old group were vomiting (2.3%), diarrhea (1.7%), renal failure (1.7%), and dehydration (1.2%).1

No dose modifications are recommended for patients with mild to moderate hepatic impairment (Child Pugh A or B). Patients with severe, pre-existing hepatic impairment (Child Pugh Class C) experienced a reduction in neratinib clearance and an increase in Cmax and AUC. Reduce the neratinib maleate dosage for patients with severe hepatic impairment.1

Common Adverse Effects

The most common adverse reactions (> 5%) were diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, AST or ALT increase, nail disorder, dry skin, abdominal distention, decreased weight, and urinary tract infection.1

Advise the patient to read the FDA-approved patient labeling (Patient Information).1

Diarrhea

Inform patients that neratinib maleate has been associated with diarrhea, which may be severe in some cases.1

Instruct patients to maintain 1-2 bowel movements per day and on how to use anti-diarrheal treatment regimens.1

Advise patients to inform their healthcare provider immediately if severe (≥Grade 3) diarrhea or diarrhea associated with weakness, dizziness, or fever occurs during treatment with neratinib maleate.1

Hepatotoxicity

Inform patients that neratinib maleate has been associated with hepatotoxicity, which may be severe in some cases.1

Inform patients that they should report signs and symptoms of liver dysfunction to their healthcare provider immediately.1

Embryo-Fetal Toxicity

Advise females to inform their healthcare provider if they are pregnant or become pregnant. Inform female patients of the risk to a fetus and potential loss of the pregnancy.1

Advise females of reproductive potential to use effective contraception during treatment and for 1 month after receiving the last dose of neratinib maleate.1

Advise lactating women not to breastfeed during treatment with neratinib maleate and for at least 1 month after the last dose.1

Drug Interactions

Neratinib maleate may interact with many drugs; therefore, advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products.1

Neratinib maleate may interact with gastric acid reducing agents. Advise patients to avoid concomitant use of proton pump inhibitors or H2-receptor antagonists. Advise patients to separate the dosing of neratinib maleate by 3 hours after antacid medicine.1

Neratinib maleate may interact with grapefruit. Advise patients to avoid taking neratinib maleate with grapefruit products.1

Dosing and Administration

Instruct patients to take neratinib maleate with food at approximately the same time each day consecutively for one year.1

If a patient misses a dose, instruct the patient not to replace the missed dose, and to resume neratinib maleate with the next scheduled daily dose.1

AHFS First Release. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.