Neratinib is a kinase inhibitor that irreversibly binds to Epidermal Growth Factor Receptor (EGFR), Human Epidermal Growth Factor Receptor 2 (HER2), and HER4. In vitro, Neratinib reduces EGFR and HER2 autophosphorylation, downstream MAPK and AKT signaling pathways, and showed antitumor activity in EGFR and/or HER2 expressing carcinoma cell lines. Neratinib human metabolites M3, M6, M7 and M11 inhibited the activity of EGFR, HER2 and HER4 in vitro. In vivo, oral administration of Neratinib inhibited tumor growth in mouse xenograft models with tumor cell lines expressing HER2 and EGFR.

Absorption: The Neratinib and major active metabolites M3, M6 and M7 peak concentrations are reached in the range of 2 to 8 hours after oral administration.

Distribution: In patients, following multiple doses of Neratinib, the mean (%CV) apparent volume of distribution at steady-state (Vss/F) was 6433 (19%) L. In vitro protein binding of Neratinib in human plasma was greater than 99% and independent of concentration. Neratinib bound predominantly to human serum albumin and human alpha-1 acid glycoprotein.

Elimination: Following 7 days of daily 240 mg oral doses of Neratinib in healthy subjects, the mean (%CV) plasma half-life of Neratinib, M3, M6, and M7 was 14.6 (38%), 21.6 (77%), 13.8 (50%) and 10.4 (33%) hours, respectively. The mean elimination half-life of Neratinib ranged from 7 to 17 hours following a single oral dose in patients. Following multiple doses of Neratinib at once daily 240 mg in cancer patients, the mean (%CV) CL/F after first dose and at steady state (day 21) were 216 (34%) and 281 (40%) L/hour, respectively.

Metabolism: Neratinib is metabolized primarily in the liver by CYP3A4 and to a lesser extent by flavin-containing monooxygenase (FMO).

Excretion: After oral administration of 200 mg (0.83 times of approved recommended dosage) radiolabeled neratinib oral formulation, fecal excretion accounted for approximately 97.1% and urinary excretion accounted for 1.13% of the total dose. Sixty one percent of the excreted radioactivity was recovered within 96 hours and 98% was recovered after 10 days.

Extended Adjuvant Treatment of Early-Stage Breast Cancer: Neratinib as a single agent is indicated for the extended adjuvant treatment of adult patients with early-stage human epidermal growth factor receptor 2 (HER 2 )- positive breast cancer, to follow adjuvant Trastuzumab-based therapy.

Advanced or Metastatic Breast Cancer: Neratinib in combination with Capecitabine is indicated for the treatment of adult patients with advanced or metastatic HER 2 -positive breast cancer who have received two or more prior anti-HER 2 based regimens in the metastatic setting.

Antidiarrheal Prophylaxis: Antidiarrheal prophylaxis is recommended during the first 2 cycles (56 days) of treatment and should be initiated with the first dose of Neratinib. Additional antidiarrheal agents may be required to manage diarrhea in patients with loperamide-refractory diarrhea. Neratinib dose interruptions and dose reductions may also be required to manage diarrhea. The recommended dose of Neratinib is 240 mg (six tablets) given orally once daily with food, continuously for one year. Patients should be instructed to take Neratinib at approximately the same time every day. Neratinib tablets should be swallowed whole (tablets should not be chewed, crushed, or split prior to swallowing). If a patient misses a dose, missed dose should not be replaced, and patients should be instructed to resume Neratinib with the next scheduled daily dose. Or, as directed by the registered physicians.

Dose Modifications: For Adverse Reactions: Neratinib dose modification is recommended based on individual safety and tolerability. Neratinib should be discontinued for patients who fail to recover to Grade 0-1 from treatment-related toxicity, for toxicities that result in a treatment delay >3 weeks, or for patients that are unable to tolerate 120 mg daily. Additional clinical situations may result in dose adjustments as clinically indicated (e.g. intolerable toxicities, persistent Grade 2 adverse reactions, etc.).

Recommended starting dose: 240 mg daily

First dose reduction: 200 mg daily

Second dose reduction: 160 mg daily

Third dose reduction: 120 mg daily

It is contraindicated in patients with known hypersensitivity to Neratinib or any other components of this product.

Diarrhea, Hepatotoxicity.

Overdose Effects

There is no specific antidote, and the benefit of hemodialysis in the treatment of Neratinib overdose is unknown. In the event of an overdose, administration should be withheld and general supportive measures undertaken. In the clinical trial setting, a limited number of patients reported overdose. The adverse reactions experienced by these patients were diarrhea, nausea, vomiting, and dehydration. The frequency and severity of gastrointestinal disorders (diarrhea, abdominal pain, nausea and vomiting) appear to be dose related.

Diarrhea: Aggressively manage diarrhea occurring despite recommended prophylaxis with additional antidiarrheals, fluids, and electrolytes as clinically indicated. Withhold Meratinib in patients experiencing severe and/or persistent diarrhea. Permanently discontinue Meratinib in patients experiencing Grade 4 diarrhea or Grade ≥ 2 diarrhea that occurs after maximal dose reduction.

Hepatotoxicity: Monitor liver function tests monthly for the first 3 months of treatment, then every 3 months while on treatment and as clinically indicated. Withhold Meratinib in patients experiencing Grade 3 liver abnormalities and permanently discontinue Meratinib in patients experiencing Grade 4 liver abnormalities.

Embryo-Fetal Toxicity: Meratinib can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception.

Use in Special Populations

Pediatric Use: The safety and efficacy of Neratinib in pediatric patients has not been established.

Geriatric Use: The incidence of serious adverse reactions in the Neratinib 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%).

Hepatic Impairment: 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. Neratinib dosage should be reduced for patients with severe hepatic impairment.

Pregnancy & Lactation

Neratinib can cause fetal harm when administered to a pregnant woman. There are no available data in pregnant women to inform the drug-associated risk. Pregnant women should be advised of the potential risk to a fetus. 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, lactating women should be advised not to breastfeed while taking Neratinib and for at least 1 month after the last dose.

Neratinib 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. Females: Females of reproductive potential should be advised to use effective contraception during treatment with Neratinib and for at least 1 month after the last dose. Males: Male patients with female partners of reproductive potential should be advised to use effective contraception during treatment and for 3 months after the last dose of Neratinib.