Active Ingredient: Neratinib
Neratinib is indicated for the extended adjuvant treatment of adult patients with early-stage hormone receptor positive HER2-overexpressed/amplified breast cancer and who completed adjuvant trastuzumab-based therapy less than one year ago.
For this indication, competent medicine agencies globally authorize below treatments:
For:
Oral, 240 milligrams neratinib, once daily to breakfast, over the duration of 1 year.
The recommended dose of neratinib is 240 mg taken orally once daily, continuously for one year. Neratinib should be taken with food, preferably in the morning. Patients should initiate treatment within 1 year after completion of trastuzumab therapy.
Neratinib dose modification is recommended based on individual safety and tolerability. Management of some adverse reactions may require dose interruption and/or dose reduction as shown in Table 1, Table 2, Table 3, and Table 4.
Neratinib should be discontinued for patients who:
Additional clinical situations may result in dose adjustments as clinically indicated (e.g. intolerable toxicities, persistent Grade 2 adverse reactions, etc.).
Table 1. Neratinib dose modifications for adverse reactions:
| Dose level | Neratinib dose |
|---|---|
| Recommended starting dose | 240 mg daily |
| First dose reduction | 200 mg daily |
| Second dose reduction | 160 mg daily |
| Third dose reduction | 120 mg daily |
Table 2. Neratinib dose modifications and management – general toxicities*:
| Severity of toxicity† | Action |
|---|---|
| Grade 3 | Stop neratinib until recovery to Grade ≤1 or baseline within 3 weeks of stopping treatment. Then resume neratinib at the next lower dose level. If grade 3 toxicity does not recover within 3 weeks, discontinue neratinib permanently. |
| Grade 4 | Discontinue neratinib permanently. |
* Refer to Table 3 and Table 4 below for management of diarrhoea and hepatotoxicity
† Per CTCAE v4.0
Diarrhoea management requires the correct use of an anti-diarrhoeal medicinal product, dietary changes, and appropriate dose modifications of neratinib. Guidelines for adjusting doses of neratinib in the setting of diarrhoea are shown in Table 3.
Table 3. Dose modifications for diarrhoea:
| Severity of diarrhoea* | Action |
|---|---|
| • Grade 1 diarrhoea [increase of <4 stools per day over baseline] • Grade 2 diarrhoea [increase of 4-6 stools per day over baseline] lasting <5 days • Grade 3 diarrhoea [increase of ≥7 stools per day over baseline; incontinence; hospitalization indicated; limiting self-care activities of daily living] lasting ≤2 days | • Adjust anti-diarrhoeal treatment • Diet modifications • Fluid intake of ~2 L/day should be maintained to avoid dehydration • Once event resolves to Grade ≤1 or baseline, consider restarting anti-diarrhoeal prophylaxis, if appropriate with each subsequent neratinib administration. |
| • Any grade with complicated features† • Grade 2 diarrhoea lasting 5 days or longer‡ • Grade 3 diarrhoea lasting between 2 days and 3 weeks‡ | • Interrupt neratinib treatment • Diet modifications • Fluid intake of ~2 L/day should be maintained to avoid dehydration • If diarrhoea resolves to Grade ≤1 in one week or less, then resume neratinib treatment at the same dose. • If diarrhoea resolves to Grade ≤1 in longer than one week, then resume neratinib treatment at reduced dose (see Table 1). • Once event resolves to Grade ≤1 or baseline, consider restarting anti-diarrhoeal prophylaxis, if appropriate with each subsequent neratinib administration. • If grade 3 diarrhoea persists longer than 3 weeks, discontinue neratinib permanently. |
| • Grade 4 diarrhoea [life-threatening consequences; urgent intervention indicated] | • Permanently discontinue neratinib treatment |
| • Diarrhoea recurs to Grade 2 or higher at 120 mg per day | • Permanently discontinue neratinib treatment |
* Per CTCAE v4.0
† Complicated features include dehydration, fever, hypotension, renal failure, or Grade 3 or 4 neutropenia
‡ Despite being treated with optimal medical therapy
Guidelines for dose adjustment of neratinib in the event of liver toxicity are shown in Table 4.
Table 4. Dose modifications for hepatotoxicity:
| Severity of hepatotoxicity* | Action |
|---|---|
| • Grade 3 ALT (>5-20 x ULN) OR • Grade 3 bilirubin (>3-10 x ULN) | • Stop neratinib until recovery to Grade ≤1 • Evaluate alternative causes • Resume neratinib at the next lower dose level if recovery to Grade ≤1 occurs within 3 weeks. If Grade 3 ALT or bilirubin occurs again despite one dose reduction, permanently discontinue neratinib. • If grade 3 hepatotoxicity persists longer than 3 weeks, discontinue neratinib permanently |
| • Grade 4 ALT (>20 x ULN) OR • Grade 4 bilirubin (>10 x ULN) | • Permanently discontinue neratinib • Evaluate alternative causes |
ULN = Upper Limit Normal; ALT = Alanine Aminotransferase
* Per CTCAE v4.0
Missed doses should not be replaced and treatment should resume with the next scheduled daily dose.
No dose adjustment is required. There is no data in patients ≥85 years of age.
Neratinib should be taken with food, preferably in the morning.
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