Neratinib

Uses

Neratinib is a kinase inhibitor used for the extended adjuvant treatment of adult patients with early stage HER2-overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy.
Pediatric Use: The safety and efficacy of Neratinib in pediatric patients has not been established.

Neratinib is also used to associated treatment for these conditions: Breast Cancer

How Neratinib works

Neratinib binds to and irreversibly inhibits EGFR, HER2, and HER4 [FDA Label]. This prevents auotphoshorylation of tyrosine residues on the receptor and reduces oncogenic signalling through the mitogen-activated protein kinase and Akt pathways.

Dosage

Neratinib dosage

Antidiarrheal prophylaxis: Initiate loperamide with the first dose of Neratinib and continue during first 2 cycles (56 days) of treatment. Instruct patients to maintain 1-2 bowel movements per day and on how to use antidiarrheal treatment regimens

Recommended dose: 240 mg (6 tablets) given orally once daily with food, continuously for one year. Dose interruptions and/or dose reductions are recommended based on individual safety and tolerability

Hepatic Impairment: Reduce starting dose to 80 mg in patients with severe hepatic impairment.

Side 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, weight decreased and urinary tract infection.

Toxicity

Use of neratinib may produce diarrhea and hepatotoxicity as clinically significant adverse effects [FDA Label]. Serious adverse reactions in the neratinib arm of the clinical trials included diarrhea (1.6%), vomiting (0.9%), dehydration (0.6%), cellulitis (0.4%), renal failure (0.4%), erysipelas (0.4%), alanine aminotransferase increase (0.3%), aspartate aminotransferase increase (0.3%), nausea (0.3%), fatigue (0.2%), and abdominal pain (0.2%).

Precaution

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.

Interaction

Gastric acid reducing agents: Avoid concomitant use with proton pump inhibitors (PPI) and H2-receptor antagonists. Separate Neratinib by 3 hours after antacid dosing.

Strong or moderate CYP3A4 inhibitors: Avoid concomitant use.

Strong or moderate CYP3A4 inducers: Avoid concomitant use. 

P-glycoprotein (P-gp) substrates: Monitor for adverse reactions of narrow therapeutic agents that are P-gp substrates when used concomitantly with Neratinib.

Food Interaction

• Avoid grapefruit products. Grapefruit inhibits CYP3A metabolism, which may increase the serum concentration of neratinib.
• Exercise caution with St. John's Wort. This herb induces CYP3A metabolism and may reduce serum levels of neratinib.
• Take at the same time every day.
• Take separate from antacids. Take antacids at least 3 hours before or after neratinib.
• Take with food.

[Major] GENERALLY AVOID: Grapefruit, grapefruit juice, grapefruit hybrids, pomelos, star-fruit, and Seville oranges may increase the plasma concentrations of neratinib.

The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in these fruits.

Inhibition of hepatic CYP450 3A4 may also contribute.

In a study consisting of 24 healthy subjects, neratinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 3.2- and 4.8-fold, respectively, when a single 240 mg oral dose of neratinib was administered with the potent CYP450 3A4 inhibitor ketoconazole (400 mg once daily for 5 days).

Also, mean apparent oral clearance of neratinib decreased by approximately 75% and mean elimination half-life increased by 54%.

The interaction has not been studied with these fruits.

In general, for example, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands.

Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition.

Increased exposure to neratinib may increase adverse effects such as diarrhea, nausea, vomiting, abdominal pain, stomatitis, anorexia, and hepatotoxicity.

Food with a high fat content enhances the oral bioavailability of neratinib.

In healthy volunteers, administration of neratinib 240 mg with a high-fat meal (approximately 55% fat; 31% carbohydrate; 14% protein) increased neratinib peak plasma concentration (Cmax) and systemic exposure (AUC) by 1.7- and 2.2-fold, respectively, compared to administration under fasting conditions.

By contrast, a standard breakfast (approximately 50% carbohydrate; 35% fat; 15% protein) increased the Cmax and AUC of neratinib by 1.2- and 1.1-fold, respectively.

MANAGEMENT: The manufacturer recommends administering neratinib with food at approximately the same time every day.

Patients should avoid consumption of grapefruit, grapefruit juice, grapefruit hybrids, pomelos, star-fruit, and Seville oranges during treatment with neratinib.

Neratinib Drug Interaction

Moderate: calcium / vitamin d, docetaxelUnknown: aripiprazole, phentermine, fluticasone / salmeterol, erenumab, zolpidem, anastrozole, thyroid desiccated, exemestane, mometasone, aspirin, lorazepam, cyanocobalamin, nebivolol, loratadine, loratadine / pseudoephedrine, docusate, trastuzumab, cholecalciferol

Neratinib Disease Interaction

Major: liver dysfunction

Volume of Distribution

The apparent volume of distribution at steady state is 6433 L [FDA Label].

Elimination Route

Neratinib and its major active metabolites M3. M6, and M7 have a Tmax of 2-8 h [FDA Label]. Administration with a high fat meal increases Cmax by 1.7-fold and total exposure by 2.2-fold. Administration with a standard meal increases Cmax by 1.2-fold and total exposure by 1.1-fold. Administration with gastric acid reducing agents such as proton pump inhibitors reduces Cmax by 71% and total exposure by 65%.

Half Life

The mean half life of elimination ranges from 7-17 h following a single dose [FDA Label]. The mean plasma half life during multiple doses is 14.6 h for neratinib, 21.6 h for M3, 13.8 h for M6, and 10.4 h for M7.

Clearance

The total clearance during multiple doses is 216 L/h for after the first dose and 281 L/h during steady state [FDA Label].

Elimination Route

97.1% of the total dose is excreted in the feces and 1.13% in the urine [FDA Label].

Pregnancy & Breastfeeding use

There are no available data in pregnant women to inform the drug-associated risk. 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.

Contraindication

None

Acute Overdose

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.

Storage Condition

Store Neratinib at room temperature between 20° to 25°C. Keep Neratinib and all medicines out of the reach of children.

Innovators Monograph

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