Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Nerlynx: 40 mg
Pharmacology
Mechanism of Action
Neratinib is an irreversible tyrosine kinase inhibitor of human epidermal growth factor receptor 1, 2, and 4 (HER1, HER2, and HER4) (Chan 2016), as well as epidermal growth factor receptor (EGFR). Neratinib reduces EGFR and HER2 autophosphorylation and downstream MAPK and AKT signaling pathways and demonstrates antitumor activity in EGFR and/or HER2 expressing cancer cell lines.
Pharmacokinetics/Pharmacodynamics
Absorption
A high-fat meal increases neratinib Cmax and AUCinf by 1.7- and 2.2-fold, respectively. A standard breakfast increased neratinib Cmax by 1.2-fold and AUCinf by 1.1-fold.
Distribution
Vss/F: 6,433 L
Metabolism
Primarily hepatic via CYP3A4 (major) and flavin-containing monooxygenase (minor) to active metabolites M3, M6, M7, and M11.
Excretion
Feces (~97%); urine (~1%)
Time to Peak
2 to 8 hours (parent drug and active metabolites M3, M6, and M7)
Half-Life Elimination
7 to 17 hours
Protein Binding
>99% to serum albumin and alpha-1 acid glycoprotein
Use in Specific Populations
Special Populations: Hepatic Function Impairment
In a single dose study of neratinib 120 mg in noncancer patients with chronic hepatic impairment, Cmax and AUC were increased by 273% and 281%, respectively, in patients with severe (Child-Pugh class C) hepatic impairment compared to patients with normal hepatic function.
Use: Labeled Indications
Breast cancer: Extended adjuvant treatment of early stage human epidermal growth receptor type 2-positive breast cancer (following adjuvant trastuzumab-based therapy).
Contraindications
There are no contraindications listed in the US manufacturer's labeling.
Canadian labeling: Hypersensitivity to neratinib or any component of the formulation.
Dosage and Administration
Dosing: Adult
Note: Antidiarrheal prophylaxis is recommended during the first 8 weeks (56 days) of therapy; initiate with the first neratinib dose (see Premedications below).
Breast cancer (human epidermal growth receptor type 2-positive), extended adjuvant therapy: Oral: 240 mg once daily for 1 year (Chan 2016).
Missed dose: If a dose is missed, resume therapy with the next scheduled daily dose; do not replace the missed dose.
Premedication: Antidiarrheal prophylaxis is recommended during the first 8 weeks (56 days) of therapy; initiate with the first neratinib dose. Titrate to 1 to 2 bowel movements/day. Additional antidiarrheal medication may be required for loperamide-refractory diarrhea.
Weeks 1 to 2 (days 1 to 14): Loperamide 4 mg orally 3 times daily.
Weeks 3 to 8 (days 15 to 56): Loperamide 4 mg orally twice daily.
Weeks 9 to 52 (days 57 to 365): Loperamide 4 mg as needed (maximum: 16 mg/day).
Dosing: Geriatric
Refer to adult dosing.
Dosing: Adjustment for Toxicity
Discontinue neratinib if toxicity does not recover to ≤ grade 1, for toxicities that result in a treatment delay of >3 weeks, or in patients unable to tolerate the 120 mg once daily dose.
Recommended neratinib dose reductions for toxicity:
Initial (usual) starting dose: 240 mg once daily.
First dose reduction: 200 mg once daily.
Second dose reduction: 160 mg once daily.
Third dose reduction: 120 mg once daily.
Diarrhea:
Grade 1: Increase of <4 stools/day over baseline.
Grade 2: Increase of 4 to 6 stools/day over baseline.
Grade 3: Increase of ≥7 stools/day over baseline; incontinence; hospitalization indicated; limiting self-care activities of daily living.
Grade 4: Life-threatening consequences; urgent intervention necessary.
Grade 1, grade 2 (lasting <5 days), or grade 3 diarrhea (lasting ≤2 days): Adjust antidiarrheal medication and diet; maintain fluid intake of ~2 L. When diarrhea has improved to ≤ grade 1 or baseline, initiate loperamide 4 mg with each subsequent neratinib dose.
Grade 2 diarrhea lasting 5 days or longer, or grade 3 diarrhea lasting longer than 2 days (despite optimal antidiarrheal management), or any grade diarrhea with complicating features (eg, dehydration, fever, hypotension, renal failure, grade 3/4 neutropenia): Interrupt neratinib treatment. Modify diet; maintain fluid intake of ~2 L. If diarrhea improves to ≤ grade 1 in 1 week or less, resume neratinib at the same dose. If diarrhea improves to ≤ grade 1 in more than 1 week, resume neratinib at the next lower dose. When diarrhea has improved to ≤ grade 1 or baseline, initiate loperamide 4 mg with each subsequent neratinib dose.
Recurrent ≥ grade 2 diarrhea (occurring at 120 mg once daily dose): Permanently discontinue neratinib.
Grade 4 diarrhea: Permanently discontinue neratinib.
Other toxicities:
Grade 3: Interrupt neratinib treatment until toxicity improves to ≤ grade 1 or baseline within 3 weeks of stopping neratinib. Upon recovery, resume neratinib at the next lower dose.
Grade 4: Permanently discontinue neratinib.
Administration
Administer orally with food at approximately the same time each day. Swallow tablets whole; do not crush, chew, or split tablets. Antidiarrheal prophylaxis is recommended during the first 8 weeks (see Dosing). Avoid concomitant use with proton pump inhibitors. If H2-receptor antagonist use is necessary, administer neratinib at least 2 hours before or 10 hours after the H2-receptor antagonist dose. If antacids are necessary, administer neratinib 3 hours after antacids.
Storage
Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F).
Drug Interactions
Afatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: Reduce afatinib by 10 mg if not tolerated. Some non-US labeling recommends avoiding combination if possible. If used, administer the P-gp inhibitor simultaneously with or after the dose of afatinib. Consider therapy modification
Antacids: May decrease the serum concentration of Neratinib. Specifically, antacids may reduce neratinib absorption. Management: Separate the administration of neratinib and antacids by giving neratinib at least 3 hours after the antacid. Consider therapy modification
Betrixaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Betrixaban. Management: Decrease the adult betrixaban dose to an initial single dose of 80 mg followed by 40 mg once daily if combined with a P-glycoprotein inhibitor. Consider therapy modification
Bilastine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bilastine. Management: Consider alternatives when possible; bilastine should be avoided in patients with moderate to severe renal insufficiency who are receiving p-glycoprotein inhibitors. Consider therapy modification
Brentuximab Vedotin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. Monitor therapy
Celiprolol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Celiprolol. Monitor therapy
Cimetidine: May increase the serum concentration of Neratinib. Cimetidine may decrease the serum concentration of Neratinib. Specifically, cimetidine may reduce neratinib absorption. Management: Avoid concomitant use of neratinib and cimetidine. Avoid combination
Ciprofloxacin (Systemic): May increase the serum concentration of Neratinib. Management: Avoid concomitant use of neratinib and ciprofloxacin if possible. If combined, monitor for increased neratinib effects/toxicities. Consider therapy modification
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
Clotrimazole (Oral): May increase the serum concentration of Neratinib. Management: Avoid concomitant use of neratinib and clotrimazole if possible. If combined, monitor for increased neratinib effects/toxicities. Consider therapy modification
Colchicine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Colchicine. Colchicine distribution into certain tissues (e.g., brain) may also be increased. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a p-glycoprotein inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. See full monograph for details. Consider therapy modification
Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination
CycloSPORINE (Systemic): May increase the serum concentration of Neratinib. Management: Avoid concomitant use of neratinib and cyclosporine if possible. If combined, monitor for increased neratinib effects/toxicities. Consider therapy modification
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Neratinib. Avoid combination
CYP3A4 Inducers (Strong): May decrease the serum concentration of Neratinib. Avoid combination
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Neratinib. Avoid combination
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Neratinib. Avoid combination
Dabigatran Etexilate: P-glycoprotein/ABCB1 Inhibitors may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Monitor therapy
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Digoxin: Neratinib may increase the serum concentration of Digoxin. Monitor therapy
DOXOrubicin (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to P-glycoprotein inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification
Edoxaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban. Management: See full monograph for details. Reduced doses are recommended for patients receiving edoxaban for venous thromboembolism in combination with certain P-gp inhibitors. Similar dose adjustment is not recommended for edoxaban use in atrial fibrillation. Consider therapy modification
Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
Everolimus: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Everolimus. Monitor therapy
FluvoxaMINE: May increase the serum concentration of Neratinib. Management: Avoid concomitant use of neratinib and fluvoxamine if possible. If combined, monitor for increased neratinib effects/toxicities. Consider therapy modification
Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination
Histamine H2 Receptor Antagonists: May decrease the serum concentration of Neratinib. Specifically, histamine H2 receptor antagonists may reduce neratinib absorption. Management: Administer neratinib at least 2 hours before or 10 hours after administration of a histamine H2 receptor antagonist to minimize the impact of this interaction. Avoid combination
Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination
Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
Larotrectinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Larotrectinib. Monitor therapy
Naldemedine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naldemedine. Monitor therapy
Naloxegol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naloxegol. Monitor therapy
Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
PAZOPanib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of PAZOPanib. Avoid combination
P-glycoprotein/ABCB1 Substrates: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Exceptions: Loperamide. Monitor therapy
Proton Pump Inhibitors: May decrease the serum concentration of Neratinib. Specifically, proton pump inhibitors may reduce neratinib absorption. Avoid combination
Prucalopride: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Prucalopride. Monitor therapy
Ranolazine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ranolazine. Monitor therapy
RifAXIMin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RifAXIMin. Monitor therapy
Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Silodosin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Silodosin. Monitor therapy
Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Simeprevir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification
Talazoparib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Talazoparib. Management: These listed exceptions are discussed in detail in separate interaction monographs. Monitor therapy
Tegaserod: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Tegaserod. Monitor therapy
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Tofisopam: May increase the serum concentration of Neratinib. Management: Avoid concomitant use of neratinib and tofisopam if possible. If combined, monitor for increased neratinib effects/toxicities. Consider therapy modification
Topotecan: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Topotecan. Avoid combination
Ubrogepant: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ubrogepant. Management: Use an initial ubrogepant dose of 50 mg and second dose (if needed) of 50 mg when used with a P-gp inhibitor. Consider therapy modification
Venetoclax: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Consider a venetoclax dose reduction by at least 50% in patients requiring concomitant treatment with P-glycoprotein (P-gp) inhibitors. Consider therapy modification
VinCRIStine (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of VinCRIStine (Liposomal). Avoid combination
Adverse Reactions
>10%:
Central nervous system: Fatigue (27%)
Dermatologic: Skin rash (18%)
Gastrointestinal: Diarrhea (95%), nausea (43%), abdominal pain (36%), vomiting (26%), stomatitis (14%), decreased appetite (12%)
Neuromuscular & skeletal: Muscle spasm (11%)
1% to 10%:
Dermatologic: Nail disease (8%), xeroderma (6%), skin fissure (2%)
Endocrine & metabolic: Weight loss (5%), dehydration (4%)
Gastrointestinal: Dyspepsia (10%), abdominal distension (5%), xerostomia (3%), severe diarrhea (2%)
Genitourinary: Urinary tract infection (5%)
Hepatic: Increased serum alanine aminotransferase (9% to 10%), increased serum aspartate aminotransferase (5% to 7%)
Respiratory: Epistaxis (5%)
Frequency not defined: Hepatic: Hepatotoxicity
<1%, postmarketing, and/or case reports: Cellulitis, erysipelas, renal failure syndrome, severe abdominal pain, severe fatigue, severe nausea, severe vomiting
Warnings/Precautions
Concerns related to adverse effects:
- GI toxicity: 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 (antidiarrhea prophylaxis was not used in the trial); the majority developed diarrhea during the first month of treatment. The median time to onset of ≥ grade 3 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 has been shown to lower the incidence and severity of diarrhea; loperamide is recommended during the first 8 weeks (56 days) of therapy (begin with the first dose of neratinib); consider adding other agents to loperamide as clinically necessary. 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.
- Hepatoxicity: Hepatotoxicity characterized by elevated liver enzymes has been reported with neratinib therapy. ALT and AST elevations have been observed; transaminase elevations and hepatotoxicity 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 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:
- Hepatic impairment: 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:
- Drug-drug interactions: 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.
- Drugs that affect gastric pH: 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. Administer neratinib at least 2 hours before or 10 hours after the dose of an H2-receptor antagonist. If antacid administration is necessary, administer neratinib 3 hours after antacids.
Special populations:
- Elderly: The incidence of serious adverse reactions and treatment discontinuation was higher in patients ≥65 years of age (compared to patients <65 years of age) in a clinical trial. The most commonly reported serious adverse reactions in elderly patients included vomiting, diarrhea, renal failure, and dehydration.
Other warnings/precautions:
- Appropriate use: Guidelines from the American Society of Clinical Oncology (ASCO) for selection of optimal adjuvant chemotherapy and targeted therapy in early breast cancer supports the use of extended adjuvant neratinib therapy in patients with early stage human epidermal growth receptor type 2-positive, hormone receptor-positive, and node-positive breast cancer, with patients beginning neratinib within 1 year of completion of trastuzumab therapy deriving the most benefit (ASCO [Denduluri 2018]).
Monitoring Parameters
Liver function tests (ALT, AST, bilirubin, and alkaline phosphatase) prior to treatment initiation, monthly for the first 3 months, then every 3 months thereafter or as clinically indicated; fractionated bilirubin and prothrombin time if clinically necessary; pregnancy test prior to therapy initiation in women of reproductive potential; monitor for diarrhea and signs/symptoms of dehydration and hepatotoxicity (eg, worsening fatigue, nausea, vomiting, right upper quadrant tenderness or pain, fever, rash, or eosinophilia). Monitor adherence.
Pregnancy
Pregnancy Considerations
Based on the mechanism of action and data from animal reproduction studies, use of neratinib in pregnancy may cause fetal harm. Women of reproductive potential should have a pregnancy test prior to treatment; effective contraception should be used during therapy and for at least 1 month after the last neratinib dose. Male patients with female partners of reproductive potential should also use effective contraception during therapy and for at least 3 months after the last neratinib dose.
Patient Education
What is this drug used for?
- It is used to treat breast cancer.
Frequently reported side effects of this drug
- Loss of strength and energy
- Mouth irritation
- Mouth sores
- Lack of appetite
- Muscle spasm
- Nail changes
- Dry skin
- Weight loss
- Abdominal pain
- Nausea
- Vomiting
- Lack of appetite
Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:
- Fluid and electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, severe dizziness, passing out, fast heartbeat, increased thirst, seizures, loss of strength and energy, lack of appetite, unable to pass urine or change in amount of urine passed, dry mouth, dry eyes, or nausea or vomiting
- Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain
- Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes
- Urinary tract infection like blood in the urine, burning or painful urination, passing a lot of urine, fever, lower abdominal pain, or pelvic pain
- More than 2 bowel movements in 1 day
- Abdominal swelling
- Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.
Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.
Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.
