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Neratinib

Medically reviewed by Drugs.com. Last updated on Jun 6, 2020.

Pronunciation

(ne RA ti nib)

Index Terms

  • HKI-272

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Nerlynx: 40 mg

Brand Names: U.S.

  • Nerlynx

Pharmacologic Category

  • Antineoplastic Agent, Anti-HER2
  • Antineoplastic Agent, Epidermal Growth Factor Receptor (EGFR) Inhibitor
  • Antineoplastic Agent, Tyrosine Kinase Inhibitor

Pharmacology

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.

Absorption

A high-fat meal increases neratinib Cmax and AUCinf by 70% and 120%, respectively. A standard breakfast increased neratinib Cmax by 20% and AUCinf by 10%.

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

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 173% and 181%, respectively, in patients with severe (Child-Pugh class C) hepatic impairment compared to normal hepatic function controls.

Use: Labeled Indications

Breast cancer:

Extended adjuvant treatment (as a single agent) of early-stage human epidermal growth receptor type 2 (HER2)-positive breast cancer (following adjuvant trastuzumab-based therapy).

Treatment of advanced or metastatic HER2-positive breast cancer (in combination with capecitabine) in patients who have received 2 or more prior anti-HER2 based regimens in the metastatic setting.

Contraindications

There are no contraindications listed in the manufacturer's US labeling.

Canadian labeling: Hypersensitivity to neratinib or any component of the formulation.

Dosing: Adult

Note: Antidiarrheal prophylaxis is recommended during the first 56 days of therapy; initiate with the first neratinib dose (see Premedications below).

Breast cancer (HER2-positive), extended adjuvant therapy: Oral: 240 mg once daily (as a single agent) until disease recurrence or for up to 1 year (Chan 2016).

Breast cancer (HER2-positive), advanced or metastatic: 240 mg once daily on days 1 to 21 of a 21-day cycle (in combination with capecitabine [on days 1 to 14 only]) until disease progression or unacceptable toxicity (Saura 2020).

Reduced initial dosing strategy (off-label dosing): To improve neratinib tolerability and decrease the rate, severity, and duration of neratinib-induced diarrhea, a dose escalation strategy has been described; loperamide was administered as needed in addition to neratinib dose escalation (Barcenas 2020):

Days 1 to 7: Neratinib 120 mg once daily.

Days 8 to 14: Neratinib 160 mg once daily.

Day 15 and thereafter: Neratinib 240 mg once daily.

Missed dose: If a dose is missed, resume neratinib with the next scheduled daily dose; do not replace the missed dose.

Premedication (manufacturer's labeling): Administer antidiarrheal prophylaxis during the first 56 days of therapy; initiate with the first neratinib dose. After day 56, titrate loperamide to achieve 1 to 2 bowel movements/day. Additional antidiarrheal medication, fluids, and electrolytes 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; titrate loperamide dose to achieve 1 to 2 bowel movements per day).

Note: The addition of budesonide or colestipol to loperamide prophylaxis has also been described to decrease the rate, severity, and duration of neratinib-induced diarrhea (Barcenas 2020):

Budesonide 9 mg orally once daily in the morning for the first 28 days, in addition to loperamide prophylaxis as described above.

Colestipol 2 g orally twice daily for the first 28 days, in addition to loperamide prophylaxis as described above.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

Discontinue neratinib if toxicity does not recover to ≤ grade 1 or baseline, for toxicities that result in a treatment delay of >3 weeks, or in patients unable to tolerate neratinib 120 mg once daily.

Capecitabine may also require dose adjustment due to toxicity; refer to capecitabine monograph for further information.

Recommended neratinib dose reductions for toxicity:

Neratinib monotherapy:

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.

Neratinib (in combination with capecitabine):

Initial (usual) neratinib starting dose: 240 mg once daily.

First neratinib dose reduction: 160 mg once daily.

Second neratinib dose reduction: 120 mg once daily.

Diarrhea:Management may require antidiarrheal medications, dietary changes, fluid and electrolyte replacement, and dose modification.

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.

Neratinib monotherapy dose adjustments for diarrhea:

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 grade 3 diarrhea lasting >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 level. 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.

Neratinib (in combination with capecitabine) dose adjustments for diarrhea:

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. No dose adjustment necessary for either neratinib or capecitabine.

Persisting and intolerable grade 2 diarrhea lasting >5 days, grade 3 diarrhea lasting >2 days, or grade 4 diarrhea: Interrupt neratinib and capecitabine treatment. Adjust antidiarrheal therapy. Modify diet; maintain fluid intake of ~2 L.

If diarrhea improves to ≤ grade 1 in ≤1 week, resume neratinib and capecitabine at the same dose.

If diarrhea improves to ≤ grade 1 in 1 to 3 weeks, resume neratinib at the next lower dose level (resume capecitabine at the same dose).

If event occurs a second time and the neratinib dose has not already been reduced, reduce neratinib to 160 mg daily (maintain the same capecitabine dose). If neratinib dose has already been reduced, reduce capecitabine dose to 550 mg/m2 twice daily (maintain the same neratinib dose).

If subsequent events occur, reduce the neratinib or capecitabine dose to the next lower dose level in an alternate fashion (ie, reduce capecitabine to 375 mg/m2 twice daily if neratinib was previously reduced, or reduce neratinib to 120 mg daily if capecitabine was previously reduced).

When diarrhea has improved to ≤ grade 1 or baseline, initiate loperamide 4 mg with each subsequent neratinib dose level.

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 level.

Grade 4: Permanently discontinue neratinib.

Administration

Oral: 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

Abametapir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Afatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: If combined, administer the P-gp inhibitor simultaneously with, or after, the dose of afatinib. Monitor closely for signs and symptoms of afatinib toxicity and if the combination is not tolerated, reduce the afatinib dose by 10 mg. Consider therapy modification

Aliskiren: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Aliskiren. Monitor therapy

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

Aprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Betrixaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Betrixaban. Management: Decrease adult betrixaban dose to an initial single dose of 80 mg followed by 40 mg once daily if combined with a P-gp inhibitor. Avoid concomitant use of betrixaban and P-gp inhibitors in patients with severe renal impairment (CrCL less than 30 mL/min). Consider therapy modification

Bilastine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bilastine. Avoid combination

Celiprolol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Celiprolol. Monitor therapy

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

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-gp inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. See interaction monograph for details. Consider therapy modification

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

CycloSPORINE (Systemic): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of CycloSPORINE (Systemic). Monitor therapy

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. Monitor therapy

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

Digitoxin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Digitoxin. Monitor therapy

Digoxin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Digoxin. Management: Measure digoxin serum concentrations before initiating treatment with these P-glycoprotein (P-gp) inhibitors. Reduce digoxin concentrations by either reducing the digoxin dose by 15% to 30% or by modifying the dosing frequency. Consider therapy modification

DOXOrubicin (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Conventional). Avoid combination

Duvelisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Edoxaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban. Management: Exceptions to this monograph are discussed in separate Lexi-Interact monographs. Monitor therapy

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

Etoposide: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Etoposide. Monitor therapy

Etoposide Phosphate: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Etoposide Phosphate. Monitor therapy

Everolimus: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Everolimus. Monitor therapy

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fosnetupitant: 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

Glecaprevir and Pibrentasvir: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Glecaprevir and Pibrentasvir. Monitor therapy

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. Consider therapy modification

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Inhibitors of CYP3A4 (Moderate) and P-glycoprotein: May increase the serum concentration of Neratinib. Avoid combination

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Lapatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Lapatinib. 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

Lefamulin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Lefamulin. Management: Avoid concomitant use of lefamulin tablets with P-glycoprotein/ABCB1 inhibitors. If concomitant use is required, monitor for lefamulin adverse effects. Consider therapy modification

Morphine (Systemic): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Morphine (Systemic). Monitor therapy

Nadolol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Nadolol. 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

Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). 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

Proton Pump Inhibitors: May decrease the serum concentration of Neratinib. Specifically, proton pump inhibitors may reduce neratinib absorption. Avoid combination

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

Rimegepant: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Rimegepant. Avoid combination

RisperiDONE: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RisperiDONE. Monitor therapy

RomiDEPsin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RomiDEPsin. 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

Sirolimus: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Sirolimus. Management: Avoid concurrent use of sirolimus with P-glycoprotein (P-gp) inhibitors when possible and alternative agents with lesser interaction potential with sirolimus should be considered. Monitor for increased sirolimus concentrations/toxicity if combined. Consider therapy modification

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

Tacrolimus (Systemic): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Tacrolimus (Systemic). Monitor therapy

Talazoparib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Talazoparib. Monitor therapy

Tegaserod: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Tegaserod. Monitor therapy

Teniposide: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Teniposide. Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Tolvaptan: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Tolvaptan. Monitor therapy

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 (at least 2 hours later 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: Reduce the venetoclax dose by at least 50% in patients requiring concomitant treatment with P-glycoprotein (P-gp) inhibitors. Resume the previous venetoclax dose 2 to 3 days after discontinuation of a P-gp inhibitor. Consider therapy modification

VinCRIStine (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of VinCRIStine (Liposomal). Avoid combination

Adverse Reactions

>10%:

Dermatologic: Skin rash (18%)

Gastrointestinal: Abdominal pain (36%; severe abdominal pain: <1%), decreased appetite (12%), diarrhea (95%; severe diarrhea: 2%), nausea (43%; severe nausea: <1%), stomatitis (14%; grade 3: <1%), vomiting (26%; severe vomiting: <1%)

Nervous system: Fatigue (27%; severe fatigue: <1%)

Neuromuscular & skeletal: Muscle spasm (11%)

1% to 10%:

Dermatologic: Nail disease (8%), skin fissure (2%), xeroderma (6%)

Endocrine & metabolic: Dehydration (4%; severe dehydration: <1%), weight loss (5%)

Gastrointestinal: Abdominal distension (5%), dyspepsia (10%), xerostomia (3%)

Genitourinary: Urinary tract infection (5%)

Hepatic: Increased serum alanine aminotransferase (9% to 10%; severely increased serum alanine aminotransferase: <1%), increased serum aspartate aminotransferase (5% to 7%; severely increased serum aspartate aminotransferase: <1%)

Respiratory: Epistaxis (5%)

<1%:

Dermatologic: Cellulitis, erysipelas

Renal: Renal failure syndrome

Frequency not defined: Hepatic: Hepatotoxicity

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 (both as monotherapy and in combination with capecitabine) treatment. The majority of patients receiving neratinib in clinical trials experienced diarrhea; most developed diarrhea during the first month of treatment (antidiarrhea prophylaxis was not required in one trial, although was required during cycle one in another trial). The median time to onset of ≥ grade 3 diarrhea was 8 to 11 days (range: 1 day to 728 days); the median cumulative duration of toxicity was 3 to 5 days (range: 1 day to 139 days). Antidiarrheal prophylaxis has been shown to lower the incidence and severity of diarrhea; multiple strategies have been described to prevent and treat neratinib-induced diarrhea. Per the manufacturer, loperamide is recommended during the first 56 days of therapy (begin with the first dose of neratinib); after day 56, titrate loperamide dose to achieve 1 to 2 bowel movements per day. Utilizing a neratinib dose escalation strategy or adding budesonide or colestipol to loperamide have been shown to further decrease diarrhea incidence (Barcenas 2020). 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:

• 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 clinical trials. The most commonly reported serious adverse reactions in elderly patients included vomiting, diarrhea, acute kidney injury, 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

LFTs (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; evaluate pregnancy status prior to therapy initiation (in females 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.

Reproductive Considerations

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 3 months after the last neratinib dose.

Pregnancy Considerations

Based on the mechanism of action and data from animal reproduction studies, use of neratinib in pregnancy may cause fetal harm.

Patient Education

What is this drug used for?

• It is used to treat breast cancer.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• 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

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• 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 an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, 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 limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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