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Neratinib

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 growth factor receptor 1, 2, and 4 (HER1, HER2, and HER 4) (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 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 M1

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 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 (HER2) overexpressed/amplified breast cancer (following adjuvant trastuzumab-based therapy).

Contraindications

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

Dosing: Adult

Note: Antidiarrheal prophylaxis is recommended during the first 2 cycles of therapy; initiate with the first neratinib dose (see Premedications below)

Breast cancer (HER2-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 2 cycles 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.

Days 1 to 14: Loperamide 4 mg orally 3 times daily

Days 15 to 56: Loperamide 4 mg orally twice daily

Days 57 to 365: Loperamide 4 mg as needed (maximum: 16 mg/day)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer's labeling; however, renal function does not have a clinically significant effect on neratinib pharmacokinetics.

Dosing: Hepatic Impairment

Preexisting hepatic impairment:

Mild to moderate (Child-Pugh class A or B) impairment: No dosage adjustment is necessary.

Severe (Child-Pugh class C) impairment: Reduce initial dose to 80 mg once daily.

Hepatotoxicity during treatment:

ALT >5 to 20 times ULN (grade 3) or bilirubin >3 to 10 times ULN (grade 3): Interrupt neratinib until recovery to ≤ grade 1 (evaluate for alternative hepatotoxic causes); resume therapy at the next lower dose level (see Dosage Adjustment for Toxicity) if recovery to ≤ grade 1 occurs within 3 weeks.

Recurrent grade 3 ALT or bilirubin elevation despite one dose reduction: Discontinue permanently.

ALT >20 times ULN (grade 4) or bilirubin >10 times ULN (grade 4): Permanently discontinue and evaluate for alternative hepatotoxic causes.

Dosing: Adjustment for Toxicity

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

Recommended neratinib dose reductions for toxicity:

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 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, or grade 3/4 neutropenia): Interrupt 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 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 once daily 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 2 cycles (see Dosing). Avoid concomitant use with proton pump inhibitors and H2-receptor antagonists; 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: Per US labeling: reduce afatinib by 10mg if not tolerated. Per Canadian labeling: avoid 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 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

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. 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. Management: Dabigatran dose reductions may be needed. Specific recommendations vary considerably according to US vs Canadian labeling, specific P-gp inhibitor, renal function, and indication for dabigatran treatment. Refer to full monograph or dabigatran labeling. Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). 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 inhibitors. Similar dose adjustment is not recommended for edoxaban use in atrial fibrillation. Consider therapy modification

Everolimus: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Everolimus. Management: Everolimus dose reductions are required for patients being treated for subependymal giant cell astrocytoma or renal cell carcinoma. See prescribing information for specific dose adjustment and monitoring recommendations. Consider therapy modification

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. Avoid combination

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

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.). Monitor therapy

Pitolisant: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Combined use of pitolisant with a CYP3A4 substrate that has a narrow therapeutic index should be avoided. Other CYP3A4 substrates should be monitored more closely when used with pitolisant. Consider therapy modification

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. Avoid combination

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

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

Venetoclax: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring these combinations. 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%)

Genitourinary: Urinary tract infection (5%)

Hepatic: Increased serum ALT (9% to 10%), inceased serum AST (5% to 7%)

Respiratory: Epistaxis (5%)

<1%, postmarketing, and/or case reports: Cellulitis, dehydration, erysipelas, renal failure, severe abdominal pain, severe diarrhea, 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; the majority developed diarrhea during the first month of treatment. The median time to onset of grade 3 or higher 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 with loperamide has been shown to lower the incidence and severity of diarrhea and is recommended during the first 2 cycles of therapy (begin with the first dose of neratinib). 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, and 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 or higher 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 and H2-receptor antagonists. If antacid administration is necessary, administer neratinib 3 hours after the antacid.

Special populations:

• Elderly: The incidence of serious adverse reactions and treatment discontinuation was higher in patients 65 years and older (compared to patients younger than 65 years) in a clinical trial. The most commonly reported serious adverse reactions in elderly patients included vomiting, diarrhea, renal failure, and dehydration.

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 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 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 dose.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience loss of strength and energy, mouth irritation, mouth sores, lack of appetite, muscle spasm, nail changes, dry skin, or weight loss. Have patient report immediately to prescriber signs of fluid and electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, severe dizziness, passing out, tachycardia, increased thirst, seizures, loss of strength and energy, lack of appetite, urinary retention or change in amount of urine passed, dry mouth, dry eyes, or nausea or vomiting), signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of a urinary tract infection (hematuria, burning or painful urination, polyuria, fever, lower abdominal pain, or pelvic pain), fecal incontinence, severe or persistent diarrhea, or abdominal edema (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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