Neratinib (Nerlynx) - Uses, MOA, Dose, Side effects

Neratinib (Nerlynx) is a tyrosine kinase inhibitor that is indicated in the early treatment of HER-2 positive breast cancer after surgical resection for an extended period of time.

Neratinib (Nerlynx) Uses:

  • Breast cancer:

    • Extended adjuvant treatment of initial stage human epidermal growth receptor type 2 (HER2) overexpressed/ amplified breast cancer (following adjuvant trastuzumab-based therapy).

Neratinib (Nerlynx) Dose in Adults

Note:

  • During the first 2 cycles of therapy, Antidiarrheal prophylaxis is recommended.
  • Initiate with the first neratinib dose (see Premedications below)

Neratinib (Nerlynx) Dose in the treatment of HER2-positive Breast cancer, extended adjuvant therapy:

  • P/O:
    • 240 mg once daily for one year.
  • Missed dose:
    • Resume therapy with the next scheduled daily dose if a dose is missed.
    • do not replace the missed dose.
  • Premedication:
    • During the first 2 cycles of therapy, Antidiarrheal prophylaxis is recommended.
    • Initiate with the first neratinib dose.
    • Titrate to 1 to 2 bowel movements/day.
    • For loperamide-refractory diarrhea, additional antidiarrheal medication may be required.
    • Days 1-14:
      • Loperamide 4 mg orally 3 times daily
    • Days 15-56:
      • Loperamide 4 mg orally twice daily
    • Days 57-365:
      • Loperamide 4 mg as needed (max: 16 mg/day)

Use in Children:

Not recommended

Neratinib (Nerlynx) Pregnancy Risk Category: N (not defined)

  • Pregnancy may be a risk with neratinib. This is based on data from animal reproduction studies and the mechanism of action.
  • Women with reproductive potential should undergo a pregnancy test before they are treated.
  • Effective contraception must be used during therapy and for at least one month after the last dose.
  • Effective contraception should be used by male patients who have female partners with reproductive potential.

Use of Neratinib while breastfeeding

  • It is unknown if neratinib can be found in breast milk.
  • According to the manufacturer, breastfeeding is not advised during therapy or for at most one month following the last dose of neratinib.

Neratinib (Nerlynx) Dose in Kidney Disease:

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

Neratinib (Nerlynx) Dose in Liver disease:

  • 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):
      • Until recovery to ≤ grade 1, Interrupt neratinib (evaluate for alternative hepatotoxic causes).
      • If recovery to ≤ grade 1 occurs within 3 weeks, resume therapy at the next lower dose level (see Dosage Adjustment for Toxicity).
    • 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 & evaluate for alternative hepatotoxic causes.

Common Side Effects of Neratinib (Nerlynx):

  • Central Nervous System:

    • Fatigue
  • Dermatologic:

    • Skin Rash
  • Gastrointestinal:

    • Diarrhea
    • Nausea
    • Abdominal Pain
    • Vomiting
    • Stomatitis
    • Decreased Appetite
  • Neuromuscular & Skeletal:

    • Muscle Spasm

Less Common Side Effects of Neratinib (Nerlynx):

  • Dermatologic:

    • Nail Disease
    • Xeroderma
    • Skin Fissure
  • Endocrine & Metabolic:

    • Weight Loss
    • Dehydration
  • Gastrointestinal:

    • Dyspepsia
    • Abdominal Distension
    • Xerostomia
  • Genitourinary:

    • Urinary Tract Infection
  • Hepatic:

    • Increased Serum ALT
    • Increased Serum AST
  • Respiratory:

    • Epistaxis

Contraindications to Neratinib (Nerlynx):

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

Warnings and precautions

  • Toxicity to the GI:

    • Severe diarrhea can be caused by neratinib treatment. This may lead to hypotension, dehydration, and even renal failure.
    • Nearly all of the patients who received neratinib suffered from diarrhea in a clinical trial.
    • The majority of patients developed diarrhea within the first month of treatment.
    • The median time it took for grade 3 or higher diarrhea to start was 8 days. This ranges from 1 day to 350 days.
    • The median cumulative duration for toxicities was five days. (range: 1 to 139 days).
    • Antidiarrheal prophylaxis using loperamide has been proven to lower the incidence. It is recommended for the first two cycles of therapy (begin by taking the first dose of neurotinib).
    • Pay attention to possible complications such as diarrhea.
    • Other antidiarrheals might be required.
    • As needed, administer fluids and electrolytes.
    • To rule out infectious causes of diarrhea, stool cultures may be necessary.
    • Diarrhea can require treatment interruption, dosage reductions, and discontinuation.
    • There have been reports of nausea, vomiting, stomach pain, and stomatitis.
  • Hepatoxicity

    • Hepatotoxicity, which is characterized by high liver enzymes, has been reported with neratinib therapy.
    • Some patients have experienced ALT & AST elevations, which have caused them to stop receiving treatment.
    • Before treatment initiation, perform liver function tests (ALT and AST, total bilirubin and alkaline phosphatase) monthly for the first three months and then every three months thereafter, or as clinically necessary.
    • Patients with diarrhea of grade 3 or greater who require IV fluids, or those suffering from signs/symptoms such as worsening fatigue, nausea or vomiting, right-upper quadrant pain, tenderness or fever, or eosinophilia, should have their liver function tested.
    • You may need to interrupt therapy, reduce doses, or discontinue treatment.
  • Hepatic impairment

    • Patients with hepatic impairment should be cautious.
    • Patients with severe hepatic dysfunction may have their neratinib clearance reduced.
    • Patients with severe preexisting conditions (Child-Pugh Class C) may need to be reduced in dose.

Neratinib: Drug Interaction

Note: Drug Interaction Categories:

  • Risk Factor C: Monitor When Using Combination
  • Risk Factor D: Consider Treatment Modification
  • Risk Factor X: Avoid Concomitant Use

Risk Factor C (Monitor therapy)

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.
Celiprolol P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Celiprolol.
Clofazimine May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Deferasirox May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Digoxin Neratinib may increase the serum concentration of Digoxin.
Erdafitinib May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Erdafitinib May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Everolimus P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Everolimus.
Fosaprepitant May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Ivosidenib May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Larotrectinib May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Larotrectinib P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Larotrectinib.
Naldemedine P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naldemedine.
Naloxegol P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naloxegol.
Palbociclib May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
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.
Prucalopride P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Prucalopride.
Ranolazine P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ranolazine.
RifAXIMin P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RifAXIMin.
Sarilumab May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Silodosin P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Silodosin.
Siltuximab May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Simeprevir May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Talazoparib P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Talazoparib. Management: These listed exceptions are discussed in detail in separate interaction monographs.
Tegaserod P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Tegaserod.
Tocilizumab May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).

Risk Factor D (Consider therapy modification)

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. Iif used, administer the P-gp inhibitor simultaneously with or after the dose of afatinib.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.

Risk Factor X (Avoid combination)

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.
Conivaptan May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
CYP3A4 Inducers (Moderate) May decrease the serum concentration of Neratinib.
CYP3A4 Inducers (Strong) May decrease the serum concentration of Neratinib.
CYP3A4 Inhibitors (Moderate) May increase the serum concentration of Neratinib.
CYP3A4 Inhibitors (Strong) May increase the serum concentration of Neratinib.
Fusidic Acid (Systemic) May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
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.
Idelalisib May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
PAZOPanib P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of PAZOPanib.
Proton Pump Inhibitors May decrease the serum concentration of Neratinib. Specifically, proton pump inhibitors may reduce neratinib absorption.
Topotecan P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Topotecan.
VinCRIStine (Liposomal) P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of VinCRIStine (Liposomal).

Monitoring parameters:

  • Before treatment initiation, liver function tests (ALT and AST bilirubin and alkaline phosphatase) are performed monthly for the first three months. Then, they are repeated every three months or as indicated by clinical judgment.
  • Fractionated bilirubin or prothrombin times may be used if clinically indicated.
  • Before therapy initiation, women with reproductive potential should have a pregnancy test.
  • You should look out for signs and symptoms such as diarrhea, dehydration, and hepatotoxicity, such as worsening fatigue and nausea, vomiting and right upper quadrant tenderness/pain, fever or eosinophilia.
  • Check for adherence.
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How to administer Neratinib (Nerlynx)?

  • Take the medication orally daily, along with food, at the same time every day.
  • Take the tablet whole.
  • Do not crush, chew or split tablets.
  • Antidiarrheal therapy is recommended for the first two cycles (see Dosing).
  • Avoid using proton pump inhibitors in conjunction.
  • If H-2 antagonist use is required, administer neratinib no less than 2 hours or more before the dose.
  • If antacids are required, administer neratinib within 3 hours.

Mechanism of action of Neratinib (Nerlynx):

  • Neratinib, an irreversible tyrosine kinase inhibitor of human growth factor receptors 1, 2 and 4 (HER1, HER2, HER4, and HER4) (Chan 2016, as well as epidermal grow factor receptor (EGFR)
  • Neratinib decreases EGFR & HER2 Autophosphorylation & downstream MaPK & AKT Signaling Pathways & demonstrates antitumor activities in EGFR & HER2 expressing Cancer Cell Lines.

Absorption:

  • A high-fat meal increases neratinib C & AUC by 1.7- & 2.2-fold, respectively.
  • A standard breakfast increased neratinib C by 1.2-fold & AUC by 1.1-fold.

Protein binding:

  • >99% to serum albumin and alpha-1 acid glycoprotein

Metabolism:

  • Primarily hepatic via CYP3A4 (major) & flavin-containing monooxygenase (minor) to active metabolites M3, M6, M7, and M1

Half-life elimination:

  • 7-17 hours

Time to peak:

  • 2-8 hours (parent drug and active metabolites M3, M6, and M7)

Excretion:

 

  • Feces (~97%).
  • Urine (~1%)

International Brands of Neratinib:

  • Nerlynx

Neratinib Brand Names in Pakistan:

No Brands Available in Pakistan.

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