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

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.