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

Neratinib is a tyrosine kinase inhibitor (TKI) that specifically targets human epideral growth factor receptor 2 (HER2)-positive cancer cells. HER2 is a protein that can promote the growth of cancer cells. In some cancers, high levels of HER2 are present. This is called HER2-positive cancer. Neratinib is used to treat HER2-positive breast cancer.

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:

  • When you start taking neratinib (a medication), it's common to experience diarrhea as a side effect.
  • To prevent this, your doctor may suggest taking another medicine that stops or reduces diarrhea.
  • You should start taking this diarrhea-preventing medicine at the same time as your first neratinib dose.
  • This is usually done for the first two cycles of your neratinib treatment.
  • It's a way to help manage one of the side effects of the medication from the very beginning.

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

  • Main Treatment: Take a 240 mg tablet of neratinib once a day for a whole year.

If you forget a dose:

  • If you miss taking your neratinib one day, don't take two the next day. Just go on with your usual single daily dose.

Diarrhea prevention:

  • Diarrhea is a common side effect of neratinib.
  • To manage it, you'll need to take another medicine called loperamide, especially during the first part of your treatment.

How to take loperamide:

  • First 2 weeks: Take 4 mg of loperamide three times a day.
  • Weeks 3 to 8: Reduce to taking 4 mg of loperamide twice a day.
  • After 8 weeks until the end of the year: Only take loperamide when you need it, but no more than 16 mg in one day.

This is just to help with the diarrhea.

Use in Children:

Not recommended

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

  • Taking neratinib while pregnant might harm the baby, based on studies and how the drug works.
  • Before starting the medicine, women who can have babies should take a pregnancy test.
  • Women should also use birth control during treatment and for a month after stopping neratinib.
  • Men taking this medicine should use birth control with their partners for three months after they finish neratinib.

Use of Neratinib while breastfeeding

  • We're not sure if neratinib gets into breast milk.
  • Based on the drug maker's advice, mothers shouldn't breastfeed while taking neratinib and for one month after the last dose.

Neratinib (Nerlynx) Dose in Kidney Disease:

  • The drug maker hasn't given any changes to the dosage based on kidney function.
  • Still, how well the kidneys work doesn't really affect how the body processes neratinib.

Neratinib (Nerlynx) Dose in Liver disease:

For those with liver problems before taking neratinib:

  • If you have mild or moderate liver issues (known as Child-Pugh class A or B): You can take the usual dose of neratinib. No changes are needed.
  • If you have severe liver problems (Child-Pugh class C): Start with a lower dose, 80 mg daily.

If you develop liver problems while on neratinib:

  • If your liver test (ALT) goes up 5-20 times the normal limit or another liver test (bilirubin) goes up 3-10 times the normal limit: Stop taking neratinib until the test results are closer to normal. If they get better within 3 weeks, you can start neratinib again but at a lower dose. Always check if something else might be causing the liver issues.
  • If the high liver test results happen again even after reducing the dose once: Stop neratinib forever.
  • If your liver test (ALT) goes up more than 20 times the normal limit or the bilirubin goes up more than 10 times: Stop neratinib forever. Again, check if something else could be causing the liver issues.

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):

  • The drug maker hasn't listed any specific conditions or situations where you shouldn't take neratinib.

Warnings and precautions

Toxicity to the GI:

  • Neratinib can often cause severe diarrhea, which can lead to dehydration, low blood pressure, and kidney problems.
  • Almost everyone who takes neratinib in a clinical trial gets diarrhea, and most get it in the first month of treatment.
  • The severe diarrhea usually starts about 8 days after starting the medicine and lasts for about 5 days.
  • To help with this, doctors recommend taking loperamide (a medicine to stop diarrhea) during the first two cycles of treatment, starting with the first neratinib dose.
  • Be on the lookout for diarrhea and any related problems.
  • Sometimes, more medicines might be needed to control it.
  • If it's severe, treatment might need to be paused, or the dosage reduced, or even stopped.
  • Other side effects like nausea, vomiting, stomach pain, and mouth sores have also been reported with neratinib.

Hepatoxicity

  • Neratinib can sometimes harm your liver.
  • It might make certain liver enzymes, like ALT and AST, go up.
  • In some cases, this has forced people to stop taking the medicine.
  • To make sure your liver is okay while you're on neratinib, your doctor will check your liver function with blood tests before you start, then every month for the first three months, and then every three months after that.
  • If you have really bad diarrhea that needs IV fluids, or if you show signs of liver trouble like extreme tiredness, nausea, vomiting, pain in the upper right part of your belly, fever, rash, or unusual levels of white blood cells, your doctor may need to stop or reduce your neratinib treatment.

Hepatic impairment

  • If you have liver problems, you need to be careful when using neratinib.
  • People with serious liver issues might not clear the drug from their body as quickly.
  • If you already have a severe liver condition (referred to as Child-Pugh class C), your doctor will give you a smaller dose of neratinib.

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:

Liver Checks:

  • Before starting treatment, check:
    • ALT
    • AST
    • Bilirubin
    • Alkaline phosphatase
  • For the first 3 months: Check monthly.
  • After that: Check every 3 months or when needed.
  • If there's a concern, also check:
    • Fractionated bilirubin
    • Prothrombin time

Pregnancy Test:

  • Women who can have babies should have a pregnancy test before starting treatment.

Diarrhea and Dehydration:

  • Keep an eye out for:
    • Diarrhea
    • Signs of dehydration

Liver Problems (Hepatotoxicity):

  • Watch for:
    • Getting very tired
    • Feeling sick
    • Throwing up
    • Pain or discomfort in the upper right side of the belly
    • Fever
    • Skin rashes
    • Unusual white blood cell counts (eosinophilia)

Taking Medicine Properly:

  • Monitor to ensure the patient is taking the medicine as prescribed.

How to administer Neratinib (Nerlynx)?

When and How:

  • Take once a day with food.
  • Try to take it at the same time daily.
  • Swallow tablets whole. Don't crush, chew, or split them.

Diarrhea Prevention:

  • It's advised to take medicine to prevent diarrhea during the first 2 cycles. (Check the dosing guidelines.)

Other Medications:

  • Don't take neratinib with proton pump inhibitors.
  • If you need to take H-receptor antagonists:
    • Take neratinib at least 2 hours before or 10 hours after the H-receptor antagonist.
  • If you need antacids:
    • Wait 3 hours after taking antacids to take neratinib.

Mechanism of action of Neratinib (Nerlynx):

  • Neratinib is a drug that blocks certain growth signals in cancer cells.
  • It specifically targets receptors named HER1, HER2, HER4, and another one called EGFR.
  • By doing so, it turns off pathways in the cells that help them grow and spread.
  • This means it can help fight cancers that have these receptors.
  • It's been shown to work against cancer cells in the lab that have these specific growth signals.

Absorption with Food:

  • A high-fat meal: Increases the amount (C) and overall exposure (AUC) of neratinib by 1.7 times and 2.2 times, respectively.
  • A regular breakfast: Increases the amount by 1.2 times and overall exposure by 1.1 times.

Distribution in Body:

  • Volume (V/F): 6,433 L.

Binding to Proteins:

  • Binds >99% to proteins in the blood, mainly to serum albumin and alpha-1 acid glycoprotein.

How It's Processed (Metabolism):

  • Mainly in the liver.
  • Majorly by an enzyme called CYP3A4.
  • Minorly by another enzyme, flavin-containing monooxygenase.
  • Changes into active forms known as M3, M6, M7, and M1.

Half-Life:

  • 7 to 17 hours (The time it takes for half the drug to leave the body).

Time to Maximum Level:

  • 2 to 8 hours (Time it takes to reach peak levels in the body).

How It's Removed (Excretion):

  • Mostly through feces (about 97%).
  • A tiny bit (about 1%) through urine.

International Brands of Neratinib:

  • Nerlynx

Neratinib Brand Names in Pakistan:

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