Nerlynx (neratinib): Breast Cancer Treatment Side Effects & Dosage

Generic drug: neratinib

Brand name: Nerlynx

What is Nerlynx (neratinib), and how does it work?

Nerlynx (neratinib) is a prescription medicine used alone to treat adults with early-stage human epidermal growth factor receptor 2 (HER2)-positive breast cancer and who have previously been treated with trastuzumab-based therapy.
Nerlynx is also used with a medicine called capecitabine to treat adults with HER2-positive breast cancer that has spread to other parts of the body (metastatic) and who have received 2 or more anti-HER2 therapy medicines for metastatic breast cancer.

It is not known if Nerlynx is safe and effective in children.

What are the side effects of Nerlynx?

Nerlynx may cause serious side effects, including:

Liver problems. Changes in liver function tests are common with
Nerlynx. Your healthcare provider should do blood tests before you begin treatment, monthly during the first 3 months, and then every 3 months as needed during treatment with
Nerlynx. Your healthcare provider will stop your treatment with Nerlynx if your liver tests show severe problems. Call your healthcare provider right away if you get any of the following signs or symptoms of liver problems:
- tiredness
- fever
- nausea
- rash
- vomiting
- itching
- pain in the right upper stomach-area (abdomen)
- yellowing of your skin or whites of your eyes

The most common side effects of
Nerlynx when used alone include:

diarrhea
nausea
stomach-area (abdomen) pain
tiredness
vomiting
rash
dry or inflamed mouth, or mouth sores
decreased appetite
muscle spasms
upset stomach
nail problems including color change
dry skin
swelling of your stomach-area
nosebleed
weight loss
urinary tract infection

The most common side effects of
Nerlynx when used with capecitabine include:

diarrhea
nausea
vomiting
decreased appetite
constipation
tiredness/weakness
weight loss
dizziness
back pain
joint pain
urinary tract infection
upper respiratory tract infection
swelling of your stomach-area
kidney problems
muscle spasms

These are not all of the possible side effects of
Nerlynx. For more information, ask your Healthcare Provider.

Tell your doctor if you have any side effects that bother you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What is the dosage for Nerlynx?

Antidiarrheal Prophylaxis

Administer antidiarrheal prophylaxis during the first 56 days of treatment and initiate with the first dose of Nerlynx. Instruct patients to take loperamide as directed in Table 1. Titrate loperamide to 1–2 bowel movements per day.

Table 1: Loperamide Prophylaxis

Time on Nerlynx
Loperamide Dose and Frequency

Weeks 1-2 (days 1-14)
4 mg three times daily

Weeks 3-8 (days 15-56)
4 mg twice daily

Weeks 9-52 (days 57-365)
4 mg as needed, not to exceed 16 mg per day; titrate dosing to achieve 1-2 bowel movements per day

If diarrhea occurs despite prophylaxis, treat with additional antidiarrheals, fluids and electrolytes as clinically indicated. Nerlynx dose interruptions and dose reductions may also be required to manage diarrhea.

Recommended Dose And Schedule

Extended Adjuvant Treatment Of Early Stage Breast Cancer

The recommended dose of Nerlynx is 240 mg (six tablets) given orally once daily, with food, continuously until disease recurrence or for up to one year.

Advanced Or Metastatic Breast Cancer

The recommended dose of Nerlynx is 240 mg (six tablets) given orally once daily with food on Days 1–21 of a 21-day cycle plus capecitabine (750 mg/m² given orally twice daily) on Days 1–14 of a 21-day cycle until disease progression or unacceptable toxicities.

Instruct patients to take Nerlynx at approximately the same time every day. Nerlynx tablets should be swallowed whole (tablets should not be chewed, crushed, or split prior to swallowing).

If a patient misses a dose, do not replace missed dose, and instruct the patient to resume Nerlynx with the next scheduled daily dose.

Dose Modifications

Dose Modifications For Adverse Reactions

Nerlynx dose modification is recommended based on individual safety and tolerability. Management of some adverse reactions may require dose interruption and/or dose reduction as shown in Table 2 to Table 7. Discontinue Nerlynx for patients with adverse reactions that fail to recover to Grade 0–1 or baseline, with toxicities that result in a treatment delay >3 weeks, or if unable to tolerate 120 mg daily. Additional clinical situations may result in dose adjustments as clinically indicated (e.g. intolerable toxicities, persistent Grade 2 adverse reactions, etc.).

When Nerlynx is used in combination with capecitabine, refer to the capecitabine prescribing information for dose modifications of capecitabine.

Table 2: Nerlynx Monotherapy Dose Modifications for Adverse Reactions

Dose Level
Nerlynx Dose

Recommended starting dose
240 mg daily (six 40 mg tablets)

First dose reduction
200 mg daily (five 40 mg tablets)

Second dose reduction
160 mg daily (four 40 mg tablets)

Third dose reduction
120 mg daily (three 40 mg tablets)

Table 3: Nerlynx in Combination with Capecitabine Dose Modifications for Adverse Reactions

Dose Level
Nerlynx Dose

Recommended starting dose
240 mg daily (six 40 mg tablets)

First dose reduction
160 mg daily (four 40 mg tablets)

Second dose reduction
120 mg daily (three 40 mg tablets)

Table 4: Nerlynx Dose Modifications and Management — General Toxicities*

Severity of Toxicity†
Action

Grade 3
Hold Nerlynx until recovery to Grade ≤1 or baseline within 3 weeks of stopping treatment. Then resume Nerlynx at the next lower dose level.

Grade 4
Discontinue Nerlynx permanently.

* Refer to Table 5, Table 6, and Table 7 below for management of diarrhea and hepatotoxicity
† Per CTCAE v4.0

Dose Modifications For Diarrhea

Guidelines for adjusting doses of Nerlynx in the setting of diarrhea are shown in Table 5 and Table 6. Diarrhea management may require use of antidiarrheal medications, dietary changes, replacement of fluids and electrolytes and appropriate dose modifications of Nerlynx as clinically indicated.

Table 5: Dose Modifications of Nerlynx Monotherapy for Diarrhea

Severity of Diarrhea*
Action

Grade 1 diarrhea [increase of <4 stools per day over baseline]
Grade 2 diarrhea [increase of 4-6 stools per day over baseline] lasting ≤5 days
Grade 3 diarrhea [increase of ≥7 stools per day over baseline; incontinence; hospitalization indicated; limiting self-care activities of daily living] lasting ≤2 days

Adjust antidiarrheal treatment
Diet modifications
Fluid intake of ~2 L should be maintained to avoid dehydration
Once event resolves to ≤Grade 1 or baseline, start loperamide 4 mg with each subsequent Nerlynx administration

Any grade with complicated features†
Grade 2 diarrhea lasting longer than 5 days‡
Grade 3 diarrhea lasting longer than 2 days‡

Interrupt Nerlynx treatment
Diet modifications
Fluid intake of ~2 L should be maintained to avoid dehydration
If diarrhea resolves to Grade 0-1 in one week or less, then resume Nerlynx treatment at the same dose.
If diarrhea resolves to Grade 0-1 in longer than one week, then resume Nerlynx treatment at reduced dose (see Table 2)
Once event resolves to ≤Grade 1 or baseline, start loperamide 4 mg with each subsequent Nerlynx administration

Grade 4 diarrhea [life-threatening consequences; urgent intervention indicated]

Permanently discontinue Nerlynx treatment

Diarrhea recurs to Grade 2 or higher at 120 mg per day

Permanently discontinue Nerlynx treatment

* Per CTCAE v4.0
† Complicated features include dehydration, fever, hypotension, renal failure, or Grade 3 or 4 neutropenia
‡ Despite being treated with optimal medical therapy

Table 6: Dose Modifications of Nerlynx and Capecitabine for Diarrhea

Severity of Diarrhea*
Actions

Grade 1 Diarrhea [Increase of <4 stools per day over baseline]
Grade 2 Diarrhea [Increase of 4-6 stools per day over baseline] lasting ≤5 days
Grade 3 Diarrhea: [Increase of ≥7 stools per day over baseline; incontinence; hospitalization indicated; limiting selfcare and activities of daily living] lasting ≤2 days

Adjust antidiarrheal treatment
Continue Nerlynx and capecitabine at full doses
Diet modifications
Fluid intake of ~2 L/day should be maintained to avoid dehydration
Once the event resolved to Grade ≤1 or baseline, start loperamide 4 mg with each subsequent Nerlynx administration

Persisting and intolerable Grade 2 Diarrhea: lasting >5 days
Grade 3 Diarrhea lasting >2 days
Grade 4 diarrhea [Life-threatening consequences; urgent intervention indicated]

Adjust antidiarrheal treatment
Hold Nerlynx and capecitabine until recovery to Grade ≤1 or baseline
Diet modifications
Fluid intake of ~2 L/day should be maintained intravenously, if needed
If recovery occurs:
≤1 week after withholding treatment, resume same doses of Nerlynx and capecitabine
Within 1–3 weeks after withholding treatment, reduce Nerlynx dose to 160 mg and maintain the same dose of capecitabine
If event occurs a second time and the Nerlynx dose has not already been decreased, reduce Nerlynx dose to 160 mg (maintain the same dose of capecitabine). If Nerlynx dose has already been reduced, then reduce the dose of capecitabine to 550 mg/m2 given twice dailya (maintain the same dose of Nerlynx).
If subsequent events occur, reduce the dose of Nerlynx or capecitabine to the next lower dose level in an alternate fashion (i.e., reduce capecitabine to 375 mg/m² given twice daily^a if Nerlynx was previously reduced, or reduce Nerlynx to 120 mg if capecitabine was previously reduced).
Once the event resolved to Grade ≤1 or baseline, start loperamide 4 mg with each subsequent Nerlynx administration.

Abbreviations: L: liter
* NCI CTCAE v.4.0
^a Since capecitabine is provided as 150 mg or 500 mg tablets, it is recommended that the capecitabine dose reduction(s) is rounded down to the nearest 500 mg or multiple of 150 mg for the twice daily dose. If the patientâ€™s body surface area is >2.0, the standard of care for the study center can be utilized for capecitabine mg/m² dosing.

Dose Modifications For Hepatic Impairment

Reduce the Nerlynx starting dose to 80 mg in patients with severe hepatic impairment (Child Pugh C). No dose modifications are recommended for patients with mild to moderate hepatic impairment (Child Pugh A or B).

Dose Modifications For Hepatotoxicity

Guidelines for dose adjustment of Nerlynx in the event of liver toxicity are shown in Table 7. Patients who experience =Grade 3 diarrhea requiring IV fluid treatment or any signs or symptoms of hepatotoxicity, such as worsening of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or eosinophilia, should be evaluated for changes in liver function tests. Fractionated bilirubin and prothrombin time should also be collected during hepatotoxicity evaluation.

Table 7: Dose Modifications for Hepatotoxicity

Severity of Hepatotoxicity*
Action

Grade 3 ALT or AST (>5-20x ULN) OR
Grade 3 bilirubin (>3-10* ULN)

Hold Nerlynx until recovery to ≤Grade 1
Evaluate alternative causes
Resume Nerlynx at the next lower dose level if recovery to =Grade 1 occurs within 3 weeks. If Grade 3 ALT or AST, or bilirubin occurs again despite one dose reduction, permanently discontinue Nerlynx

Grade 4 ALT or AST (>20× ULN) OR
Grade 4 bilirubin (>10× ULN)

Permanently discontinue Nerlynx
Evaluate alternative causes

ALT=Alanine Aminotransferase; AST=Aspartate Aminotransferase; ULN=Upper Limit Normal
* Per CTCAE v4.0

Concomitant Use With Gastric Acid Reducing Agents

Proton Pump Inhibitors (PPI)

Avoid concomitant use with Nerlynx. H2-receptor antagonists: Take Nerlynx at least 2 hours before the next dose of the H2-receptor antagonist or 10 hours after the H2-receptor antagonist.

Antacids

Separate dosing of Nerlynx by 3 hours after antacids.

QUESTION

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What drugs interact with Nerlynx?

Effect Of Other Drugs On Nerlynx

Table 10 includes drug interactions that affect the pharmacokinetics of neratinib.

Table 10: Drug Interactions That Affect Neratinib

Gastric Acid Reducing AgentsClinical ImpactConcomitant use of
Nerlynx with a proton pump inhibitor, H2-receptor
antagonist, or antacid may decrease neratinib plasma concentration.
Decreased neratinib AUC may reduce Nerlynx activity. Lansoprazole (PPI)
resulted in a decrease of neratinib Cmax by 71% and AUC by 65%.Prevention or Management

PPIs

Avoid concomitant use.

H2-receptor antagonists

Take
Nerlynx at least 2 hours before the next dose of the H2-receptor
antagonist or 10 hours after the H2-receptor antagonist.

Antacids

Separate Nerlynx dosing by 3 hours after antacids.Strong CYP3A4 InhibitorsClinical Impact

Concomitant use of
Nerlynx with a strong CYP3A4 inhibitor (ketoconazole)
increased neratinib Cmax by 221% and AUC by 381%.
Concomitant use of
Nerlynx with other strong CYP3A4 inhibitors may increase neratinib concentrations.
Increased neratinib concentrations may increase the risk of toxicity.

Prevention or ManagementAvoid concomitant use of
Nerlynx with strong CYP3A4 inhibitors.Moderate CYP3A4 and P-gp Dual InhibitorsClinical Impact

Simulated concomitant use of Nerlynx with a moderate CYP3A4 and Pgp dual
inhibitor (verapamil) suggest the neratinib Cmax and AUC may increase by
203% and 299%, respectively.
Concomitant use of Nerlynx with other moderate CYP3A4 and P-gp dual inhibitors may increase neratinib concentrations.
Increased neratinib concentrations may increase the risk of toxicity.

Prevention or ManagementAvoid concomitant use of
Nerlynx with other moderate CYP3A4 and P-gp dual inhibitors.Strong or Moderate CYP3A4 InducersClinical Impact

Concomitant use of
Nerlynx with a strong CYP3A4 inducer (rifampin) reduced
neratinib Cmax by 76% and AUC by 87%.
Concomitant use of Nerlynx with other strong or moderate CYP3A4 inducers may decrease
Nerlynx concentrations.
Decreased neratinib AUC may reduce Nerlynx activity.

Prevention or ManagementAvoid concomitant use of
Nerlynx with strong or moderate CYP3A4 inducers.AUC=Area Under Curve; Cmax=Maximum Concentration
* These examples are a guide and not considered a comprehensive list of all possible drugs that may fit this category. The healthcare provider should consult appropriate references for comprehensive information.

Effect Of
Nerlynx On Other Drugs

P-glycoprotein (P-gp) Substrates

Concomitant use of Nerlynx with digoxin, a P-gp substrate, increased digoxin
concentrations. Increased concentrations of digoxin may lead to increased risk of adverse reactions including cardiac toxicity.
Refer to the digoxin prescribing information for dosage adjustment recommendations due to drug interactions.
Nerlynx may inhibit the transport of other P-gp substrates (e.g., dabigatran, fexofenadine).

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Is Nerlynx safe to use while pregnant or breastfeeding?

Based on findings from animal studies and the mechanism of action,
Nerlynx can cause fetal harm when administered to a pregnant woman.
There are no available data in pregnant women to inform the drug-associated risk.
No data are available regarding the presence of neratinib or its metabolites in human milk or its effects on the breastfed infant or on milk production.
Because of the potential for serious adverse reactions in breastfed infants from
Nerlynx, advise lactating women not to breastfeed while taking Nerlynx and for at least 1 month after the last dose.