Usual Adult Dose for Breast Cancer - Adjuvant

240 mg orally once a day continuously for 1 year

NOTE: Antidiarrheal prophylaxis is recommended during the first 2 cycles (56 days) of therapy and should be initiated with the first dose. Titrate loperamide to 1 to 2 bowel movements per day.
MANUFACTURER SUGGESTED PROPHYLACTIC LOPERAMIDE DOSING:

• Weeks 1 and 2 (days 1 through 14): 4 mg orally 3 times a day
• Weeks 3 through 8 (days 15 through 56): 4 mg orally 2 times a day
• Weeks 9 through 52 (days 57 through 365): 4 mg as needed (not to exceed 16 mg per day)

Use: For the extended adjuvant treatment of adult patients with early stage HER2-overexpressed/amplified breast cancer (to follow adjuvant trastuzumab-based therapy)

Renal Dose Adjustments

There are no dosage recommendations provided in the manufacturer product information; however, renal function does not have a clinically significant effect on the pharmacokinetics of this drug.

Liver Dose Adjustments

DOSE MODIFICATIONS FOR HEPATIC IMPAIRMENT:

• Mild to moderate hepatic impairment (Child Pugh A or B): No adjustment recommended.
• Severe hepatic impairment (Child Pugh C): Reduce the starting dose to 80 mg.

DOSE MODIFICATIONS FOR HEPATOTOXICITY:

• Grade 3 ALT (greater than 5 to 20 times upper limit of normal [ULN]) OR Grade 3 bilirubin (greater than 3 to 10 x ULN): Withhold therapy until recovery to Grade 1 or less; evaluate alternative causes; resume therapy at the next lower dose level if recovery to Grade 1 or less occurs within 3 weeks; if Grade 3 ALT or bilirubin occurs again despite one dose reduction, permanently discontinue therapy.
• Grade 4 ALT (greater than 20 x ULN) OR Grade 4 bilirubin (greater than 10 x ULN): Permanently discontinue therapy; evaluate alternative causes

Dose Adjustments

DOSE MODIFICATIONS FOR ADVERSE REACTIONS:

• Dose modification is recommended based on tolerability.
• Management of some adverse reactions may require dose interruption and/or dose reduction.
• Discontinue therapy in patients who fail to recover to Grade 0 to 1 from therapy-related toxicity, for toxicities that result in therapy delay longer than 3 weeks, or who cannot tolerate 120 mg daily.

Dose Modifications for Adverse Reactions:

• Recommended starting dose: 240 mg daily
• First dose reduction: 200 mg daily
• Second dose reduction: 160 mg daily
• Third dose reduction: 120 mg daily

DOSE MODIFICATIONS FOR TOXICITY:

• Grade 3: Withhold therapy until recovery to Grade 1 or less or baseline within 3 weeks of stopping therapy; resume at the next lower dose level.
• Grade 4: Permanently discontinue therapy.

DOSE MODIFICATIONS FOR DIARRHEA:

• Grade 1 (increase of less than 4 stools per day over baseline) OR Grade 2 (increase of 4 to 6 stools per day over baseline) lasting less than 5 days OR Grade 3 (increase of 7 or more stools per day over baseline; incontinence; hospitalization indicated; limiting self-care activities of daily living) lasting 2 days or less: Adjust antidiarrheal treatment and make diet modifications; fluid intake of approximately 2L should be maintained to avoid dehydration; when event resolves to Grade 1 or less or baseline, start loperamide 4 mg with each subsequent dose of this drug.
• Any grade with complicated features (e.g., dehydration, fever, hypotension, renal failure, Grade 3 or 4 neutropenia) OR Grade 2 diarrhea lasting 5 days or longer (despite treatment) OR Grade 3 diarrhea lasting longer than 2 days (despite treatment): Withhold therapy and make diet modifications; fluid intake of approximately 2L should be maintained to avoid dehydration; if diarrhea resolves to Grade 0 or 1 in one week or less, then resume therapy at the same dose; if diarrhea resolves to Grade 0 or 1 in longer than one week, then resume therapy at reduced dose; when event resolves to Grade 1 or less or baseline, start loperamide 4 mg with each dose of this drug.
• Grade 4 (life-threatening consequences; urgent intervention indicated): Permanently discontinue therapy.

Diarrhea that recurs to Grade 2 or higher at 120 mg per day: Permanently discontinue therapy.

DRUG INTERACTIONS:
GASTRIC ACID REDUCING AGENTS:

• Concomitant use of this drug with a proton pump inhibitor, H 2-receptor antagonist, or antacid may decrease neratinib plasma concentration. Decreased neratinib AUC may reduce its activity. Lansoprazole (PPI) resulted in a decrease of neratinib C max by 71% and AUC by 65%.
• PPIs: Avoid concomitant use.
• H2-receptor antagonists: Take neratinib at least 2 hours before the next dose of the H2-receptor antagonist or 10 hours after the H2-receptor antagonist.
• Antacids: Separate neratinib dosing by 3 hours after antacids.

STRONG AND MODERATE CYP450 3A4 INHIBITORS:

• Concomitant use of neratinib with a strong CYP450 3A4 inhibitor (ketoconazole) increased neratinib C max by 321% and AUC by 481%.
• Concomitant use of neratinib with other strong or moderate CYP450 3A4 inhibitors may increase neratinib concentrations.
• Increased neratinib concentrations may increase the risk of toxicity.

Recommendation:

• Avoid concomitant use of neratinib with strong or moderate CYP450 3A4 inhibitors.

STRONG OR MODERATE CYP450 3A4 INDUCERS:

• Concomitant use of neratinib with a strong CYP450 3A4 inducer (rifampin) reduced neratinib C max by 76% and AUC by 87%.
• Concomitant use of neratinib with other strong or moderate CYP450 3A4 inducers may decrease neratinib concentrations.
• Decreased neratinib AUC may reduce its activity.

Recommendation:

• Avoid concomitant use of neratinib with strong or moderate CYP450 3A4 inducers.

Precautions

CONTRAINDICATIONS:

• None

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.

Dialysis

Data not available

Other Comments

Administration Advice:

• This drug should be taken with food at approximately the same time every day.
• Swallow tablets whole; do not chew, crush, or split tablets.
• Do not replace a missed dose; resume therapy with the next scheduled dose.
• Antidiarrheal prophylaxis with loperamide is recommended during the first 2 cycles (56 days) of therapy and should be initiated with the first dose and titrated to 1 to 2 bowel movements per day.
• Additional antidiarrheal agents may be needed to manage diarrhea in patients with loperamide-refractory diarrhea.
• Dose interruption or reduced doses of this drug may be required to manage diarrhea.

Storage Requirements:

• Store at controlled room temperature: 20C to 25C (68F to 77 F); excursions permitted to 15C to 30C (59F to 86 F).

General:

• Overdosage: No specific antidote; benefit of hemodialysis is unknown.

Monitoring:

• Gastrointestinal: Diarrhea (throughout treatment); stool cultures (as clinically indicated)
• Hepatic: Total bilirubin, AST, ALT, alkaline phosphatase (prior to treatment initiation, monthly for the first 3 months of treatment, then every 3 months during treatment and as clinically indicated); fractionated bilirubin and prothrombin time (as clinically indicated)

Patient Advice:

• Avoid grapefruit products during therapy with this drug.
• This drug may cause side effects including fatigue and muscle spasms; avoid potentially dangerous activities such as driving and operating machinery until you know how this drug affects you.

Frequently asked questions

• What’s the difference between tucatinib and neratinib?
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