Neratinib (Monograph)

Brand name: Nerlynx
Drug class: Antineoplastic Agents
- Kinase Inhibitors
- Receptor Tyrosine Kinase Inhibitors
- Tyrosine Kinase Inhibitors
- HER2 Dimerization Inhibitor
- Epidermal Growth Factor Receptor Inhibitors
- EGFR Inhibitors
- EGF Receptor Inhibitors
Chemical name: (E)-N-[4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide
Molecular formula: C₃₀H₂₉ClN₆O₃
CAS number: 698387-09-6

Medically reviewed by Drugs.com on Sep 28, 2022. Written by ASHP.

Introduction

Antineoplastic agent; a potent, selective, and irreversible inhibitor of human epidermal growth factor receptor type 2 (HER2), HER4, and epidermal growth factor receptor (EGFR) tyrosine kinases.

Uses for Neratinib

Extended Adjuvant Therapy for Breast Cancer

Single-agent therapy for extended adjuvant treatment of HER2-positive, early-stage breast cancer in adults who have received adjuvant trastuzumab therapy. Subgroup analysis suggests a greater effect on invasive disease-free survival in patients with hormone receptor-positive disease, those treated with sequential adjuvant trastuzumab therapy, and those who completed adjuvant trastuzumab therapy within 1 year of randomization.

Guidelines generally suggest neratinib as an option for extended adjuvant therapy in patients with early-stage, HER2-positive breast cancer after receiving treatment with trastuzumab plus chemotherapy; the greatest potential benefit appears to be derived when neratinib is administered within 1 year of completion of trastuzumab treatment.

Advanced or Metastatic Breast Cancer

Used in combination with capecitabine for advanced or metastatic HER2-positive breast cancer in adults who have received ≥2 prior anti-HER2 regimens in the metastatic setting.

In clinical practice guidelines, neratinib in combination with capecitabine is recommended as one of several potential third-line treatment options in patients whose advanced HER2-positive breast cancer has progressed during or after 2 previous anti-HER2 regimens.

Neratinib Dosage and Administration

General

Pretreatment Screening

Measure total bilirubin, AST, ALT, and alkaline phosphatase prior to initiating treatment with neratinib.
Perform pregnancy testing in females of reproductive potential prior to starting neratinib.

Patient Monitoring

Measure liver function tests monthly for the first 3 months of treatment with neratinib, then every 3 months during treatment and as clinically indicated.
Monitor patients for diarrhea during treatment with neratinib and treat with antidiarrheals as needed.

Premedication and Prophylaxis

To minimize the incidence and severity of treatment-related diarrhea, antidiarrheal prophylaxis with loperamide (initiated with the first dose of neratinib and continued during the first 56 days of treatment) is recommended in patients not using a dose escalation approach. The manufacturer recommends taking loperamide hydrochloride 4 mg 3 times daily during weeks 1–2 (days 1–14), followed by 4 mg twice daily during weeks 3–8 (days 15–56), and then 4 mg as needed from week 9 until discontinuance of neratinib; the daily dosage of loperamide hydrochloride should not exceed 16 mg. After the first 56 days of therapy, dosage of loperamide should be adjusted to maintain a bowel movement frequency of 1–2 per day.

Administration

Oral Administration

Administer orally once daily with food at approximately the same time each day.

Swallow tablets whole; do not chew, crush, or split.

Dosage

Available as neratinib maleate; dosage expressed in terms of neratinib.

Adults

Breast Cancer

Extended Adjuvant Therapy of Early-stage Breast Cancer

Oral

240 mg once daily, given continuously for up to one year or until disease recurrence; initiate neratinib after completion of adjuvant trastuzumab therapy.

A 2-week dose escalation may be considered to minimize the risk of diarrhea (see Table 1):

Recommended dosage

Table 1: Neratinib Dose Escalation Schedule1
Time on Neratinib	Dose
Week 1 (days 1–7)	120 mg daily (three 40-mg tablets)
Week 2 (days 8–14)	160 mg daily (four 40-mg tablets)
Week 3 and onwards	240 mg daily (six 40-mg tablets)

Advanced or Metastatic Breast Cancer.

Oral

240 mg once daily on days 1–21 of a 21-day cycle in combination with capecitabine 750 mg/m² twice daily on days 1–14 of a 21-day cycle. Continue therapy until disease progression or unacceptable toxicity occurs.

A 2-week dose escalation may be considered to minimize the risk of diarrhea (see Table 2):

Recommended dosage

Table 2: Neratinib Dose Escalation Schedule1
Time on Neratinib	Dose
Week 1 (days 1–7)	120 mg daily (three 40-mg tablets)
Week 2 (days 8–14)	160 mg daily (four 40-mg tablets)
Week 3 and onwards	240 mg daily (six 40-mg tablets)

Dosage Modification for Toxicity

Oral

Adverse effects may require temporary interruption and/or dosage reduction or permanent discontinuance. Adjust dosage based on individual safety and tolerability.

Discontinue therapy in patients with persistent grade 2 or greater adverse effects that do not recover to grade 0–1 or baseline and patients with any toxicity that requires a treatment delay of greater than 3 weeks; discontinuance of therapy also recommended in those who cannot tolerate a dosage of 120 mg once daily.

Neratinib Monotherapy

If dosage modification of neratinib monotherapy is required for toxicity, reduce the dosage of neratinib as described in Table 3.

Table 3: Recommended Dosage Modification for Toxicity with Neratinib Monotherapy1
Dose Reduction Level	Neratinib Dosage (Starting Dosage = 240 mg once daily)
First	Restart at 200 mg daily (five 40-mg tablets)
Second	Restart at 160 mg daily (four 40-mg tablets)
Third	Restart at 120 mg daily (three 40-mg tablets)

If an adverse reaction occurs, modify dosage accordingly (see Table 4).

Additional complicating features include dehydration, pyrexia, hypotension, renal failure, or grade 3–4 neutropenia

Table 4. Recommended Dosage Modification for Toxicity with Neratinib Monotherapy1
Adverse Reaction and Severity	Modification
Diarrhea
Grade 1 (<4 stools per day over baseline) or Grade 2 (4–6 stools per day over baseline) lasting ≤5 days or Grade 3 (≥7 stools per day over baseline, fecal incontinence, need for hospitalization, limiting self-care activities of daily living) lasting ≤2 days	Adjust antidiarrheal treatment, modify diet, and maintain fluid intake of about 2 L/day to avoid dehydration Once diarrhea resolves to ≤ grade 1, initiate loperamide hydrochloride 4 mg with each subsequent administration of neratinib
Any grade with additional complicating features or Grade 2 lasting >5 days despite treatment with optimal medical therapy or Grade 3 lasting >2 days despite treatment with optimal medical therapy	Withhold therapy; modify diet, and maintain fluid intake of about 2 L/day to avoid dehydration If diarrhea resolves to ≤grade 1 within 1 week, resume neratinib at same dosage If diarrhea resolves to ≤grade 1 in longer than 1 week, resume neratinib at a reduced dosage (see Table 3) Once event resolves to ≤ grade 1 or baseline, initiate loperamide hydrochloride 4 mg with each subsequent administration of neratinib
Grade 4 (life-threatening diarrhea or need for urgent intervention)	Permanently discontinue therapy
Recurrence of grade 2 or higher diarrhea at a dosage of 120 mg daily	Permanently discontinue therapy
Hepatotoxicity
Grade 3 ALT or AST (>5–20 × ULN) or Grade 3 bilirubin (>3–10 × ULN)	Withhold therapy until recovery to ≤grade 1 and evaluate for alternative causes If recovery to ≤grade 1 occurs within 3 weeks, resume neratinib at the next lower dose level (see Table 3) If grade 3 hepatotoxicity recurs after one dose reduction, permanently discontinue therapy
Grade 4 ALT or AST (>20 × ULN) or Grade 4 bilirubin (>10 × ULN)	Permanently discontinue therapy and evaluate for alternative causes
Other Adverse Effects
Grade 3	Withhold therapy; if adverse effect resolves to ≤ grade 1 or baseline within 3 weeks, resume at next dose level (see Table 3)
Grade 4	Permanently discontinue therapy

Neratinib Combination Therapy with Capecitabine

If an adverse reaction occurs when neratinib is used in combination with capecitabine, refer to the prescribing information for capecitabine for dosage modifications of capecitabine and reduce the dosage of neratinib as described in Table 5.

Table 5: Recommended Dosage Modification for Toxicity with Neratinib in Combination with Capecitabine1
Dose Reduction Level	Neratinib Dosage (Starting Dosage = 240 mg once daily)
First	Restart at 160 mg daily (four 40-mg tablets)
Second	Restart at 120 mg daily (three 40-mg tablets)

If an adverse reaction occurs when neratinib is used in combination with capecitabine, modify the dosage accordingly (see Table 6).

Since capecitabine is provided as 150-mg or 500-mg tablets, it is recommended to round the dose reduction down to the nearest 500 mg or multiple of 150 mg for the twice daily dose. If the patient’s body surface area is >2 m², the standard of care for the study center can be utilized for capecitabine mg/m² dosing.

Fluid intake should be maintained intravenously, if needed

Table 6. Recommended Dosage Modification for Toxicity with Neratinib in Combination with Capecitabine1
Adverse Reaction and Severity	Modification
Diarrhea
Grade 1 (<4 stools per day over baseline) or Grade 2 (4–6 stools per day over baseline) lasting ≤5 days or Grade 3 (≥7 stools per day over baseline, fecal incontinence, need for hospitalization, limiting self-care activities of daily living) lasting ≤2 days	Continue neratinib and capecitabine at full doses Adjust antidiarrheal treatment, modify diet, and maintain fluid intake of about 2 L/day to avoid dehydration Once diarrhea resolves to grade ≤1 or baseline, initiate loperamide hydrochloride 4 mg with each subsequent administration of neratinib
Persistent/intolerable grade 2 lasting >5 days or Grade 3 lasting >2 days Grade 4 (life-threatening diarrhea or need for urgent intervention)	Withhold neratinib and capecitabine until recovery to grade ≤1 or baseline; if recovered within 1 week, resume both drugs at same dosage; if recovered in 1–3 weeks, resume neratinib at reduced dosage and continue capecitabine at same dosage (see Table 5) Adjust antidiarrheal treatment, modify diet, and maintain fluid intake of about 2 L/day to avoid dehydration If recovery occurs within 1 week of withholding treatment, resume both drugs at same dosage; if recovery occurs within 1–3 weeks of withholding treatment, reduce neratinib dose to 160 mg and maintain same dose of capecitabine If event occurs a second time and the dosage of neratinib has not already been decreased, reduce neratinib dose to 160 mg and maintain same dose of capecitabine; if the dosage of neratinib has already been reduced, reduce the dosage of capecitabine to 550 mg/m² twice daily and maintain the same dosage of neratinib If subsequent events occur, reduce the dose of neratinib or capecitabine to the next lower dose level in an alternating fashion Once the event resolves to grade ≤1 of baseline, initiate loperamide hydrochloride 4 mg with each subsequent administration of neratinib
Hepatotoxicity
Grade 3 ALT or AST (>5–20 × ULN) or Grade 3 bilirubin (>3–10 × ULN)	Withhold neratinib until recovery to grade ≤1 and evaluate for alternative causes If recovery to grade ≤1 within 3 weeks, resume neratinib at next lower dose level (see Table 5) If grade 3 hepatotoxicity recurs after dosage reduction, permanently discontinue neratinib
Grade 4 ALT or AST (>20 × ULN) or Grade 4 bilirubin (>10 × ULN)	Permanently discontinue neratinib and evaluate for alternative causes
Other Adverse Effects
Grade 3	Withhold neratinib; if adverse effect resolves to grade≤1 or baseline within 3 weeks, resume therapy at the next lower dose level(see Table 5)
Grade 4	Permanently discontinue neratinib

Special Populations

Hepatic Impairment

Mild or moderate preexisting hepatic impairment (Child-Pugh class A or B): No dosage adjustment required.

Severe preexisting hepatic impairment (Child-Pugh class C): Reduce initial dosage to 80 mg once daily.

Renal Impairment

No dosage adjustment required.

Geriatric Patients

No specific dosage recommendations at this time.

Cautions for Neratinib

Contraindications

None.

Warnings/Precautions

Diarrhea

Severe diarrhea associated with dehydration, hypotension, and renal impairment reported; generally occurs during the first month of therapy. Median time to onset of grade 3 or greater diarrhea was 8 days. Median cumulative duration of grade 3 or greater diarrhea was 5 days.

Antidiarrheal prophylaxis recommended with loperamide during initial 56 days of neratinib therapy in patients not using dose escalation approach. After day 56, titrate loperamide to maintain 1–2 bowel movements per day and consider other antidiarrheal agents as clinically indicated.

A 2-week dosage escalation can be considered as an alternate approach to diarrhea management. Monitor patients for development of diarrhea; if necessary, treat with appropriate therapy (e.g., antidiarrheal agents, fluid replacement).

Perform stool cultures as clinically indicated if grade 3 or 4 diarrhea or diarrhea of any severity associated with dehydration, pyrexia, or neutropenia occurs. In addition, evaluate liver function tests in patients experiencing grade 3 or greater diarrhea.

If diarrhea occurs, temporary interruption, dosage reduction, or discontinuance of neratinib may be necessary.

Hepatic Toxicity

Elevations in ALT or AST concentrations reported.

Monitor liver function tests (i.e., ALT, AST, total bilirubin, alkaline phosphatase concentrations) at baseline, monthly for first 3 months of therapy, and then every 3 months thereafter during therapy, and as clinically indicated. Also evaluate liver function tests in patients experiencing grade 3 or greater diarrhea or signs or symptoms of hepatotoxicity (e.g., worsening fatigue, nausea, vomiting, right upper quadrant pain or tenderness, pyrexia, rash, eosinophilia).

If grade 3 or 4 serum ALT or AST or bilirubin elevations occur, temporary interruption followed by dosage reduction or discontinuance of neratinib may be necessary; also consider alternate causes of hepatotoxicity.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm based on mechanism of action and animal findings; embryofetal toxicity and teratogenicity demonstrated in animals. Effects on long-term memory observed in male pups.

Avoid pregnancy during therapy. If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard. (See Females and Males of Reproductive Potential under Cautions.)

Specific Populations

Pregnancy

May cause fetal harm. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether neratinib or its metabolites are distributed into human milk. Effects on nursing infants and milk production also unknown.

Discontinue nursing during therapy and for ≥1 month after drug discontinuance.

Females and Males of Reproductive Potential

Advise women of childbearing potential to use effective contraception while receiving neratinib and for ≥1 month after discontinuance of the drug. Advise men who are partners of such women to use effective contraceptive methods while receiving neratinib and for 3 months after the last dose.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

Higher incidences of discontinuance of neratinib due to adverse reactions but similar incidences of serious adverse reactions (e.g., vomiting, diarrhea, renal failure, dehydration) observed in patients ≥65 years of age receiving neratinib monotherapy for early stage breast cancer compared with younger adults.

Serious adverse reactions observed in patients ≥65 years of age receiving neratinib in combination with capecitabine for advanced breast cancer were similar to younger adults.

Hepatic Impairment

Mild or moderate preexisting hepatic impairment (Child-Pugh class A or B): Peak plasma concentrations and systemic exposure not substantially altered. No dosage adjustment required.

Severe preexisting hepatic impairment (Child-Pugh class C): Peak plasma concentrations and systemic exposure increased substantially. Dosage adjustment required.

Renal Impairment

No clinically important effects on pharmacokinetics of neratinib. No dosage adjustment required.

Common Adverse Effects

Neratinib monotherapy (≥5%): Diarrhea, nausea, abdominal pain, abdominal distension, fatigue, vomiting, rash, stomatitis, decreased appetite, nail disorders, dry skin, muscle spasms, epistaxis, decreased weight, increased AST or ALT, urinary tract infections, dyspepsia.

Neratinib in combination with capecitabine (≥5%): diarrhea, nausea, vomiting, decreased appetite, constipation, fatigue, decreased weight, dizziness, back pain, arthralgia, urinary tract infection, upper respiratory tract infection, abdominal distension, renal impairment, muscle spasms.

Drug Interactions

Neratinib is primarily metabolized by CYP3A4 and, to a lesser extent, by flavin-containing monooxygenase (FMO).

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Potent or moderate CYP3A4 inhibitors: Possible increased systemic exposure to neratinib and increased risk of adverse effects. Avoid concomitant use with potent or moderate CYP3A4 inhibitors. Moderate CYP3A4 inhibitors not specifically studied, but consider potential for clinically important pharmacokinetic interactions.

Potent or moderate CYP3A4 inducers: Possible decreased systemic exposure to neratinib and its active metabolites, reducing efficacy of neratinib. Avoid concomitant use with potent or moderate CYP3A4 inducers. Moderate CYP3A4 inducers not specifically studied, but consider potential for clinically important pharmacokinetic interactions.

P-Glycoprotein and Moderate CYP3A4 Dual Inhibitors

Possible increased systemic exposure to neratinib and increased risk of adverse effects.

Avoid concomitant use with P-gp and moderate CYP3A4 dual inhibitors.

Substrates of P-Glycoprotein Transport Systems

Potential pharmacokinetic interaction (increased systemic exposure of substrates).

Monitor for adverse reactions of certain P-gp substrates for which minimal concentration changes may lead to serious adverse reactions when used concomitantly with neratinib.

Drugs Affecting Gastric Acidity

Potential pharmacokinetic interaction (decreased oral bioavailability and reduced efficacy of neratinib) with drugs that increase gastric pH.

Specific Drugs and Foods

Drug or Food	Interaction	Comments
Antacids	Possible decreased bioavailability and reduced efficacy of neratinib	Separate administration of neratinib by at least 3 hours after administration of antacids
Anticonvulsants (e.g., carbamazepine, phenytoin)	Possible decreased systemic exposure to neratinib and its metabolites (M6, M7) and reduced neratinib efficacy	Avoid concomitant use
Antifungals, azoles (e.g., fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole)	Possible increased systemic exposure to neratinib and increased adverse effects Ketoconazole: Increased peak concentrations and AUC of neratinib by 221 and 381%, respectively	Avoid concomitant use
Aprepitant	Possible increased systemic exposure to neratinib and increased adverse effects	Avoid concomitant use
Bosentan	Possible decreased systemic exposure to neratinib and its metabolites (M6, M7) and reduced neratinib efficacy	Avoid concomitant use
Calcium-channel blocking agents, nondihydropyridine (e.g., diltiazem, verapamil)	Possible increased systemic exposure to neratinib and increased adverse effects	Avoid concomitant use
Ciprofloxacin	Possible increased systemic exposure to neratinib and increased adverse effects	Avoid concomitant use
Clotrimazole	Possible increased systemic exposure to neratinib and increased adverse effects	Avoid concomitant use
Cobicistat	Possible increased systemic exposure to neratinib and increased adverse effects	Avoid concomitant use
Conivaptan	Possible increased systemic exposure to neratinib and increased adverse effects	Avoid concomitant use
Crizotinib	Possible increased systemic exposure to neratinib and increased adverse effects	Avoid concomitant use
Cyclosporine	Possible increased systemic exposure to neratinib and increased adverse effects	Avoid concomitant use
Dabigatran	Possible increased systemic exposure to dabigatran	Use with caution
Digoxin	Increased peak plasma concentration and AUC of digoxin by 54 and 32%, respectively	Consider digoxin dosage reduction; use with caution
Dronedarone	Possible increased systemic exposure to neratinib and increased adverse effects	Avoid concomitant use
Efavirenz	Decreased peak plasma concentration and AUC of neratinib by 36 and 52%, respectively	Avoid concomitant use
Elvitegravir	Ritonavir-boosted elvitegravir: Possible increased systemic exposure to neratinib and increased adverse effects	Avoid concomitant use
Enzalutamide	Possible decreased systemic exposure to neratinib and its metabolites (M6, M7) and reduced neratinib efficacy	Avoid concomitant use
Fexofenadine	Possible increased systemic exposure to fexofenadine	Use with caution
Fluconazole	Increased peak plasma concentration and AUC of neratinib by 30 and 68%, respectively	Avoid concomitant use
Fluvoxamine	Possible increased systemic exposure to neratinib and increased adverse effects	Avoid concomitant use
Grapefruit or grapefruit juice	Possible increased systemic exposure to neratinib and increased adverse effects	Avoid concomitant use
HCV antivirals (fixed combination of ombitasvir, paritaprevir, and ritonavir with or without dasabuvir)	Possible increased systemic exposure to neratinib and increased adverse effects	Avoid concomitant use
Histamine H₂-receptor antagonists	Possible decreased neratinib bioavailability secondary to decreased solubility at higher pH Administration of the histamine H₂-receptor antagonist ranitidine 2 hours prior to neratinib decreased peak plasma concentration and AUC of neratinib by 57 and 48%, respectively; administration of ranitidine 2 hours after neratinib reduced peak plasma concentration and AUC of neratinib by 44 and 32%, respectively	Administer neratinib at least 2 hours before or 10 hours after histamine H₂-receptor antagonists
HIV nonnucleoside reverse transcriptase inhibitors (NNRTIs) (e.g., efavirenz, etravirine)	Possible decreased systemic exposure to neratinib and its metabolites (M6, M7) and reduced neratinib efficacy	Avoid concomitant use
HIV protease inhibitors (e.g., ritonavir-boosted indinavir, lopinavir/ritonavir, nelfinavir, ritonavir, ritonavir-boosted saquinavir, ritonavir-boosted tipranavir)	Possible increased systemic exposure to neratinib and increased adverse effects	Avoid concomitant use
Idelalisib	Possible increased systemic exposure to neratinib and increased adverse effects	Avoid concomitant use
Imatinib	Possible increased systemic exposure to neratinib and increased adverse effects	Avoid concomitant use
Macrolides (e.g., clarithromycin, erythromycin)	Possible increased systemic exposure to neratinib and increased adverse effects	Avoid concomitant use
Mitotane	Possible decreased systemic exposure to neratinib and its metabolites (M6, M7) and reduced neratinib efficacy	Avoid concomitant use
Modafinil	Possible decreased systemic exposure to neratinib and its metabolites (M6, M7) and reduced neratinib efficacy	Avoid concomitant use
Nefazodone	Possible increased systemic exposure to neratinib and increased adverse effects	Avoid concomitant use
Proton-pump inhibitors	Possible decreased neratinib bioavailability secondary to decreased solubility at higher pH Concomitant administration of the proton-pump inhibitor lansoprazole with neratinib decreased peak plasma concentration and AUC of neratinib by 71 and 65%, respectively	Avoid concomitant use
Rifampin	Decreased AUC of neratinib and its active metabolites (M6, M7) by 87 and 37–49%, respectively; peak plasma concentration of neratinib decreased by 76%	Avoid concomitant use
St. John’s wort (Hypericum perforatum)	Possible decreased systemic exposure to neratinib and its metabolites (M6, M7) and reduced neratinib efficacy	Avoid concomitant use
Verapamil	Increased peak plasma concentration and AUC of neratinib by 203 and 299%, respectively	Avoid concomitant use

Neratinib Pharmacokinetics

Absorption

Bioavailability

Following oral administration, peak plasma concentrations and AUC of neratinib and its major active metabolites (M3, M6, M7) attained in approximately 2–8 hours.

Systemic exposure increases in a less than proportional manner following administration of neratinib 40–400 mg once daily; mean accumulation ratio is 1.14.

Food

Administration with high-fat meal increased neratinib peak plasma concentrations and AUC by 70 and 120%, respectively.

Administration with a standard breakfast increased neratinib peak plasma concentrations and AUC by 20 and 10%, respectively.

Special Populations

Peak plasma concentrations and AUC increased by 173 and 181%, respectively, in individuals with severe hepatic impairment (Child-Pugh class C). Mild or moderate hepatic impairment (Child-Pugh class A or B) does not substantially affect systemic exposure.

Pharmacokinetics not studied in renal impairment; however, neratinib is not extensively eliminated in urine.

Age, sex, and race do not substantially affect pharmacokinetics.

Distribution

Extent

Not known whether distributed into human milk.

Plasma Protein Binding

>99% (mainly albumin and α₁-acid glycoprotein), independent of concentration.

Elimination

Metabolism

Principally metabolized by CYP3A4 and, to a lesser extent, by FMO to active pyridine N-oxide (M3), N-desmethyl (M6), dimethylamine N-oxide (M7), and bis-N-oxide (M11) metabolites.

Elimination Route

Eliminated in feces (approximately 97% of recovered dose) and urine (1.1%).

Half-life

Neratinib: 14.6 hours.

M3: 21.6 hours.

M6: 13.8 hours.

M7: 10.4 hours.

Stability

Storage

Oral

Tablets

20–25°C (excursions permitted between 15–30°C).

Actions

Potent, selective, and irreversible inhibitor of HER2, HER4, and EGFR tyrosine kinases.
Reduces phosphorylation of EGFR and HER2.
Inhibits downstream signaling of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K/Akt) pathways.

Advice to Patients

Importance of reading the manufacturer's patient information.
If a dose is missed, importance of administering the next dose at the regularly scheduled time; an additional dose should not be administered to make up for a missed dose.
For patients undergoing extended adjuvant treatment for early-stage breast cancer, instruct patients to take neratinib with food at approximately the same time each day consecutively until disease recurrence or for up to 1 year.

For patients undergoing treatment for metastatic breast cancer, instruct patients to take neratinib with food on days 1–21 of a 21-day cycle, with capecitabine on days 1–14 of a 21-day cycle until disease progression or unacceptable toxicities occur.
Risk of diarrhea. Importance of informing patients how to manage diarrhea (e.g., dietary modification, antidiarrheal agents) to maintain 1–2 bowel movements per day. Instruct patients who are not using dose escalation to initiate antidiarrheal prophylaxis with the first dose of neratinib. Instruct patients who are using dose escalation to initiate 2 weeks of lower-dose neratinib prior to receiving the recommended full dose. Importance of informing clinician if severe diarrhea or diarrhea associated with weakness, dizziness, or fever occurs.
Risk of hepatotoxicity. Importance of advising patients to immediately report possible signs and symptoms of hepatotoxicity (e.g., worsening fatigue, nausea, vomiting, right upper quadrant pain, jaundice, fever, rash, pruritus) to their clinician.
Risk of fetal harm. Necessity of advising females of childbearing potential to use effective methods of contraception while receiving neratinib and for at least 1 month after the drug is discontinued. Importance of advising male patients who are partners of such females of childbearing potential to use effective methods of contraception while receiving the drug and for 3 months after discontinuance of therapy. Importance of females informing clinicians if they are or plan to become pregnant. If pregnancy occurs, advise females of potential risk to the fetus.
Neratinib may interact with gastric acid reducing agents. Advise patients to avoid concomitant use of proton pump inhibitors. When patients require gastric acid reducing agents, use an H₂-receptor antagonist or antacid. Advise patients to separate the dosing of neratinib by 3 hours after antacid medicine, and to take neratinib at least 2 hours before or 10 hours after a H₂-receptor antagonist.
Neratinib may interact with grapefruit. Advise patients to avoid taking neratinib with grapefruit products.
Importance of advising females to avoid breast-feeding while receiving the drug and for at least 1 month after discontinuance of therapy.
Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.
Advise patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.