Neratinib

Neratinib
	Adult Indications & Dosage
	Pediatric Indications & Dosage
	Contraindications
	Warnings & Precautions
	Adverse Reactions
	Drug Interactions
	Use in Specific Populations
	Administration & Monitoring
	Overdosage
	Pharmacology
	Clinical Studies
	How Supplied
	Images
	Patient Counseling Information
	Precautions with Alcohol
	Brand Names
	Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sonya Gelfand

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Overview

Neratinib is a kinase inhibitor that is FDA approved for the extended adjuvant treatment of adult patients with early stage HER2-overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy. Common adverse reactions include diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, AST or ALT increase, nail disorder, dry skin, abdominal distention, weight decreased and urinary tract infection.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Indication

NERLYNX is indicated for the extended adjuvant treatment of adult patients with early stage HER2-overexpressed/amplified breast cancer, to follow adjuvant trastuzumab based therapy.

Antidiarrheal Prophylaxis

Antidiarrheal prophylaxis is recommended during the first 2 cycles (56 days) of treatment and should be initiated with the first dose of NERLYNX.
Instruct patients to take loperamide as directed in TABLE 1, titrating to 1-2 bowel movements per day.

This image is provided by the National Library of Medicine.

Additional antidiarrheal agents may be required to manage diarrhea in patients with loperamide-refractory diarrhea. NERLYNX dose interruptions and dose reductions may also be required to manage diarrhea.

Recommended Dose and Schedule

The recommended dose of NERLYNX is 240 mg (six tablets) given orally once daily with food, continuously for one year.
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 5. Discontinue NERLYNX for patients who fail to recover to Grade 0-1 from treatment-related toxicity, for toxicities that result in a treatment delay > 3 weeks, or for patients that are 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.).

Dose Modifications for Diarrhea

Diarrhea management requires the correct use of antidiarrheal medication, dietary changes, and appropriate dose modifications of NERLYNX. Guidelines for adjusting doses of NERLYNX in the setting of diarrhea are shown in TABLE 4.

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 5. 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.

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 H 2-receptor antagonist or 10 hours after the H2-receptor antagonist.
Antacids: Separate dosing of NERLYNX by 3 hours after antacids.

Dosage Forms and Strengths

Tablets: 40 mg neratinib (equivalent to 48.31 mg of neratinib maleate).
Film-coated, red, oval shaped and debossed with ‘W104’ on one side and plain on the other side.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding neratinib Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.

Non–Guideline-Supported Use

There is limited information regarding neratinib Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Neratinib FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding neratinib Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.

Non–Guideline-Supported Use

There is limited information regarding neratinib Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.

Contraindications

None.

Warnings

Diarrhea

Severe diarrhea and sequelae, such as dehydration, hypotension, and renal failure, have been reported during treatment with NERLYNX. Diarrhea was reported in 95% of NERLYNX-treated patients in ExteNET, a randomized placebo controlled trial. In the NERLYNX arm, Grade 3 diarrhea occurred in 40% and Grade 4 diarrhea occurred in 0.1% of patients. The majority of patients (93%) had diarrhea in the first month of treatment, the median time to first onset of Grade ≥ 3 diarrhea was 8 days (range, 1-350), and the median cumulative duration of Grade ≥ 3 diarrhea was 5 days (range, 1-139).
Antidiarrheal prophylaxis with loperamide has been shown to lower the incidence and severity of diarrhea. Instruct patients to initiate antidiarrheal prophylaxis with loperamide along with the first dose of NERLYNX and continue during the first two cycles (56 days) of treatment.
Monitor patients for diarrhea and treat with additional antidiarrheals as needed. When severe diarrhea with dehydration occurs, administer fluid and electrolytes as needed, interrupt NERLYNX, and reduce subsequent doses. Perform stool cultures as clinically indicated to exclude infectious causes of Grade 3 or 4 diarrhea or diarrhea of any grade with complicating features (dehydration, fever, neutropenia).

Hepatotoxicity

NERLYNX has been associated with hepatotoxicity characterized by increased liver enzymes. In ExteNET, 9.7% of patients experienced an alanine aminotransferase (ALT) increase ≥ 2 x ULN, 5.1% of patients experienced an aspartate aminotransferase (AST) increase ≥ 2 x ULN, and 1.7% of patients experienced an AST or ALT elevation > 5 x ULN (≥ Grade 3). Hepatotoxicity or increases in liver transaminases led to drug discontinuation in 1.7% of NERLYNX-treated patients.
Total bilirubin, AST, ALT, and alkaline phosphatase should be measured prior to starting treatment with NERLYNX monthly for the first 3 months of treatment, then every 3 months while on treatment and as clinically indicated. These tests should also be performed in patients experiencing Grade 3 diarrhea or any signs or symptoms of hepatotoxicity, such as worsening of fatigue, nausea, vomiting, right upper quadrant tenderness, fever, rash, or eosinophilia.

Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, NERLYNX can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of neratinib to pregnant rabbits during organogenesis caused abortions, embryo-fetal death and fetal abnormalities in rabbits at maternal AUCs approximately 0.2 times the AUC in patients receiving the recommended dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for at least 1 month after the last dose.

Adverse Reactions

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

ExteNET

The data described below reflect exposure of NERLYNX as a single agent in ExteNET, a multicenter, randomized, double-blind, placebo-controlled study of NERLYNX within 2 years after completion of adjuvant treatment with trastuzumab-based therapy in women with HER2-positive early-stage breast cancer. Patients who received NERLYNX in this trial were not required to receive any prophylaxis with antidiarrheal agents to prevent the NERLYNX-related diarrhea. The median duration of treatment was 11.6 months in the NERLYNX arm and 11.8 months in the placebo arm. The median age was 52 years (60% were ≥ 50 years old, 12% were ≥ 65 years old); 81% were Caucasian, 3% Black or African American, 14% Asian and 3% other. A total of 1408 patients were treated with NERLYNX.
NERLYNX dose reduction due to an adverse reaction of any grade occurred in 31.2% of patients receiving NERLYNX compared to 2.6% of patients receiving placebo. Permanent discontinuation due to any adverse reaction was reported in 27.6% of NERLYNX-treated patients. The most common adverse reaction leading to discontinuation was diarrhea, accounting for 16.8% of NERLYNX-treated patients.
The most common adverse reactions (>5%) were diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, AST or ALT increase, nail disorder, dry skin, abdominal distention, weight decreased and urinary tract infection. The most frequently reported Grade 3 or 4 adverse reactions were diarrhea, vomiting, nausea, and abdominal pain.
Serious adverse reactions in the NERLYNX arm included diarrhea (1.6%), vomiting (0.9%), dehydration (0.6%), cellulitis (0.4%), renal failure (0.4%), erysipelas (0.4%), alanine aminotransferase increased (0.3%), aspartate aminotransferase increased (0.3%), nausea (0.3%), fatigue (0.2%), and abdominal pain (0.2%).
TABLE 6 summarizes the adverse reactions in ExteNET.

Postmarketing Experience

There is limited information regarding Neratinib Postmarketing Experience in the drug label.

Drug Interactions

Effect of Other Drugs on NERLYNX
Effect of NERLYNX on Other Drugs

Effect of Other Drugs on NERLYNX

TABLE 7 includes drug interactions that affect the pharmacokinetics of neratinib.

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).

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

Risk Summary

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. In animal reproduction studies, administration of neratinib to pregnant rabbits during organogenesis resulted in abortions, embryo-fetal death and fetal abnormalities in rabbits at maternal exposures (AUC) approximately 0.2 times exposures in patients at the recommended dose. Advise pregnant women of the potential risk to a fetus.
The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies in the U.S. general population.

Data (Animal)

In a fertility and early embryonic development study in female rats, neratinib was administered orally for 15 days before mating to Day 7 of pregnancy, which did not cause embryonic toxicity at doses up to 12 mg/kg/day in the presence of maternal toxicity. A dose of 12 mg/kg/day in rats is approximately 0.5 times the maximum recommended dose of 240 mg/day in patients on a mg/m² basis.
In an embryo-fetal development study in rats, pregnant animals received oral doses of neratinib up to 15 mg/kg/day during the period of organogenesis. No effects on embryo-fetal development or survival were observed. Maternal toxicity was evident at 15 mg/kg/day (approximately 0.6 times the AUC in patients receiving the maximum recommended dose of 240 mg/day).
In an embryo-fetal development study in rabbits, pregnant animals received oral doses of neratinib up to 9 mg/kg/day during the period of organogenesis. Administration of neratinib at doses ≥ 6 mg/kg/day resulted in maternal toxicity, abortions and embryo-fetal death (increased resorptions). Neratinib administration resulted in increased incidence of fetal gross external (domed head), soft tissue (dilation of the brain ventricles and ventricular septal defect), and skeletal (misshapen anterior fontanelles and enlarged anterior and/or posterior fontanelles) abnormalities at ≥ 3 mg/kg/day. The AUC_(0-t) at 6 mg/kg/day and 9 mg/kg/day in rabbits were approximately 0.5 and 0.8 times, respectively, the AUCs in patients receiving the maximum recommended dose of 240 mg/day.
In a peri and postnatal development study in rats, oral administration of neratinib from gestation day 7 until lactation day 20 resulted in maternal toxicity at ≥ 10 mg/kg/day (approximately 0.4 times the maximum recommended dose of 240 mg/day in patients on a mg/m² basis) including decreased body weights, body weight gains, and food consumption. Effects on long-term memory were observed in male offspring at maternal doses ≥ 5 mg/kg/day (approximately 0.2 times the maximum recommended dose of 240 mg/day in patients on a mg/m² basis).

Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Neratinib in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Neratinib during labor and delivery.

Nursing Mothers

Risk Summary

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.

Pediatric Use

The safety and efficacy of NERLYNX in pediatric patients has not been established.

Geriatic Use

In the ExteNET trial, the mean age was 52 years in the NERLYNX arm; 1236 patients were < 65 years, 172 patients were ≥ 65 years, of whom 25 patients were 75 years or older.
There was a higher frequency of treatment discontinuations due to adverse reactions in the ≥ 65 years age group than in the < 65 years age group; in the NERLYNX arm, the percentages were 44.8% compared with 25.2%, respectively, and in the placebo arm 6.4% and 5.3%, respectively.
The incidence of serious adverse reactions in the NERLYNX arm vs. placebo arm was 7.0% vs. 5.7% (< 65 years-old) and 9.9% vs. 8.1% (≥ 65 years-old). The serious adverse reactions most frequently reported in the ≥ 65 years-old group were vomiting (2.3%), diarrhea (1.7%), renal failure (1.7%), and dehydration (1.2%).

Gender

There is no FDA guidance on the use of Neratinib with respect to specific gender populations.

Race

There is no FDA guidance on the use of Neratinib with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Neratinib in patients with renal impairment.

Hepatic Impairment

No dose modifications are recommended for patients with mild to moderate hepatic impairment (Child Pugh A or B). Patients with severe, pre-existing hepatic impairment (Child Pugh Class C) experienced a reduction in neratinib clearance and an increase in C_max and AUC. Reduce the NERLYNX dosage for patients with severe hepatic impairment.

Females of Reproductive Potential and Males

Pregnancy

Based on animal studies, NERLYNX can cause fetal harm when administered to a pregnant woman. Females of reproductive potential should have a pregnancy test prior to starting treatment with NERLYNX.

Contraception

Females

Based on animal studies, NERLYNX can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with NERLYNX and for at least 1 month after the last dose.

Males

Based on findings in animal reproduction studies, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of NERLYNX.

Immunocompromised Patients

There is no FDA guidance one the use of Neratinib in patients who are immunocompromised.

Administration and Monitoring

Administration

Oral

Monitoring

Disease response or stabilization may indicate efficacy.
FTL3 mutation: Prior to initiation, with an FDA-approved companion diagnostic test available at http://www.fda/gov/CompanionDiagnostics.
Pregnancy status (women of reproductive potential): Within 7 days prior to initiation of therapy.
CBC: At least weekly for the first 4 weeks, every other week for the next 8 weeks, and monthly thereafter during therapy; include a differential.
Toxicities, including nausea, vomiting, and other non-hematologic toxicities: At least weekly for the first 4 weeks, every other week for the next 8 weeks, and monthly thereafter during therapy.
Pulmonary symptoms of interstitial lung disease or pneumonitis.

IV Compatibility

There is limited information regarding the compatibility of Neratinib and IV administrations.

Overdosage

There is no specific antidote, and the benefit of hemodialysis in the treatment of NERLYNX overdose is unknown. In the event of an overdose, administration should be withheld and general supportive measures undertaken.
In the clinical trial setting, a limited number of patients reported overdose. The adverse reactions experienced by these patients were diarrhea, nausea, vomiting, and dehydration. The frequency and severity of gastrointestinal disorders (diarrhea, abdominal pain, nausea and vomiting) appear to be dose related.

Pharmacology


Neratinib
Systematic (IUPAC) name
(2E)-N-[4-[[3-Chloro-4-[(pyridin-2-yl)methoxy]phenyl]amino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide
Identifiers
CAS number	698387-09-6
ATC code	none
PubChem	9915743
Chemical data
Formula	Template:OrganicBox atom Template:OrganicBox atom Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox atom Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox atom Template:OrganicBox Template:OrganicBox atom Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox
Mol. mass	557.04 g/mol
SMILES	eMolecules & PubChem
Pharmacokinetic data
Bioavailability	?
Metabolism	?
Half life	?
Excretion	?
Therapeutic considerations
Pregnancy cat.	?
Legal status	[[Prescription drug\|Template:Unicode-only]](US)
Routes	Oral

Mechanism of Action

Neratinib is a kinase inhibitor that irreversibly binds to Epidermal Growth Factor Receptor (EGFR), Human Epidermal Growth Factor Receptor 2 (HER2), and HER4. In vitro, neratinib reduces EGFR and HER2 autophosphorylation, downstream MAPK and AKT signaling pathways, and showed antitumor activity in EGFR and/or HER2 expressing carcinoma cell lines. Neratinib human metabolites M3, M6, M7 and M11 inhibited the activity of EGFR, HER2 and HER4 in vitro. In vivo, oral administration of neratinib inhibited tumor growth in mouse xenograft models with tumor cell lines expressing HER2 and EGFR.

Structure

Pharmacodynamics

Cardiac Electrophysiology

The effect of NERLYNX on the QTc interval was evaluated in a randomized, placebo and positive controlled, double-blind, single-dose, crossover study in 60 healthy subjects. At 2.4-fold the therapeutic exposures of NERLYNX, there was no clinically relevant effect on the QTc interval.

Pharmacokinetics

Neratinib exhibits a non-linear PK profile with less than dose proportional increase of AUC with the increasing daily dose over the range of 40 to 400 mg.

Absorption

The neratinib and major active metabolites M3, M6 and M7 peak concentrations are reached in the range of 2 to 8 hours after oral administration.

Effect of Food

The food-effect assessment was conducted in healthy volunteers who received NERLYNX 240 mg under fasting conditions and with high fat food (approximately 55% fat, 31% carbohydrate, and 14% protein) or standard breakfast (approximately 50% carbohydrate, 35% fat, and 15% protein). A high fat meal increased neratinib C_max and AUC_inf by 1.7-fold (90% CI: 1.1- 2.7) and 2.2-fold (90% CI: 1.4- 3.5), respectively. A standard breakfast increased the C_max and AUC_inf by 1.2-fold (90% CI: 0.97- 1.42) and 1.1-fold (90% CI: 1.02- 1.24), respectively.

Distribution

In patients, following multiple doses of NERLYNX, the mean (%CV) apparent volume of distribution at steady-state (V_ss/F) was 6433 (19%) L. In vitro protein binding of neratinib in human plasma was greater than 99% and independent of concentration. Neratinib bound predominantly to human serum albumin and human alpha-1 acid glycoprotein.

Elimination

Following 7 days of daily 240 mg oral doses of NERLYNX in healthy subjects, the mean (%CV) plasma half-life of neratinib, M3, M6, and M7 was 14.6 (38%), 21.6 (77%), 13.8 (50%) and 10.4 (33%) hours, respectively. The mean elimination half-life of neratinib ranged from 7 to 17 hours following a single oral dose in patients. Following multiple doses of NERLYNX at once-daily 240 mg in cancer patients, the mean (%CV) CL/F after first dose and at steady state (day 21) were 216 (34%) and 281 (40%) L/hour, respectively.

Metabolism

Neratinib is metabolized primarily in the liver by CYP3A4 and to a lesser extent by flavin-containing monooxygenase (FMO).
After oral administration of NERLYNX, neratinib represents the most prominent component in plasma. At steady state after 240 mg daily oral doses of NERLYNX in a healthy subject study (n=25), the systemic exposures (AUC) of the active metabolites M3, M6, M7 and M11were 15%, 33%, 22% and 4% of the systemic neratinib exposure (AUC) respectively.

Excretion

After oral administration of 200 mg (0.83 times of approved recommended dosage) radiolabeled neratinib oral formulation, fecal excretion accounted for approximately 97.1% and urinary excretion accounted for 1.13% of the total dose. Sixty-one percent of the excreted radioactivity was recovered within 96 hours and 98% was recovered after 10 days.

Specific Populations

Age, gender, race and renal function do not have a clinically significant effect on neratinib pharmacokinetics.

Patients with Hepatic Impairment

Neratinib is mainly metabolized in the liver. Single doses of 120 mg NERLYNX were evaluated in non-cancer patients with chronic hepatic impairment (n=6 each in Child Pugh Class A, B, and C) and in healthy subjects (n=9) with normal hepatic function. Neratinib exposures in the patients with Child Pugh Class A (mild impairment) and Child Pugh Class B (moderate impairment) were similar to that in normal healthy volunteers. Patients with severe hepatic impairment (Child Pugh Class C) had neratinib C_max and AUC increased by 273% and 281%, respectively, as compared to the normal hepatic function controls.

Drug Interaction Studies

Gastric Acid Reducing Agents: NERLYNX solubility decreases with increasing GI tract pH values. Drugs that alter the pH values of the GI tract may alter the solubility of neratinib and hence its absorption and systemic exposure. When multiple doses of lansoprazole (30 mg daily), a proton pump inhibitor, were co-administered with a single 240 mg oral doses of NERLYNX, the neratinib C_max and AUC decreased by 71% and 65%, respectively. When a single oral dose of 240 mg NERLYNX was administered 2 hours following a daily dose of 300 mg ranitidine, an H-2 receptor antagonist, the neratinib C_max and AUC were reduced by 57% and 48%, respectively. When a single oral dose of 240 mg NERLYNX was administered 2 hours prior to 150 mg ranitidine twice daily (administered in the morning and evening, approximately 12 hours apart), the neratinib C_maxand AUC were reduced by 44% and 32%, respectively.
Strong and Moderate CYP3A4 Inhibitors: Concomitant use of ketoconazole (400 mg once-daily for 5 days), a strong inhibitor of CYP3A4, with a single oral 240 mg NERLYNX dose in healthy subjects (n=24) increased neratinib C_max by 321% and AUC by 481%.
The effect of moderate CYP3A4 inhibition has not been studied. Given neratinib is predominantly metabolized by the CYP3A4 pathway and had a significant exposure change with strong CYP3A4 inhibition, the potential impact on NERLYNX safety from concomitant use with moderate CYP3A4 inhibitors warrants consideration.
Strong and Moderate CYP3A4 Inducers: Concomitant use of rifampin, a strong inducer of CYP3A4, with a single oral 240 mg NERLYNX dose in healthy subjects (n=24) reduced neratinib C_max by 76% and AUC by 87%. The AUC of active metabolites M6 and M7 were also reduced by 37-49% when compared to NERLYNX administered alone.
The effect of moderate CYP3A4 induction has not been studied. Given neratinib is predominantly metabolized by the CYP3A4 pathway and had a significant exposure change with strong CYP3A4 induction, the potential impact on NERLYNX efficacy from concomitant use with moderate CYP3A4 inducers warrants consideration.
Effect of NERLYNX on P-gp Transporters: Concomitant use of digoxin (a single 0.5 mg oral dose), a P-gp substrate, with multiple oral doses of NERLYNX 240 mg in healthy subjects (n=18) increased the mean digoxin C_max by 54% and AUC by 32%.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

A two-year carcinogenicity study was conducted in rats at oral neratinib doses of 1, 3, and 10 mg/kg/day. Neratinib was not carcinogenic in male and female rats at exposure levels > 25 times the AUC in patients receiving the maximum recommended dose of 240 mg/day. Neratinib was not carcinogenic in a 26-week study in Tg.rasH2 transgenic mice when administered daily by oral gavage at doses up to 50 mg/kg/day in males and 125 mg/kg/day in females.
Neratinib was not mutagenic in an in vitro bacterial reverse mutation (AMES) assay or clastogenic in an in vitro human lymphocyte chromosomal aberration assay or an in vivo rat bone marrow micronucleus assay.
In a fertility study in rats, neratinib administration up to 12 mg/kg/day (approximately 0.5 times the maximum recommended dose of 240 mg/day in patients on a mg/m 2 basis) caused no effects on mating or the ability of animals to become pregnant. In repeat-dose toxicity studies in dogs with oral administration of neratinib daily for up to 39 weeks, tubular hypoplasia of the testes was observed at ≥ 0.5 mg/kg/day. This finding was observed at AUCs that were approximately 0.4 times the AUC in patients at the maximum recommended dose of 240 mg.

Clinical Studies

Extended Adjuvant Treatment in Breast Cancer

The safety and efficacy of NERLYNX were investigated in the ExteNET trial (NCT00878709), a multicenter, randomized, double-blind, placebo-controlled study of NERLYNX after adjuvant treatment with trastuzumab in women with HER2-positive breast cancer.
A total of 2840 patients with early-stage HER2-positive breast cancer within two years of completing treatment with adjuvant trastuzumab was randomized to receive either NERLYNX (n=1420) or placebo (n=1420). Randomization was stratified by the following factors: hormone receptor status, nodal status (0, 1-3 vs 4 or more positive nodes) and whether trastuzumab was given sequentially versus concurrently with chemotherapy. NERLYNX 240 mg or placebo was given orally once daily for one year. The major efficacy outcome measure was invasive disease-free survival (iDFS) defined as the time between the date of randomization to the first occurrence of invasive recurrence (local/regional, ipsilateral, or contralateral breast cancer), distant recurrence, or death from any cause, with 2 years and 28 days of follow-up.
Patient demographics and tumor characteristics were generally balanced between treatment arms. Patients had a median age of 52 years (range 23 to 83) and 12% of patients were 65 or older. The majority of patients were White (81%), and most patients (99.7%) had an ECOG performance status of 0 or 1. Fifty-seven percent (57%) had hormone receptor positive disease (defined as ER-positive and/or PgR-positive), 24% were node negative, 47% had one to three positive nodes and 30% had four or more positive nodes. Ten percent (10%) of patients had Stage I disease, 41% had Stage II disease and 31% had Stage III disease. The majority of patients (81%) were enrolled within one year of completion of trastuzumab treatment. Median time from the last adjuvant trastuzumab treatment to randomization was 4.4 months in the NERLYNX arm vs. 4.6 months in the placebo arm. Median duration of treatment was 11.6 months in the NERLYNX arm vs. 11.8 months in the placebo arm.
The efficacy results from the ExteNET trial are summarized in TABLE 8 and FIGURE 1.

Approximately 75% of patients were re-consented for extended follow-up beyond 24 months. Observations with missing data were censored at the last date of assessment. This exploratory analysis suggests that the iDFS results at 5 years are consistent with the 2-year iDFS results observed in ExteNET. At the time of the iDFS analysis, 2% of patients had died, and Overall Survival data were immature.

How Supplied

NERLYNX 40 mg film-coated tablets are red, oval shaped and debossed with ‘W104’ on one side and plain on the other side.
NERLYNX is available in:

Bottles of 180 tablets: NDC 70437-240-18
Bottles of 126 tablets: NDC 70437-240-26

Storage

Store at controlled room temperature, 20°C to 25°C (68°F to 77°F); excursions permitted to 15-30°C (59–86°F).

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling

Diarrhea

Inform patients that NERLYNX has been associated with diarrhea which may be severe in some cases.
Instruct patients to maintain 1-2 bowel movements per day and on how to use anti-diarrheal treatment regimens.
Advise patients to inform their healthcare provider immediately if severe (≥Grade 3) diarrhea or diarrhea associated with weakness, dizziness, or fever occurs during treatment with NERLYNX.

Hepatotoxicity

Inform patients that NERLYNX has been associated with hepatotoxicity which may be severe in some cases.

Inform patients that they should report signs and symptoms of liver dysfunction to their healthcare provider immediately.

Embryo-Fetal Toxicity

Advise females to inform their healthcare provider if they are pregnant or become pregnant. Inform female patients of the risk to a fetus and potential loss of the pregnancy.
Advise females of reproductive potential to use effective contraception during treatment and for 1 month after receiving the last dose of NERLYNX.
Advise lactating women not to breastfeed during treatment with NERLYNX and for at least 1 month after the last dose.

Drug Interactions

NERLYNX may interact with many drugs; therefore, advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products.
NERLYNX 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 H 2-receptor antagonist or antacid. Advise patients to separate the dosing of NERLYNX by 3 hours after antacid medicine, and to take NERLYNX at least 2 hours before or 10 hours after a H 2-receptor antagonist.
NERLYNX may interact with grapefruit. Advise patients to avoid taking NERLYNX with grapefruit products.

Dosing and Administration

Instruct patients to take NERLYNX with food at approximately the same time each day consecutively for one year.
If a patient misses a dose, instruct the patient not to replace the missed dose, and to resume NERLYNX with the next scheduled daily dose.

Precautions with Alcohol

Alcohol-Neratinib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

Brand Names

Nerlynx

Look-Alike Drug Names

There is limited information regarding Neratinib Look-Alike Drug Names in the drug label.

Drug Shortage Status

Drug Shortage

Price

References

The contents of this FDA label are provided by the National Library of Medicine.