DRUG INTERACTIONS

• Gastric acid reducing agents: Avoid concomitant use with proton pump inhibitors (PPI) and H2-receptor antagonists. Separate NERLYNX by 3 hours after antacid dosing.

• Strong or moderate CYP3A4 inhibitors: Avoid concomitant use. 

• Strong or moderate CYP3A4 inducers: Avoid concomitant use. 

• P-glycoprotein (P-gp) substrates: Monitor for adverse reactions of narrow therapeutic agents that are P-gp substrates when used concomitantly with NERLYNX.  

U.S. FDA APPROVED  DRUGS DURING 2017

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use NERLYNX safely and effectively. See full prescribing information for NERLYNX.

NERLYNX (neratinib) tablets, for oral use

Initial U.S. Approval: 2017

INDICATIONS AND USAGE

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

DOSAGE AND ADMINISTRATION _

• Antidiarrheal prophylaxis: Initiate loperamide with the first dose of NERLYNX and continue during first 2 cycles (56 days) of treatment. Instruct patients to maintain 1-2 bowel movements per day and on how to use antidiarrheal treatment regimens. 

• Recommended dose: 240 mg (6 tablets) given orally once daily with food, continuously for one year. 

• Dose interruptions and/or dose reductions are recommended based on individual safety and tolerability. 

•Hepatic Impairment: Reduce starting dose to 80 mg in patients with severe hepatic impairment. 

DOSAGE FORMS AND STRENGTHS

Tablets: 40 mg. 

ADVERSE REACTIONS

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.

CONTRAINDICATIONS

 None. 

WARNINGS AND PRECAUTIONS

 • Diarrhea: Aggressively manage diarrhea occurring despite recommended prophylaxis with additional antidiarrheals, fluids, and electrolytes as clinically indicated.

Withhold NERLYNX in patients experiencing severe and/or persistent diarrhea. Permanently discontinue NERLYNX in patients experiencing Grade 4 diarrhea or Grade = 2 diarrhea that occurs after maximal dose reduction. 

• Hepatotoxicity: Monitor liver function tests monthly for the first 3 months of treatment, then every 3 months while on treatment and as clinically indicated. Withhold NERLYNX in patients experiencing Grade 3 liver abnormalities and permanently discontinue NERLYNX in patients experiencing Grade 4 liver abnormalities. (

• Embryo-Fetal Toxicity: NERLYNX can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception.

INDICATIONS AND USAGE

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

DOSAGE AND ADMINISTRATION

• Antidiarrheal prophylaxis: Initiate loperamide with the first dose of NERLYNX and continue during first 2 cycles (56 days) of treatment. Instruct patients to maintain 1-2 bowel movements per day and on how to use antidiarrheal treatment regimens. 

• Recommended dose: 240 mg (6 tablets) given orally once daily with food, continuously for one year. 

• Dose interruptions and/or dose reductions are recommended based on individual safety and tolerability. 

• Hepatic Impairment: Reduce starting dose to 80 mg in patients with severe hepatic impairment. 

DOSAGE FORMS AND STRENGTHS

Tablets: 40 mg. 

PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

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 or H2-receptor antagonists. Advise patients to separate the dosing of NERLYNX by 3 hours after antacid medicine .

• NERLYNX may interact with grapefruit. Advise patients to avoid taking NERLYNX with grapefruit products

• 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 

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 CLINICAL PHARMACOLOGY

1 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.

2. 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.

3. 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 Cmax and AUCinf 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 Cmax and AUCinf 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 (Vss/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 flavincontaining 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 Cmax and AUC increased by 273% and 281%, respectively, as compared to the normal hepatic function controls. [see Dosage and Administration (2.3) and Use in Specific Populations (8.6)].

Drug Interaction Studies                                                                                          Gastric Acid Reducing Agents: In a trial of 15 healthy subjects, administration of a single 240 mg dose of NERLYNX combined with a 30 mg lansoprazole dose at steady state decreased neratinib Cmax and AUC by 71% and 65%, 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 Cmax 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 [see Drug Interactions (7.1)].

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 Cmax 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   

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 Cmax by 54% and AUC by 32% [see Drug Interactions (7.2)].

 USE IN SPECIFIC POPULATIONS

1. Pregnancy 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 (see Data).

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 Data 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).

2.Lactation-                                                                                                                        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.

3. Females and Males of Reproductive Potential 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 .

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

5. Geriatric 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%).

6. 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 Cmax and AUC. Reduce the NERLYNX dosage for patients with severe hepatic impairment. 

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. 11 DESCRIPTION NERLYNX (neratinib) immediate release, film-coated tablets for oral administration contain 40 mg of neratinib, equivalent to 48.31 mg neratinib maleate. Neratinib is a member of the 4-anilino quinolidine class of protein kinase inhibitors. The molecular formula for neratinib maleate is C30H29ClN6O3•C4H4O4 and the molecular weight is 673.11 Daltons. The chemical name is (E)- N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4- (dimethylamino)but-2-enamide maleate, and its structural formula is: Neratinib maleate is an off-white to yellow powder with pKas of 7.65 and 4.66. The solubility of neratinib maleate increases dramatically as neratinib becomes protonated at acidic pH. Neratinib maleate is sparingly soluble at pH 1.2 (32.90 mg/mL) and insoluble at approximate pH 5.0 and above (0.08 mg/mL or less).