Nerlynx

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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This medicinal product is subject to additional monitoring. This will allow quick identification of 
new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See Section 4.8 for how to report adverse reactions. 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nerlynx 40 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film-coated tablet contains neratinib maleate, equivalent to 40 mg neratinib. 
 
For the full list of excipients, see Section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet. 
 
Oval, red film-coated tablet with ‘W104’ debossed on one side. Tablet dimensions are 10.5 mm x 
4.3 mm with thickness of 3.1 mm. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indication 
 
Nerlynx is indicated for the extended adjuvant treatment of adult patients with early-stage hormone 
receptor positive HER2-overexpressed/amplified breast cancer and who completed adjuvant 
trastuzumab-based therapy less than one year ago. 
 
4.2 Posology and method of administration 
 
Nerlynx treatment should be initiated and supervised by a physician experienced in the administration 
of anti-cancer medicinal products. 
 
Posology 
The recommended dose of Nerlynx is 240 mg (six 40 mg tablets) taken orally once daily, 
continuously for one year. Nerlynx should be taken with food, preferably in the morning. Patients 
should initiate treatment within 1 year after completion of trastuzumab therapy. 
 
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 1, 
Table 2, Table 3, and Table 4. 
 
Discontinue Nerlynx for patients who: 

• Fail to recover to Grade 0 to 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.). 
 



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Table 1: Nerlynx dose modifications for adverse reactions 

Dose level  Nerlynx dose  

Recommended starting dose 240 mg daily 

First dose reduction 200 mg daily 

Second dose reduction 160 mg daily 

Third dose reduction 120 mg daily 

Table 2: Nerlynx dose modifications and management – general toxicities* 

Severity of toxicity† Action 

Grade 3  Stop Nerlynx until recovery to Grade 0-1 or baseline within 3 weeks 
of stopping treatment. Then resume Nerlynx at the next lower dose 
level. If grade 3 toxicity does not recover within 3 weeks, 
discontinue Nerlynx permanently. 

Grade 4 Discontinue Nerlynx permanently. 
*  Refer to Table 3 and Table 4 below for management of diarrhoea and hepatotoxicity 
†  Per CTCAE v4.0 
 
Dose modifications for diarrhoea 
Diarrhoea management requires the correct use of an anti-diarrhoeal medicinal product, dietary 
changes, and appropriate dose modifications of Nerlynx.  Guidelines for adjusting doses of Nerlynx in 
the setting of diarrhoea are shown in Table 3. 
 

Table 3: Dose modifications for diarrhoea 

Severity of diarrhoea* Action 

• Grade 1 diarrhoea [increase of 
< 4 stools per day over baseline] 

• Grade 2 diarrhoea [increase of 
4-6 stools per day over baseline] 
lasting < 5 days 

• Grade 3 diarrhoea [increase of 
≥ 7 stools per day over baseline; 
incontinence; hospitalization indicated; 
limiting self-care activities of daily 
living] lasting ≤ 2 days 

• Adjust anti-diarrhoeal treatment 
• Diet modifications 
• Fluid intake of ~2 L should be maintained to 

avoid dehydration 
• Once event resolves to Grade 0-1 or baseline, 

consider restarting anti-diarrhoeal prophylaxis, if 
appropriate with each subsequent Nerlynx 
administration (refer to section 4.4).  



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Severity of diarrhoea* Action 

• Any grade with complicated features† 
• Grade 2 diarrhoea lasting 5 days or 

longer‡ 
• Grade 3 diarrhoea lasting between 

2 days and 3 weeks‡ 

• Interrupt Nerlynx treatment 
• Diet modifications 
• Fluid intake of ~2 L should be maintained to 

avoid dehydration 
• If diarrhoea resolves to Grade 0-1 in one week or 

less, then resume Nerlynx treatment at the same 
dose.  

• If diarrhoea resolves to Grade 0-1 in longer than 
one week, then resume Nerlynx treatment at 
reduced dose (see Table 1). 

• Once event resolves to Grade 0-1 or baseline, 
consider restarting anti-diarrhoeal prophylaxis, if 
appropriate with each subsequent Nerlynx 
administration (refer to section 4.4). 

• If grade 3 diarrhoea persists longer than 3weeks, 
discontinue Nerlynx permanently. 

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

• Permanently discontinue Nerlynx treatment 

• Diarrhoea 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 
 
Dose modifications for hepatotoxicity 
Guidelines for dose adjustment of Nerlynx in the event of liver toxicity are shown in Table 4. 
(see Section 4.4). 
 

Table 4: Dose modifications for hepatotoxicity 

Severity of hepatotoxicity*  Action 

• Grade 3 ALT (>5-20 x ULN) 
OR 

• Grade 3 bilirubin (>3-10 x ULN) 

• Stop Nerlynx until recovery to Grade 0-1 
• Evaluate alternative causes 
• Resume Nerlynx at the next lower dose level if 

recovery to Grade 0-1 occurs within 3 weeks. If 
Grade 3 ALT or bilirubin occurs again despite 
one dose reduction, permanently discontinue 
Nerlynx. 

• If grade 3 hepatotoxicity persists longer than 3 
weeks, discontinue Nerlynx permanently 

• Grade 4 ALT (>20 x ULN) 
OR 

• Grade 4 bilirubin (>10 x ULN) 

• Permanently discontinue Nerlynx 
• Evaluate alternative causes 

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



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Missed dose 
Missed doses should not be replaced and treatment should resume with the next scheduled daily dose 
(see Section 4.9). 
 
Grapefruit and pomegranate  
Concomitant administration of neratinib with grapefruit or pomegranate /grapefruit or 
pomegranate juice is not recommended (see Section 4.4 and Section 4.5) 
 
Use of CYP3A4/P-gp inhibitors 
If the inhibitor cannot be avoided, reduce Nerlynx dose: 

- to 40 mg (one 40 mg tablet) taken once daily with a strong CYP3A4/P-gp inhibitor. 
- to 40 mg (one tablet) taken once daily with a moderate CYP3A4/P-gp. If well tolerated, 

increase to 80 mg for at least 1 week, then to 120 mg for at least 1 weeks, and to 160 mg as a 
maximal daily dose. Patient should be monitored carefully, especially GI effect including 
diarrhea and hepatotoxicity.  

After discontinuation of a strong or moderate CYP3A4/P-gp inhibitor, resume previous dose of 
Nerlynx 240 mg (see Section 4.4, Section 4.5 and Section 5.2).  
 
H2-receptor antagonists and antacids 
If  H2-receptor antagonists are used, Nerlynx should be taken at least 2 hours before or 10 hours after 
the intake of the H2-receptor antagonist. Separate dosing of Nerlynx and antacids by at least 3 hours 
should be applied (see Section 4.4, Section 4.5 and Section 5.2). 
 
Special populations  
 
Patients with renal impairment 
No dose adjustment is necessary in patients with mild to moderate renal impairment. Nerlynx has not 
been studied in patients with severe renal impairment including patients on dialysis. Treatment of 
patients with severe renal impairment or on dialysis is not recommended (see Section 5.2). 
 
Patients with hepatic impairment 
No dose adjustment is required in patients with Child-Pugh A or B (mild to moderate) hepatic 
impairment (see Section 5.2). 
 
 
Elderly 
No dose adjustment is required. There is no data in patients ≥85 years of age. 
 
Paediatric population 
There is no relevant use of Nerlynx in the paediatric population in the indication breast cancer. 
 
Method of administration 
Nerlynx is for oral use. The tablets should be swallowed whole preferably with water and should not 
be crushed or dissolved, and should be taken with food, preferably in the morning (see Section 5.2). 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in Section 6.1. 
 
Co-administration with the following medical products that are strong inducers of the CYP3A4/P-gp 
isoform of cytochrome P450, such as (see Section 4.5 and Section 5.2): 

• carbamazepine, phenytoin (antiepileptics) 
• St John’s wort (Hypericum perforatum) (herbal product) 
• rifampicin (antimycobacterial) 

 
Severe hepatic impairment (Child-Pugh C) (see Section 5.2). 



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4.4 Special warnings and precautions for use 
 
Diarrhoea 
Diarrhoea has been reported during treatment with Nerlynx (see Section 4.2 and Section 4.8). The 
diarrhoea may be severe and associated with dehydration. 
 
Diarrhoea generally occurs early during the first or second week of treatment with Nerlynx and may 
be recurrent. 
 
Patients should be instructed to initiate prophylactic treatment with an anti-diarrhoeal medicinal 
product with the first dose of Nerlynx, and maintain regular dosing of the anti-diarrhoeal medicinal 
product during the first 1-2 months of Nerlynx treatment, titrating to 1-2 bowel movements per day. 
 
Elderly 
Elderly patients (≥65 years of age) are at a higher risk of renal insufficiency and dehydration which 
may be a complication of diarrhoea and these patients should be carefully monitored. 
 
Patients with a significant chronic gastrointestinal disorder 
Patients with a significant chronic gastrointestinal disorder with diarrhoea as a major symptom were 
not included in the pivotal study, and should be carefully monitored. 
 
Renal impairment 
Patients with renal impairment are at a higher risk of complications of dehydration if they develop 
diarrhoea, and these patients should be carefully monitored (see Section 4.2 and Section 5.2).  
 
Liver function 
Hepatotoxicity has been reported in patients treated with Nerlynx. Liver function tests including 
alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin should be 
monitored at 1 week, then monthly for the first 3 months and every 6 weeks thereafter while on 
treatment or as clinically indicated (see Section 4.2). 
 
Patients who experience ≥ Grade 3 diarrhoea requiring IV fluid treatment or any signs or symptoms of 
hepatotoxicity, such as worsening of fatigue, nausea, vomiting, jaundice, 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. 
 
Left ventricular function 
Left ventricular dysfunction has been associated with HER2 inhibition. Nerlynx has not been studied 
in patients with less than lower limit of normal left ventricular ejection fraction (LVEF) or with 
significant cardiac history. In patients with known cardiac risk factors, conduct cardiac monitoring, 
including assessment of LVEF, as clinically indicated. 
 
Proton pump inhibitors, H2-receptor antagonists and antacids 
Treatments that increase gastrointestinal pH may lower the absorption of neratinib, thus decreasing 
systemic exposure. Co-administration with proton pump inhibitors (PPIs) is not recommended (see 
Section 4.5 and Section 5.2). 
In case of H2-receptor antagonists or antacids, modalities of administration should be adapted (see 
Section 4.2, Section 4.5 and Section 5.2). 
 
Pregnancy 
Neratinib may cause foetal harm when administered to pregnant women (see Section 4.6). 
 
Skin and subcutaneous tissue disorders 
Nerlynx is associated with skin and subcutaneous tissue disorders. Patients with symptomatic skin and 
subcutaneous tissue disorders should be carefully monitored (see Section 4.8). 
 



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Concomitant treatment with inhibitors of CYP3A4 and P-gp 
Concomitant treatment with strong or moderate CYP3A4 and P-gp inhibitors is not recommended due 
to risk of increased exposure to neratinib. If the inhibitor can not be avoided, Nerlynx dose adjustment 
should be applied (see Section 4.2, Section 4.5 and Section 5.2). 
 
Grapefruit or pomegranate juice should be avoided during treatment with Nerlynx (see Section 4.2 
and Section 4.5). 
 
Concomitant treatment with moderate inducers of CYP3A4 and P-gp 
Concomitant treatment with moderate CYP3A4 and P-gp inducer is not recommended as it may lead 
to a loss of neratinib efficacy (see Section 4.5 and Section 5.2). 
 
Concomitant treatment with substrates of P-gp 
Patients who are treated concomitantly with therapeutic agents with a narrow therapeutic window 
whose absorption involves P-gp transporters in the gastrointestinal tract should be carefully monitored 
(see Section 4.5 and Section 5.2). 
 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Effects of other substances on neratinib 
 
Neratinib is primarily metabolized by CYP3A4 and is a P-gp substrate. 
 
CYP3A4/P-gp inducers 
Clinical study demonstrated that concomitant use of strong CYP3A4/P-gp inducers significantly 
decreased neratinib exposure, therefore concurrent use of neratinib with strong CYP3A4/P-gp 
inducers is contraindicated (e.g. strong inducers: phenytoin, carbamazepine, rifampicin, or herbal 
preparations containing St John’s Wort (Hypericum perforatum)). Concurrent use of neratinib with 
moderate CYP3A4/P-gp inducers is not recommended as it may also lead to lose of efficacy (e.g. 
moderate inducers: bosentan, efavirenz, etravirine, phenobarbital, primidone, dexamethasone) (see 
Section 4.3 and Section 5.2). 
 
CYP3A4/P-gp inhibitors 
Clinical study and model-based predictions have demonstrated that concomitant use of strong or 
moderate CYP3A4/P-gp inhibitors significantly increased neratinib systemic exposure, therefore, 
concomitant use of neratinib with strong and moderate CYP3A4/P-gp inhibitors is not 
recommended (e.g. strong inhibitors: atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, 
saquinavir, lopinavir, ketoconazole, itraconazole, clarithromycin, troleandomycin, voriconazole, 
and cobicistat; moderate inhibitors: ciprofloxacin,  cyclosporine, diltiazem, fluconazole, 
erythromycin, fluvoxamine and verapamil).  If the inhibitor can not be avoided, Nerlynx dose 
adjustement shoud be applied (see Section 4.2, Section 4.4 and Section 5.2). 
 
Grapefruit/pomegranate or grapefruit/pomegranate juice may also increase neratinib plasma 
concentrations and should be avoided (see Section 4.2 and Section 4.4). 
 
Proton pump inhibitors, H2-receptor antagonists and antacids 
The in-vitro solubility of neratinib is pH-dependent. Concomitant treatment with substances that 
increase gastric pH may lower the absorption of neratinib, thus decreasing systemic exposure. Co-
administration with proton pump inhibitors (PPIs) is not recommended (e.g. omeprazole or 
lansoprazole) (see Section 4.4 and Section 5.2). 
 
Nerlynx should be taken at least 2 hours before or 10 hours after the intake of the H2-receptor 
antagonist (see Section 4.2, Section 4.4 and Section 5.2). 
Separate dosing of Nerlynx and antacids by at least 3 hours (see Section 4.2, Section 4.4 and Section 
5.2). 
 



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Antidiarreal loperamide 
Clinical study have demonstrated that there were no clinically significant differences in the 
exposure of subjects to neratinib with or without concurrent dosing with loperamide (see Section 
5.2).  
 
Effects of neratinib on other substances 
 
Hormonal contraceptives 
It is currently unknown whether Nerlynx reduces the effectiveness of systemically acting hormonal 
contraceptives. Therefore, women using systemically acting hormonal contraceptives should add a 
barrier method (see Section 4.6). 
 
P-glycoprotein efflux transporters 
In-vitro studies demonstrated that neratinib is an inhibitor of P-glycoprotein (P-gp) efflux 
transporters. This has been confirmed by clinical study using digoxin as probe substrate leading to an 
increase of 54 and 32% in Cmax and AUC, respectively. This might be clinically relevant for 
patients who are treated concomitantly with therapeutic agents with a narrow therapeutic window 
whose absorption involves P-gp transporters in the gastrointestinal tract (e.g. digoxin, colchicine, 
dabigatran, phenytoin, statins, cyclosporine, everolimus, sirolimus, tacrolimus). They should be 
carefully monitored (see Section 4.4 and Section 5.2). 
 
Breast cancer resistance protein efflux transporter 
Neratinib may inhibit breast cancer resistance protein (BCRP) at intestinal level as suggested by in 
vitro studies. A clinical study with BCRP substrates has not been conducted. As co-administration of 
neratinib with BCRP substrates may lead to an increase of their exposure, patients who are treated 
with BCRP substrates (e.g., rosuvastatin, sulfasalazine and irinotecan) should be monitored carefully 
(Section 5.2). 
 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential/Contraception in females and males 
Based on findings in animals, neratinib may cause foetal harm when administered to pregnant women. 
Women should avoid becoming pregnant while taking Nerlynx and for up to 1 month after ending 
treatment. Therefore, women of child-bearing potential must use highly effective contraceptive 
measures while taking Nerlynx and for 1 month after stopping treatment. 
 
It is currently unknown whether neratinib may reduce the effectiveness of systemically acting 
hormonal contraceptives, and therefore women using systemically acting hormonal contraceptives 
should add a barrier method. 
 
Men should use a barrier method of contraception during treatment and for 3 months after stopping 
treatment. 
 
Pregnancy 
There are no data from the use of Nerlynx in pregnant women. Studies in animals have shown 
embryo-foetal lethality and foetal morphological anomalies (see Section 5.3). The potential risk for 
humans is unknown. Nerlynx should not be used during pregnancy unless the clinical condition of the 
woman requires treatment with neratinib. 
 
If neratinib is used during pregnancy, or if the patient becomes pregnant while taking Nerlynx, the 
patient should be informed of the potential hazard to the foetus. 
 
Breast-feeding 
It is not known whether neratinib is excreted in human milk. A risk to the breast-fed infant cannot be 
excluded. A decision must be made whether to discontinue breast-feeding or to discontinue Nerlynx, 



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taking into account the importance of Nerlynx to the mother and the benefit of breast-feeding to the 
child. 
 
Fertility 
No fertility studies in women or men have been conducted. No significant changes in fertility 
parameters in male and female rats were detected in dosing up to 12 mg/kg/day (see Section 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
Nerlynx has minor or moderate influence on the ability to drive and use machines. Fatigue, dizziness, 
dehydration, and syncope have been reported as adverse reactions with neratinib. The clinical status 
of the patient should be considered when assessing the patient’s ability to perform tasks that require 
judgment, motor, or cognitive skills. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
The most common adverse reactions of any grade were diarrhoea (93.6%), nausea (42.5%), fatigue 
(27.3%), vomiting (26.8%), abdominal pain (22.7%), rash (15.4%), decreased appetite (13.7%), 
abdominal pain upper (13.2%), stomatitis (11.2%), and muscle spasms (10.0%). 
 
The most common Grade 3-4 adverse reactions were diarrhoea (Grade 3, 36.9% and Grade 4, 0.2%) 
and vomiting (Grade 3, 3.4% and Grade 4, 0.1%). 
 
Adverse reactions reported as serious included diarrhoea (1.9%), vomiting (1.3%), dehydration 
(1.1%), nausea (0.5%), alanine aminotransferase increased (0.4%), aspartate aminotransferase 
increased (0.4%), abdominal pain (0.3%), fatigue (0.3%) and decreased appetite (0.2%). 
 
Tabulated list of adverse reactions 
The table below lists adverse reactions observed with neratinib based on the assessment of pooled 
data from 1,710 patients. 
 
The MedDRA frequency convention and system organ class database has been utilised for the 
classification of frequency:  
Very common (≥ 1/10) 
Common (≥ 1/100 to < 1/10) 
Uncommon (≥ 1/1,000 to < 1/100)  
Rare (≥ 1/10,000 to < 1/1,000)  
Very rare (< 1/10,000) 
Not known (cannot be estimated from the available data) 
 
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. 
 

Table 5: Adverse drug reactions due to Nerlynx in monotherapy breast cancer 
studies 

System Organ Class Frequency Adverse Drug Reaction 
Infections and infestations Common Urinary tract infection 
Metabolism and nutrition 
disorders 

Very Common Decreased appetite 
Common Dehydration 

Respiratory, thoracic and 
mediastinal disorders Common Epistaxis 

Gastrointestinal disorders 
Very Common 

Diarrhoea, vomiting, nausea, abdominal 
pain, abdominal pain upper, and 
stomatitis1 

Common Abdominal distension, dry mouth and dyspepsia 



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System Organ Class Frequency Adverse Drug Reaction 

Hepatobiliary disorders Common 
Alanine aminotransferase increased, and 
aspartate aminotransferase increased 

Uncommon Blood bilirubin increased 

Skin and subcutaneous tissue 
disorders 

Very Common Rash2 

Common Nail disorder
3,  skin fissures and dry 

skin 
Musculoskeletal and connective 
tissue disorders Very Common Muscle spasms 

Renal and urinary disorders Common Blood creatinine increased Uncommon Renal failure  
General disorders and 
administration site conditions Very common Fatigue 

Investigations Common Weight decreased 
1 Includes stomatitis, aphthous stomatitis, mouth ulceration, oral mucosal blistering, and mucosal 
inflammation. 
2 Includes rash, rash erythematous, rash follicular, rash generalised, rash pruritic, and rash pustular. 
3 Includes nail disorder, paronychia, onychoclasis, and nail discolouration. 

 
Description of selected adverse reactions 
 
Diarrhoea 
Of the 1,660 patients treated with Nerlynx monotherapy without loperamide prophylaxis, 94.6% 
experienced at least 1 episode of diarrhoea. Grade 3 diarrhoea was reported in 37.5% of Nerlynx 
patients. 0.2% of patients had diarrhoea classified as Grade 4. Diarrhoea led to hospitalisation in 1.9% 
of Nerlynx-treated patients. 
 
Diarrhoea generally occurred in the first month, with 83.6% of patients reporting this toxicity in the 
first week, 46.9% in the second week, 40.2% in the third week and 43.2% in the fourth week (median 
time to first onset was 2 days). 
 
The median duration of a single episode of any grade diarrhoea was 2 days. The median cumulative 
duration of any grade diarrhoea was 59 days and the median cumulative duration of Grade 3 diarrhoea 
was 5 days. 
Diarrhoea was also the most common adverse reaction leading to discontinuation, 14.4 % of patients 
treated with Nerlynx without loperamide prophylaxis discontinued treatment due to diarrhoea. Dose 
reductions occurred in 24.7% of Nerlynx-treated patients. 
 
Rash 
In the Nerlynx monotherapy group, 16.7% of patients experienced rash. The incidence of Grade 1 and 
Grade 2 was 13.3% and 2.9% respectively; 0.4% of Nerlynx-treated patients experienced Grade 3 
rash. 
 
Nail disorders 
In the Nerlynx monotherapy group, 7.8% patients experience nail disorders. The incidence of Grade 1 
and Grade 2 was 6.2% and 1.4% respectively. There were 0.2% of Nerlynx treated patients who 
experienced Grade 3 nail disorder. 
 
Both rash and nail disorders led to treatment discontinuation in 0.6% of Nerlynx-treated patients. 
 
Hepatotoxicity 
Hepatic-associated adverse reactions in the pivotal phase III study, ExteNET (3004), were reported 
more frequently in the Nerlynx arm compared to the placebo arm (12.4% vs. 6.6%), due primarily to 
alanine aminotransferase (ALT) increased (8.5% vs. 3.2%), aspartate aminotransferase (AST) 
increased (7.4 vs 3.3%) and blood alkaline phosphatase increased (2.1% vs. 1.1%). Grade 3 adverse 
reactions were reported in 1.6% vs 0.5% and Grade 4 adverse reactions were reported in 0.2% vs. 
0.1%, Nerlynx- and placebo-treated patients, respectively. Grade 3 ALT increased was reported in 



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1.1% vs 0.2% and Grade 4 ALT increased was reported in 0.2% vs 0.0% of Nerlynx- vs placebo-
treated patients. Grade 3 AST increased was reported in 0.5% vs 0.3% and Grade 4 AST increased 
was reported in 0.2% vs 0.0%, of Nerlynx- vs placebo-treated patients. There was no Grade 3 or 4 
adverse reactions of blood bilirubin increased. 
 
Other special populations 
 
Elderly 
In the pivotal phase III study, ExteNET (3004), the mean age was 52 years in the Nerlynx arm, 
1236 patients were <65 years, 172 were ≥65 years, of whom 25 were 75 years or older. 
 
There was a higher frequency of treatment discontinuations due to adverse reactions in the ≥65 years 
age group than <65 years age group; in the Nerlynx arm, the respective percentages were 44.8% 
compared with 25.2%, 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%), diarrhoea (1.7%), dehydration (1.2%), and 
renal failure (1.2%). 
 
Treatment-emergent adverse reactions leading to hospitalisation in the Nerlynx arms versus the 
placebo arm was 6.3% vs 4.9% in the <65 years-old group and 8.7% vs. 8.1% in the ≥65 years-old 
group. 
 
Effect of race  
In the pivotal phase III study, ExteNET (3004), the frequency of Treatment Emergent Adverse Events 
(TEAEs) in the Skin and Subcutaneous Disorders System Organ Class (SOC) in Asian patients treated 
with Nerlynx was higher than in Caucasian patients (56.4% vs. 34.5%) but comparable in placebo 
patients (24.9% vs. 22.8%). Pooled safety data of 1710 patients treated with Nerlynx monotherapy 
showed a higher incidence of dermatologic toxicities in Asian patients (57.1%) versus Caucasian 
patients (34.6%). 
 
In the analysis of pooled safety data, the majority of TEAEs in the Skin and Subcutaneous Disorders 
SOC in Asians were Grade 1 (43.3%) and Grade 2 (12.3%); in Caucasians, the incidence of Grade 1 
and Grade 2 events was 25.6% and 7.8%, respectively. The frequency of Grade 3 events was similar 
between Asians and Caucasians (1.6% vs. 1.0%). There was no difference in frequency of SAEs in 
the Skin SOC between Asian and Caucasian subgroups. The most common TEAEs in the Skin SOC 
that occurred more frequently in Asian patients than in Caucasian patients were rash (29.4% vs. 
13.5%), Palmar-plantar erythrodysaesthesia syndrome (9.9% vs. 1.0%), and dermatitis acneiform (6.0 
vs. 1.0%). 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
There is no specific antidote, and the benefit of haemodialysis 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, adverse reactions associated with overdose were most commonly 
diarrhoea, with or without nausea, vomiting and dehydration. 
 



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In a dose escalation study in healthy volunteers, single oral doses of Nerlynx up to 800 mg were 
administered. The frequency and severity of gastrointestinal disorders (diarrhoea, abdominal pain, 
nausea and vomiting) appeared to be dose-related. Single doses of Nerlynx greater than 800 mg have 
not been administered in the clinical studies. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, protein kinase 
inhibitors, ATC code: L01XE45 
 
Mechanism of action 
Neratinib is an irreversible pan–erythroblastic leukaemia viral oncogene homolog (ERBB) tyrosine 
kinase inhibitor (TKI) that blocks mitogenic growth factor signal transduction through covalent, high 
affinity binding to the ATP binding site of 3 epidermal growth factor receptors (EGFRs): EGFR 
(encoded by ERBB1), HER2 (encoded by ERBB2), and HER4 (encoded by ERBB4) or their active 
heterodimers with HER3 (encoded by ERBB3). This results in sustained inhibition of these growth 
promoting pathways with HER2-amplified or over-expressed, or HER2-mutant breast cancers. 
Neratinib binds to the HER2 receptor, reduces EGFR and HER2 autophosphorylation, downstream 
MAPK and AKT signaling pathways, and potently inhibits tumour cell proliferation in vitro. 
Neratinib inhibited EGFR and/or HER2-expressing carcinoma cell lines with a cellular IC50 
<100 nM. 
 
Clinical efficacy and safety 
In the multicentre, randomised, double-blind, placebo-controlled, pivotal phase III study, ExteNET 
(3004), 2,840 women with early-stage HER2-positive breast cancer (as confirmed locally by assay) 
who had completed adjuvant treatment with trastuzumab were randomised 1:1 to receive either 
Nerlynx or placebo daily for one year. The median age in the intention-to-treat (ITT) population was 
52 years (59.9% was ≥50 years old, 12.3% was ≥65 years old); 81.0% were Caucasian, 2.6% black or 
African American, 13.6% Asian and 2.9% other. At baseline, 57.7% had hormone receptor positive 
disease (defined as ER-positive and/or PgR-positive), 27.2% were node negative, 41.5% had one to 
three positive nodes and 29.4% had four or more positive nodes. Approximately 10% of patients had 
Stage I tumours, approximately 40% had Stage II tumours and approximately 30% had Stage III 
tumours. Median time from the last adjuvant trastuzumab treatment to randomization was 4.5 months. 
 
The primary endpoint of the study was invasive disease-free survival (iDFS). Secondary endpoints of 
the study included disease-free survival (DFS) including ductal carcinoma in situ (DFS-DCIS), time 
to distant recurrence (TTDR), distant disease-free survival (DDFS), cumulative incidence of central 
nervous system recurrence and overall survival (OS). 
 
The primary analysis of the study after 2 years post-randomisation demonstrated that Nerlynx 
significantly reduced the risk of invasive disease recurrence or death by 33% (HR=0.67 with 95% CI 
(0.49, 0.91), two-sided p = 0.011) in the ITT population. 



13 

Table 6: Primary 2-year efficacy results – ITT and hormone receptor positive 
populations who were less than one year from completion of trastuzumab 
therapy 

Variable Estimated 2 year event free rates1 (%) 

Hazard 
ratio 

(95% CI)2 
P-value3 

 ITT population 

 Nerlynx 
(N=1420) 

Placebo 
(N=1420) 

  

Invasive disease-free survival 94.2 91.9 0.67 
(0.49, 0.91) 

0.011 

Disease-free survival including ductal 
carcinoma in situ 

94.2 91.3 0.62 
(0.46, 0.84) 

0.002 

Distant disease-free survival 95.3 94.0 0.75 
(0.53, 1.06) 

0.110 

Time to distant recurrence 95.5 94.2 0.74 
(0.52, 1.06) 

0.102 

CNS recurrence 0.92 1.16 – 0.586 

 Hormone receptor positive population who were 
less than one year from completion of trastuzumab 

 Nerlynx 
(N=671) 

Placebo 
(N=668) 

Hazard 
ratio 

(95% CI)4 
P-value5 

Invasive disease-free survival 95.3 90.9 0.50 
(0.31, 0.78) 

0.003 

Disease-free survival including ductal 
carcinoma in situ 

95.3 90.1 0.45 
(0.28, 0.71) 

<0.001 

Distant disease-free survival 96.1 93.0 0.53 
(0.31, 0.88) 

0.015 

Time to distant recurrence 96.3 93.3 0.53 
(0.30, 0.89) 

0.018 

CNS recurrence 0.34 1.01 – 0.189 
CNS = central nervous system. 
1 Event-free rates for all endpoints, except for CNS recurrence for which cumulative incidence is reported. 
2 Stratified Cox proportional hazards model  
3 Stratified 2-sided log-rank test for all endpoints, except for CNS recurrence for which Gray’s method was 
used. 
4 Unstratified Cox proportional hazards model 
5 Unstratified 2-sided log-rank test for all endpoints, except for CNS recurrence for which Gray’s method was 
used. 
 



14 

Figure 1: Kaplan-Meier plot of invasive disease-free survival – hormone receptor 
positive population who were less than one year from completion of 
trastuzumab therapy 

 

 
 
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. While the treatment 
benefit of Nerlynx over placebo was maintained at five years, the effect size cannot be reliably 
estimated. 
 
In patients that were hormone receptor negative, regardless of time from trastuzumab therapy, the 
hazard ratio for iDFS at 2 years was 0.94, with 95% CI (0.61, 1.46).  In this population, efficacy has 
not been demonstrated.  
 
For hormone receptor positive patients who were less than one year from completion of trastuzumab 
therapy, the relative treatment benefit of Nerlynx within pre-specified patient subgroups is presented 
in Figure 2. 
 



15 

Figure 2: Hormone receptor positive patients who were less than one year from 
completion of trastuzumab therapy, invasive disease-free survival by 
patient subgroup 

 

 
Note: Patients (n = 30) who had an unknown nodal status are not shown because the HR could not be estimated 
 
Paediatric population 
The European Medicines Agency has waived the obligation to submit the results of studies in all 
subsets of the paediatric population in the treatment of breast carcinoma. 
 
5.2 Pharmacokinetic properties 
 
The mass balance after administration of a single oral dose of 200 mg of neratinib was studied in six 
healthy subjects. 
 
Absorption 
Following oral administration of 240 mg neratinib, absorption was slow and peak plasma 
concentrations of neratinib occurred around 7 hours after administration. A single dose of 240 mg 
neratinib taken with food increased Cmax and AUC by approximately 17% and 23%, respectively, 
compared with administration in the fasting state. A single oral dose of 240 mg neratinib taken with a 
meal high in fat increased both Cmax and AUC by approximately 100%. In a mass balance study, the 
total recovery (urinary and fecal excretion) of intact neratinib and metabolites demonstrates that the 
fraction absorbed for neratinib is at least 10% and likely more than 20%. Moreover, model-based 
predictions suggested an overall absorbed fraction from the gut (fa) of 26%. 
In vitro neratinib solubility is pH-dependent. Treatments that increase gastrointestinal pH may lower 
the absorption of neratinib, thus decreasing systemic exposure.  
 
Distribution 
Binding of neratinib to human plasma proteins, including covalent binding to human serum albumin 
(HSA), was greater than 98% and independently of the tested neratinib concentration. Neratinib 
bound predominantly to HSA and human alpha-1 acid glycoprotein (AAG). Binding of M6 main 
metabolite (M6) to human plasma proteins was  greater than 99% and independently of the tested M6 
concentrations. 
In vitro studies demonstrated that neratinib is a substrate for P-glycoprotein (P-gp) (see Section 4.2, 
Section 4.3, Section 4.4 and Section 4.5) and BCRP. In vitro studies demonstrated that neratinib and 



16 

its main metabolite M6 are not substrates of hepatic uptake transporters OATP1B1*1a and OATP1B3 
at 10 µM.  
 
Biotransformation 
Neratinib is metabolised primarily in liver microsomes by CYP3A4 and to a lesser extent by flavin-
containing monooxygenase (FMO). 
 
Preliminary metabolite profiling in human plasma indicates that after oral administration, neratinib 
undergoes oxidative metabolism through CYP3A4. Circulating metabolites include neratinib pyridine 
N-oxide (M3), N-desmethyl neratinib (M6), neratinib dimethylamine N-oxide (M7) and traces of 
hydroxyl neratinib N-oxide and neratinib bis-N-oxide (M11). Neratinib represents the most prominent 
component in plasma and amongst circulating metabolites (M2, M3, M6, M7 and M11) none is above 
8% of neratinib plus metabolite total exposure after oral administration of neratinib. The neratinib 
metabolites M3, M6, M7 and M11 were shown to have similar potencies to neratinib in either in vitro 
enzyme (binding assays) or cell based assays against cells expressing ERBB1, ERBB2 (HER2) and 
ERBB4. 
Based on steady state exposures, neratinib provides the majority of pharmacological activity (73%), 
with 20% provided by exposure to M6, 6% provided by M3, and negligible contribution (<1%) from 
M7 and M11 AUC. 
 
Elimination 
Following single doses of neratinib, the mean apparent plasma half-life of neratinib was 17 hours in 
patients.  
 
Excretion of neratinib is primary via the faeces 
Following the administration of a single radiolabelled dose of 240 mg neratinib oral solution, 95.5% 
and 0.96% of the administered dose was recovered in the faeces and urine, respectively.  
 
The excretion was rapid and complete, with most of the dose recovered in faeces within 48 hours and 
96.5% of total radioactivity recovered in excreta after 8 days.  
Unchanged neratinib was the most abundant species in excreta accounting for 62.1% of total dose 
recovered in excreta. The most abundant metabolites in faeces were M6 (19.7% of administered 
dose), followed by M2, M3 and M7, all below 10% of administered dose.  
 
Medicinal product interactions 
 
Effect of CYP3A4/P-gp inducer on neratinib 
Following concomitant administration of 240 mg neratinib with repeated doses of 600 mg rifampicin, 
a strong CYP3A4/P-gp inducer, neratinib exposures were significantly decreased by 76% and 87% for 
Cmax and AUC, respectively, compared with neratinib administration alone (see Section 4.3 and 
Section 4.5). 
 
Effect of CYP3A4/P-gp inhibitor on neratinib 
Co-administration of a single oral dose of 240 mg of neratinib in the presence of ketoconazole 
(400 mg once daily for 5 days), a strong CYP3A4/P-gp inhibitor, increased neratinib systemic 
exposure by 3.2- and 4.8-fold for Cmax and AUC, respectively, compared with neratinib administered 
alone.  
Model-based predictions suggested that co-administration of a single oral dose of 240 mg of neratinib 
in the presence of fluconazole (200 mg once daily for 8 days), a moderate CYP3A4 inhibitor, 
increased neratinib systemic exposure by 1.3- and 1.7-fold for Cmax and AUC, compared with 
neratinib administered alone. 
Model-based predictions suggested that co-administration of a single oral dose of 240 mg of neratinib 
in the presence of verapamil (120 mg twice daily for 8 days), a moderate CYP3A4/strong P-gp 
inhibitor, increased neratinib systemic exposure by 3.0- and 4.0-fold for Cmax and AUC, compared 
with neratinib administered alone (see Section 4.2, Section 4.4 and Section 4.5). 
 



17 

Effect of gastric pH modifiers on neratinib 
Co-administration of lansoprazole or ranitidine (1x300 mg) with a 240 mg single dose of neratinib in 
healthy volunteers resulted in a decreased neratinib exposure by around 70% or 50%, respectively. 
The magnitude of ranitidine interaction on neratinib AUC was reduced by around 25%, by staggering 
the administration of ranitidine (2x150 mg) 2 hours after neratinib administration (see Section 4.2, 
Section 4.4 and Section 4.5). 
 
Effect of other treatment on neratinib 
There were no apparent clinically relevant drug-drug interactions observed for neratinib when 
administered concomitantly with capecitabine, paclitaxel, trastuzumab, vinorelbine, or antidiarrheals 
(loperamide) (see Section 4.5).  
 
Effect of neratinib on CYP substrates  
Neratinib and metabolite M6 were not potent direct inhibitors of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 
or 3A4. Time-dependent inhibition of CYP3A4 and CYP2B6 by neratinib and M6 could not be 
excluded. 
Neratinib did not induce CYP1A2, 2B6, 2C9, or 3A4. 
 
Effect of neratinib on transporters  
There was no clinically relevant inhibition of human BSEP efflux transporter activity in vitro, with a 
reported IC50 value of > 10 µM. Neratinib at 10 µM appeared to inhibit the BCRP efflux transporter 
which could be clinically relevant at intestinal level (see Section 4.5).  
In in vitro studies, neratinib was an inhibitor of P-glycoprotein (P-gp) efflux transporters, which was 
further confirmed in a clinical study. Multiple oral doses of neratinib 240 mg increase digoxin 
exposures (54 and 32% increase in Cmax and AUC, respectively) with no impact on its renal clearance 
level (see Section 4.4 and Section 4.5). 
Neratinib produced no inhibitory activity towards the uptake transporters, OATP1B1*1a, OATP1B3, 
OAT1, OAT3 and OCT2, with reported IC50 values were > 10µM. Neratinib produced inhibitory 
activity in OCT1 uptake transporter, with an IC50 of 2.9 µM. 
 
Special population 
 
Renal impairment 
Pharmacokinetic studies in patients with renal impairment or undergoing dialysis have not been 
carried out. Population pharmacokinetic modelling revealed that creatinine clearance did not explain 
the variability between patients, hence, no dose modifications are recommended for patients with mild 
to moderate renal impairment (see Section 4.2 and Section 4.4). 
 
Hepatic impairment 
Neratinib is extensively metabolised in the liver. In subjects with severe pre-existing hepatic 
impairment (Child-Pugh Class C) without cancer, the clearance of neratinib was decreased by 36% 
and exposure to neratinib increased by about 3-fold as compared to healthy volunteers (see Section 
4.2 and Section 4.3). 
 
 
5.3 Preclinical safety data 
 
Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to 
clinical exposure levels and with possible relevance to clinical use were as follows: 
 
Carcinogenesis, mutagenesis 
Nerlynx was neither clastogenic nor mutagenic in the standard battery of genotoxicity studies.  
 
Neratinib metabolites M3, M6, M7 and M11 are negative in the standard battery of in vitro 
genotoxicity studies. 
 



18 

A 6-month carcinogenicity study in Tg.rasH2 transgenic mice and the rat 2-year data showed no signs 
of carcinogenic potential. 
 
Reproductive toxicity 
In rabbits, there were no effects on mating or the ability of animals to become pregnant, but embryo-
foetal lethality and foetal morphologic anomalies (e.g. domed head, dilation of brain ventricles and 
misshapen anterior fontanelles and enlarged anterior and/or posterior fontanelles) were observed at 
doses that may be considered to be clinically relevant. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core 
Mannitol (E421) 
Microcrystalline cellulose 
Crospovidone 
Povidone 
Silica, colloidal anhydrous 
Magnesium stearate 
 
Tablet coating 
Polyvinyl alcohol 
Titanium dioxide (E171) 
Macrogol 
Talc 
Iron oxide red (E172) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years. 
 
6.4 Special precautions for storage 
 
Keep the bottle tightly closed in order to protect from moisture. 
 
This medicinal product does not require any special temperature storage conditions. 
 
6.5 Nature and contents of container 
 
White, 60 mL high density polyethylene (HDPE) round bottle with child-resistant, polypropylene 
closure, and foil induction inner seal. 
 
An HDPE desiccant canister with 1 g silica gel is enclosed with the tablets in each bottle. 
 
Each bottle contains 180 tablets. 
 
6.6 Special precautions for disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 



19 

 
7. MARKETING AUTHORISATION HOLDER 
 
Pierre Fabre Médicament 
45 place Abel Gance 
92100 Boulogne-Billancourt 
France  
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/18/1311/001 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 31st August 2018  
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
  



20 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 

 
A. MANUFACTURER RESPONSIBLE FOR BATCH 

RELEASE  
 
B. CONDITIONS OR RESTRICTIONS REGARDING 

SUPPLY AND USE 
 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION 
 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 
THE SAFE AND EFFECTIVE USE OF THE 
MEDICINAL PRODUCT 

 



21 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer responsible for batch release 
 
Pierre Fabre Médicament Production – Cahors 
Site de Cahors 
Le Payrat 
46000 Cahors 
FRANCE 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 

 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION  
 
• Periodic safety update reports  

The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal. 

The marketing authorisation holder shall submit the first periodic safety update report for this 
product within 6 months following authorisation.  

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk Management Plan (RMP) 

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent 
updates of the RMP. 

An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 

• Whenever the risk management system is modified, especially as the result of new 
information being received that may lead to a significant change to the benefit/risk profile or 
as the result of an important (pharmacovigilance or risk minimisation) milestone being 
reached.  

• Additional risk minimisation measures 

Prior to launch of Nerlynx in each Member State, the Marketing Authorisation Holder (MAH) must 
agree  the content and format of the educational programme, including communication media, 
distribution modalities, and any other aspects of the programme, with the National Competent 
Authority.  

The MAH shall ensure that in each Member State where Nerlynx is marketed, all healthcare 
professionals who are expected to prescribe/dispense Nerlynx, as well as all patients/carers who are 
expected to use Nerlynx, have access to/are provided with the following educational package: 



22 

• Physician educational material 

• Patient information pack 

The physician educational material should contain: 

o The Summary of Product Characteristics 

o Guide for healthcare professionals   

o Patient educational material 

 The Guide for healthcare professionals shall contain the following key elements: 

o Name of the product, active substance and approved indication of the product 

o Relevant information on the safety concern “Gastrointestinal toxicity (diarrhoea)”  (e.g. 
seriousness, severity, frequency, time to onset, duration, reversibility of the AE as applicable) 

o Details of the population at higher risk for the safety concern  

o Key message to convey in patients counselling on how to prevent and minimise Gastrointestinal 
toxicity through appropriate monitoring and management: 

o prophylactic treatment with antidiarrhoeal medicinal product   

o dietary changes  

o dose modification (with guideline to adjust doses)/ discontinuation of treatment 

o The importance of handing over  the educational material to the patients/carers at the end of 
counselling 

o Remarks on the importance of reporting ADRs 

 The patient educational material: 

The patient information pack should contain: 

o Patient information leaflet 

o A patient/carer treatment guide  

o “My Treatment Journal”  

The Patient/carer guide shall contain the following key messages (in lay language) 

• Name of the product, active substance and approved indication of the product 

• Relevant information of Gastrointestinal toxicity (diarrhoea)  (e.g. signs and symptoms to be 
detailed (seriousness, severity, frequency, time to onset, duration, risks and consequences)) 

• Key messages on how to prevent and minimise GI toxicity through appropriate monitoring 
(with reference to treatment journal) and management: 

o prophylactic treatment with antidiarrhoeal medicinal product  

o dietary changes   

o when to alert HCP and the importance of it for further treatment adjustment 

• Remark on importance of reading the PIL 

• Remarks on the importance of reporting ADRs 

 
  



23 

 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



24 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
  



25 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
CARTON AND BOTTLE 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Nerlynx 40 mg film-coated tablets 
neratinib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film coated tablet contains neratinib maleate equivalent to 40 mg neratinib. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
180 tablets 
 
 
5. METHOD AND ROUTE OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Do not swallow the desiccant. 
 
8. EXPIRY DATE 
 
EXP  
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Keep the bottle tightly closed in order to protect from moisture. 
 
 



26 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Pierre Fabre Médicament 
45 place Abel Gance 
92100 Boulogne-Billancourt 
France 
 
 
12. MARKETING AUTHORISATION NUMBER 
 
EU/1/18/1311/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Carton 
nerlynx 40 mg 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
Carton 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
Carton 
PC: 
SN: 
NN: 

  



27 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



28 

Package leaflet: Information for the patient 
 

Nerlynx 40 mg film-coated tablets 
neratinib 

 
This medicine is subject to additional monitoring. This will allow quick identification of new 

safety information. You can help by reporting any side effects you may get. See the end of Section 4 
for how to report side effects. 
 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See Section 4. 
 
What is in this leaflet 
 
1. What Nerlynx is and what it is used for 
2. What you need to know before you take Nerlynx 
3. How to take Nerlynx 
4. Possible side effects 
5. How to store Nerlynx 
6. Contents of the pack and other information 
 
 
1. What Nerlynx is and what it is used for 
 
What Nerlynx is 
Nerlynx contains the active substance ‘neratinib’. It belongs to a group of medicines called ‘tyrosine 
kinase inhibitors’ used to block cancer cells and treat breast cancer.  
 
What Nerlynx is used for 
Nerlynx is used for patients who have early stage breast cancer which: 
- is human epidermal growth factor receptor 2-positive (HER2-positive) and 
- has previously been treated with another medicine called ‘trastuzumab’. 
 
The ‘HER2 receptor’ is a protein found on the surface of cells in the body. It helps control how a 
healthy breast cell grows. In HER2-positive breast cancer, the cancer cells have a large amount of 
HER2 receptors on their surface. This results in the cancer cells dividing and growing faster. 
 
Before Nerlynx is used, your cancer must have been tested to show it is HER2-positive. You must 
also have previously been treated with trastuzumab. 
 
How Nerlynx works 
Nerlynx works by blocking the HER2 receptors on the cancer cells. This helps to stop the cells from 
dividing and growing. 
 
 



29 

2. What you need to know before you take Nerlynx 
 
Do not take Nerlynx 
- if you are allergic to neratinib or any of the other ingredients of this medicine (listed in 

Section 6), 
- if you have a severe liver problem, 
- if you are taking rifampicin (a medicine for tuberculosis (TB)), 
- if you are taking carbamazepine or phenytoin (medicines for seizures), 
- if you are taking St. John’s wort (herbal product for depression).  
 
Warnings and precautions 
Talk to your doctor or pharmacist before taking Nerlynx. 
 
You need to take an anti-diarrhoea medicine when you start Nerlynx 
Nerlynx can cause diarrhoea early during treatment. You should take an anti-diarrhoea medicine so 
that your diarrhoea does not become severe, and to prevent you from getting dehydrated during 
treatment with Nerlynx.  
 
Tests and checks for liver problems 
Nerlynx can cause changes in liver function – these are shown in blood tests. Your doctor will do 
blood tests before and during your treatment with Nerlynx. Your doctor will stop your treatment with 
Nerlynx if your liver tests show severe problems. 
 
Children and adolescents 
Do not use in children under 18 years of age. The safety of Nerlynx and how effective it is has not 
been studied in this age group. 
 
Other medicines and Nerlynx 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. This is because Nerlynx can affect the way some other medicines work. Also some other 
medicines can affect the way Nerlynx works. 
 
In particular tell your doctor or pharmacist if you are taking any of the following medicines: 
- rifampicin - a medicine for tuberculosis 
- carbamazepine, phenobarbital, or phenytoin - medicines for seizures 
- St John’s wort - an herbal product for depression 
- ketoconazole, voriconazole,  itraconazole or fluconazole - medicines for fungal infections 
- erythromycin or clarithromycin - medicines for bacterial infections 
- protease inhibitors - antiviral medicines 
- nefazodone – a medicine to treat depression 
- diltiazem or verapamil - medicines for high blood pressure and chest pain 
- dabigatran or digoxin - a medicine for heart problems 
- rosuvastatin – a medicine to treat high cholesterolemia 
- irinotecan – a medicine used in colorectal cancers 
- sulfasalazine – an anti-inflammatory intestinal medicine 
- medicines for stomach problems such as: 

- lansoprazole, omeprazole or similar medicines called ‘proton pump inhibitors’ or PPIs 
are not recommended. 

- ranitidine, cimetidine or similar medicines called “H2 receptor antagonists”. Neratinib 
should be taken 10 hours after the H2-receptor antagonist dosing and at least 2 hours 
before the next dose of the H2-receptor antagonist 

- antacid medicines - the dose of these medicines and Nerlynx should be separated by at 
least 3 hours. 

 
If any of the above apply to you (or you are not sure), talk to your doctor or pharmacist before taking 
Nerlynx. 
 



30 

Nerlynx with food and drink 
Do not take grapefruit or pomegranate while you are taking Nerlynx – this includes eating them, 
drinking the juice or taking a supplement that might contain them. This is because these fruits may 
interact with Nerlynx and affect how the medicine works. 
 
Pregnancy 
If you are pregnant, the doctor will assess the potential benefit to you and risk to the foetus before 
giving this medicine to you. If you become pregnant while taking this medicine, the doctor will assess 
the potential benefit to you and the risk to the foetus, of continuing this medicine.   
 
Contraception 
Women who can become pregnant must use an effective method of contraception, including a barrier 
method: 
- while taking Nerlynx and 
- for one month after treatment has finished. 
 
Men must use an effective barrier method of contraception such as a condom: 
- while taking Nerlynx and 
- for three months after treatment has finished. 
 
Breast-feeding 
Talk to your doctor before taking Nerlynx if you are breast-feeding or plan to breast-feed because 
small amounts of this medicine may pass into your breast milk. Your doctor will discuss with you the 
benefits and risks of taking Nerlynx during this time. 
 
Driving and using machines 
Nerlynx has minor or moderate influence on the ability to drive and use machines. The side effects of 
Nerlynx (for example, dehydration and dizziness resulting from diarrhoea, fatigue, and fainting) may 
affect how tasks that require judgment, motor or cognitive skills are carried out. 
 
 
3. How to take Nerlynx 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure. 
 
How much Nerlynx to take 
The recommended dose of Nerlynx is 6 tablets once a day (a total of 240 mg). 
- Take the tablets with food. Do not crush or dissolve. Do not swallow the desiccant. 
- Take all the tablets with water, at about the same time each day, preferably in the morning. 
 
The course of treatment is one year. 
 
You need to take an anti-diarrhoea medicine when you start Nerlynx 
Nerlynx can cause diarrhoea early during treatment unless anti-diarrhoea medicine is taken to prevent 
or reduce diarrhoea. Diarrhoea usually happens early in treatment with Nerlynx and may be severe, 
causing you to get dehydrated.  
- Start taking anti-diarrhoea medicine with the first dose of Nerlynx. 
- Your doctor will tell you how to take the anti-diarrhoea medicine. 
- Keep taking anti-diarrhoea medicine during the first one to two months of Nerlynx treatment. 

Your doctor will tell you if you need to keep taking anti-diarrhoea medicine after the first two 
months to control your diarrhoea.  

- Your doctor will also tell you if you need to change the dose of Nerlynx because of diarrhoea. 
 
If you take more Nerlynx than you should, contact a doctor or a hospital straight away. Take the 
medicine pack with you. 
 



31 

Some side effects associated with taking more Nerlynx than you should are: diarrhoea, nausea, 
vomiting and dehydration. 
 
If you forget to take Nerlynx 
- If you forget a dose, wait until the next day before you take the next dose. 
- Do not take a double dose to make up for a forgotten dose. 
 
If you stop taking Nerlynx 
- Do not stop taking Nerlynx without talking to your doctor. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. The 
following side effects may happen with this medicine: 
 
Diarrhoea 
Nerlynx can cause diarrhoea early during treatment unless anti-diarrhoeal medicines are taken to 
prevent or reduce diarrhoea. The diarrhoea may be severe, and you may get dehydrated. See Section 3 
for more information about the anti-diarrhoea medicine you need to take at the same time as Nerlynx. 
 
Talk to your doctor if: 
- you are having diarrhoea that does not go away - they can advise how to control your diarrhoea. 
- you feel dizzy or weak from diarrhoea - alternatively go to the hospital immediately. 
 
Liver problems 
Nerlynx can cause changes in liver function - these are shown in blood tests. You may or may not 
have signs or symptoms of liver problems (e.g., yellow skin and/or eyes, dark urine, or light-colour 
stools). Your doctor will do blood tests before and during your treatment with Nerlynx. Your doctor 
will stop your treatment with Nerlynx if your liver tests show severe problems. 
 
Other side effects 
Tell your doctor or pharmacist if you notice any of the following side effects: 
 
Very common: may affect more than 1 in 10 people 
- diarrhoea 
- stomach pain, feeling or being sick, low appetite 
- dry or inflamed mouth, including blisters or mouth ulcers 
- rash 
- muscle spasms or cramps 
- feeling very tired 
 
Common: may affect up to 1 in 10 people 
- burning sensation during urination and frequent, and urgent need to urinate, (may be symptoms 

of urinary tract infection)  
- dehydration 
- nosebleed 
- mild stomach upset 
- dry mouth 
- changes in liver blood test results 
- nail problems including nail splitting or colour change 
- dry skin including cracked skin 
- changes in kidney function test 
- weight loss 
 



32 

Uncommon: may affect up to 1 in 100 people 
- kidney failure 
- changes in liver blood test results (i.e., blood bilirubin increased) 

 
Tell your doctor or pharmacist if you notice any of the side effects above. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety 
of this medicine. 
 
 
5. How to store Nerlynx 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the bottle and carton after EXP. The 
expiry date refers to the last day of that month. 
 
Keep the bottle tightly closed in order to protect from moisture. 
 
This medicinal product does not require any special temperature storage conditions. 
 
Do not use Nerlynx if you notice any signs of damage to the packaging or if there are any signs of 
tampering (e.g., inner seal is broken). 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Nerlynx contains 
- The active substance is neratinib. Each film-coated tablet contains neratinib maleate, equivalent to 

40 mg neratinib. 
- The other ingredients are: 

- Tablet core: mannitol (E421), microcrystalline cellulose, crospovidone, povidone, 
colloidal anhydrous silica, magnesium stearate  

- Tablet coating: polyvinyl alcohol, titanium dioxide (E171), macrogol, talc, iron oxide red 
(E172) 

 
What Nerlynx looks like and contents of the pack 
The film-coated tablets are red oval shaped and debossed with ‘W104’ on one side and plain on the 
other side. 
 
Nerlynx film-coated tablets are packaged in a white, high-density polyethylene (HDPE) round bottle 
with child-resistant, polypropylene closure, and foil induction inner seal for a tamper-evident seal. 
Each bottle contains 180 film-coated tablets. 
 
An HDPE desiccant canister with 1 g silica gel is enclosed with the tablets in each bottle. Do not 
swallow the desiccant.  
 
 



33 

Marketing Authorisation Holder  
Pierre Fabre Médicament 
45 place Abel Gance 
92100 Boulogne-Billancourt 
France 
 
Manufacturer 
Pierre Fabre Médicament Production – Cahors 
Site de Cahors 
Le Payrat 
46000 Cahors 
France 
 
This leaflet was last revised in MM/YYYY 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 
------------------------------------------------------------------------------------------------------------------------ 
 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION 
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET