Leaflet NERLYNX 40mg film-coated tablets
Indicated for: breast cancer
Route of administration: oral
Substance: neratinib (tyrosine kinase inhibitor)
ATC: L01EH02 (Antineoplastic and immunomodulating agents | Protein kinase inhibitors | Human epidermal growth factor receptor 2 (HER2) tyrosine kinase inhibitors)
This medicine may affect fertility.
Handle with special care.
Effective contraception is required during treatment.
Do not use this medicine while breastfeeding.
Do not use this medicine during pregnancy.
Avoid grapefruit and grapefruit juice.
This medicine may affect the liver.
This medicine may have important interactions with other medicines.
This medicine may lower blood cell counts.
This medicine is subject to additional monitoring.
Periodic laboratory tests may be required during treatment.
Stop taking the medicine and seek urgent medical help if a severe rash occurs.
This medicine may increase the risk of heart rhythm disturbances.
Neratinib is an oral anti-cancer medicine used in certain adults with early-stage HER2-positive, hormone receptor-positive breast cancer after treatment with trastuzumab. Its aim is to lower the risk of the cancer coming back. In some countries it may also be used for advanced disease in combinations chosen by an oncology specialist.
It works by blocking growth signals inside cancer cells. Neratinib is usually taken once daily with food for the period prescribed by your doctor, and tablets should be swallowed whole. Follow the schedule exactly, including any anti-diarrhoea prevention medicine you are given. Grapefruit and some acid-reducing medicines can interact with neratinib.
The most important side effect is diarrhoea, which can be severe and may cause dehydration. Other possible effects include nausea, vomiting, abdominal pain, tiredness, reduced appetite, rash, mouth sores and changes in liver blood tests. Contact your care team quickly if diarrhoea continues, or if you feel dizzy, weak or unable to drink enough fluids.
Blood tests, especially liver tests, are needed before and during treatment. Neratinib can harm an unborn baby, so effective contraception is required and pregnancy must be reported immediately. Do not breastfeed during treatment unless your doctor says it is safe. Fever, jaundice, severe abdominal pain or signs of dehydration need urgent assessment.
General data about NERLYNX 40mg
- Substance: neratinib
- Date of latest medicines list: 01-06-2026
- Product code: W71836001
- Concentration: 40mg
- Pharmaceutical form: film-coated tablets
- Quantity: 180
- Product type: Original
- Price: 18981.17 RON
- Prescription status: P-RF - Medicines dispensed with a medical prescription that is retained by the pharmacy and cannot be renewed.
Leaflet NERLYNX 40mg
Contents of the package leaflet for the medicine NERLYNX 40mg film-coated tablets
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 x4.3 mm with thickness of 3.1 mm.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Nerlynx is indicated for the extended adjuvant treatment of adult patients with early-stage hormonereceptor positive HER2-overexpressed/amplified breast cancer and who completed adjuvanttrastuzumab-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 administrationof anti-cancer medicinal products.
PosologyThe 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. Patientsshould 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. Managementof some adverse reactions may require dose interruption and/or dose reduction as shown in Table 1,
Table 2, Table 3, and Table 4.
Nerlynx should be discontinued 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. intolerabletoxicities, persistent Grade 2 adverse reactions, etc.).
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 ≤1 or baseline within 3 weeksof stopping treatment. Then resume Nerlynx at the next lower doselevel. 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, dietarychanges, and appropriate dose modifications of Nerlynx. Guidelines for adjusting doses of Nerlynx inthe setting of diarrhoea are shown in Table 3.
Table 3: Dose modifications for diarrhoea
Severity of diarrhoea* Action
* Grade 1 diarrhoea [increase of * Adjust anti-diarrhoeal treatment< 4 stools per day over baseline] * Diet modifications
* Grade 2 diarrhoea [increase of * Fluid intake of ~2 L/day should be maintained to4-6 stools per day over baseline] avoid dehydrationlasting < 5 days
* Once event resolves to Grade ≤1 or baseline,
* Grade 3 diarrhoea [increase of consider restarting anti-diarrhoeal prophylaxis, if≥ 7 stools per day over baseline; appropriate with each subsequent Nerlynxincontinence; hospitalization indicated; administration (refer to section 4.4).limiting self-care activities of dailyliving] lasting ≤ 2 days
Severity of diarrhoea* Action
* Any grade with complicated features† * Interrupt Nerlynx treatment
* Grade 2 diarrhoea lasting 5 days or * Diet modificationslonger‡ * Fluid intake of ~2 L/day should be maintained to
* Grade 3 diarrhoea lasting between avoid dehydration2 days and 3 weeks‡ * If diarrhoea resolves to Grade ≤1 in one week orless, then resume Nerlynx treatment at the samedose.
* If diarrhoea resolves to Grade ≤1 in longer thanone week, then resume Nerlynx treatment atreduced dose (see Table 1).
* Once event resolves to Grade ≤1 or baseline,consider restarting anti-diarrhoeal prophylaxis, ifappropriate with each subsequent Nerlynxadministration (refer to section 4.4).
* If grade 3 diarrhoea persists longer than 3weeks,discontinue Nerlynx permanently.
* Grade 4 diarrhoea [life-threatening * Permanently discontinue Nerlynx treatmentconsequences; urgent interventionindicated]
* Diarrhoea recurs to Grade 2 or higher * Permanently discontinue Nerlynx treatmentat 120 mg per day
* 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) * Stop Nerlynx until recovery to Grade ≤1
OR * Evaluate alternative causes
* Grade 3 bilirubin (>3-10 x ULN) * Resume Nerlynx at the next lower dose level ifrecovery to Grade ≤1 occurs within 3 weeks. If
Grade 3 ALT or bilirubin occurs again despiteone dose reduction, permanently discontinue
Nerlynx.
* If grade 3 hepatotoxicity persists longer than3 weeks, discontinue Nerlynx permanently
* Grade 4 ALT (>20 x ULN) * Permanently discontinue Nerlynx
OR * Evaluate alternative causes
* Grade 4 bilirubin (>10 x ULN)
ULN=Upper Limit Normal; ALT= Alanine Aminotransferase
* Per CTCAE v4.0
Missed doseMissed 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 orpomegranate juice is not recommended (see sections 4.4 and 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 inhibitor. If welltolerated, increase to 80 mg for at least 1 week, then to 120 mg for at least 1 week, and to160 mg as a maximal daily dose. Patient should be monitored carefully, especially GI effectsincluding diarrhoea and hepatotoxicity.
After discontinuation of a strong or moderate CYP3A4/P-gp inhibitor, resume previous dose of
Nerlynx 240 mg (see sections 4.4, 4.5 and 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 afterthe intake of the H2-receptor antagonist. Separate dosing of Nerlynx and antacids by at least 3 hoursshould be applied (see sections 4.4, 4.5 and 5.2).
Special populationsPatients with renal impairment
No dose adjustment is necessary in patients with mild to moderate renal impairment. Nerlynx has notbeen studied in patients with severe renal impairment including patients on dialysis. Treatment ofpatients with severe renal impairment or on dialysis is not recommended (see section 5.2).
Patients with hepatic impairmentNo dose adjustment is required in patients with Child-Pugh A or B (mild to moderate) hepaticimpairment (see section 5.2).
ElderlyNo dose adjustment is required. There is no data in patients ≥85 years of age.
Paediatric populationThere is no relevant use of Nerlynx in the paediatric population in the indication of breast cancer.
Method of administrationNerlynx is for oral use. The tablets should be swallowed whole preferably with water and should notbe crushed or dissolved. The tablets should be taken with food, preferably in the morning (seesection 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-gpisoform of cytochrome P450, such as (see sections 4.5 and 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).
4.4 Special warnings and precautions for use
Diarrhoea has been reported during treatment with Nerlynx (see sections 4.2 and 4.8). The diarrhoeamay be severe and associated with dehydration.
Diarrhoea generally occurs early during the first or second week of treatment with Nerlynx and maybe recurrent.
Patients should be instructed to initiate prophylactic treatment with an anti-diarrhoeal medicinalproduct with the first dose of Nerlynx, and maintain regular dosing of the anti-diarrhoeal medicinalproduct during the first 1-2 months of Nerlynx treatment, titrating to 1-2 bowel movements per day.
ElderlyElderly patients (≥65 years of age) are at a higher risk of renal insufficiency and dehydration whichmay 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 werenot included in the pivotal study, and should be carefully monitored.
Renal impairmentPatients with renal impairment are at a higher risk of complications of dehydration if they developdiarrhoea, and these patients should be carefully monitored (see sections 4.2 and 5.2).
Liver functionHepatotoxicity has been reported in patients treated with Nerlynx. Liver function tests includingalanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin should bemonitored at 1 week, then monthly for the first 3 months and every 6 weeks thereafter while ontreatment or as clinically indicated (see section 4.2).
Patients who experience ≥ Grade 3 diarrhoea requiring intraveinous fluid treatment or any signs orsymptoms of hepatotoxicity, such as worsening of fatigue, nausea, vomiting, jaundice, right upperquadrant pain or tenderness, fever, rash, or eosinophilia, should be evaluated for changes in liverfunction tests. Fractionated bilirubin and prothrombin time should also be collected duringhepatotoxicity evaluation.
Left ventricular function
Left ventricular dysfunction has been associated with HER2 inhibition. Nerlynx has not been studiedin patients with less than lower limit of normal left ventricular ejection fraction (LVEF) or withsignificant 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 decreasingsystemic exposure. Co-administration with proton pump inhibitors (PPIs) is not recommended (seesections 4.5 and 5.2).
In case of H2-receptor antagonists or antacids, modalities of administration should be adapted (seesections 4.2, 4.5 and 5.2).
PregnancyNeratinib may cause foetal harm when administered to pregnant women (see section 4.6).
Skin and subcutaneous tissue disordersNerlynx is associated with skin and subcutaneous tissue disorders. Patients with symptomatic skin andsubcutaneous tissue disorders should be carefully monitored (see section 4.8).
Concomitant treatment with inhibitors of CYP3A4 and P-gp
Concomitant treatment with strong or moderate CYP3A4 and P-gp inhibitors is not recommended dueto risk of increased exposure to neratinib. If the inhibitor cannot be avoided, Nerlynx dose adjustmentshould be applied (see sections 4.2, 4.5 and 5.2).
Grapefruit and pomegranate
Grapefruit or pomegranate juice may inhibit CYP3A4 and/or P-gp and should be avoided duringtreatment with Nerlynx (see sections 4.2 and 4.5).
Concomitant treatment with moderate inducers of CYP3A4 and P-gp
Concomitant treatment with moderate CYP3A4 and P-gp inducers is not recommended as it may leadto a loss of neratinib efficacy (see sections 4.5 and 5.2).
Concomitant treatment with substrates of P-gp
Patients who are treated concomitantly with therapeutic agents with a narrow therapeutic windowwhose absorption involves P-gp transporters in the gastrointestinal tract should be carefully monitored(see sections 4.5 and 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
A clinical study demonstrated that concomitant use of strong CYP3A4/P-gp inducers significantlydecreased neratinib exposure, therefore concurrent use of neratinib with strong CYP3A4/P-gpinducers is contraindicated (e.g. strong inducers: phenytoin, carbamazepine, rifampicin, or herbalpreparations containing St John’s Wort (Hypericum perforatum)). Concurrent use of neratinib withmoderate CYP3A4/P-gp inducers is not recommended as it may also lead to loss of efficacy (e.g.moderate inducers: bosentan, efavirenz, etravirine, phenobarbital, primidone, dexamethasone) (seesections 4.3 and 5.2).
CYP3A4/P-gp inhibitors
A clinical study and model-based predictions have demonstrated that concomitant use of strongor moderate CYP3A4/P-gp inhibitors significantly increased neratinib systemic exposure,therefore, concomitant use of neratinib with strong and moderate CYP3A4/P-gp inhibitors is notrecommended (e.g. strong inhibitors: atazanavir, indinavir, nefazodone, nelfinavir, ritonavir,saquinavir, lopinavir, ketoconazole, itraconazole, clarithromycin, troleandomycin, voriconazole,and cobicistat; moderate inhibitors: ciprofloxacin, cyclosporin, diltiazem, fluconazole,erythromycin, fluvoxamine and verapamil). If the inhibitor can not be avoided, Nerlynx doseadjustment shoud be applied (see sections 4.2, pct. 4.4 and 5.2).
Grapefruit/pomegranate or grapefruit/pomegranate juice may also increase neratinib plasmaconcentrations and should be avoided (see section 4.2 and 4.4).
Proton pump inhibitors, H2-receptor antagonists and antacids
The in-vitro solubility of neratinib is pH-dependent. Concomitant treatment with substances thatincrease 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 orlansoprazole) (see sections 4.4 and 5.2).
Nerlynx should be taken at least 2 hours before or 10 hours after the intake of the H2-receptorantagonist (see sections 4.2, pct. 4.4 and 5.2).
Separate dosing of Nerlynx and antacids by at least 3 hours (see sections 4.2, pct. 4.4 and 5.2).
Antidiarrhoeal loperamide
A clinical study has demonstrated that there were no clinically significant differences in theexposure of subjects to neratinib with or without concurrent dosing with loperamide (see section5.2).
Effects of neratinib on other substances
Hormonal contraceptivesIt is currently unknown whether Nerlynx reduces the effectiveness of systemically acting hormonalcontraceptives. Therefore, women using systemically acting hormonal contraceptives should add abarrier method (see section 4.6).
P-glycoprotein efflux transporters
In-vitro studies demonstrated that neratinib is an inhibitor of P-glycoprotein (P-gp) effluxtransporters. This has been confirmed by a clinical study using digoxin as probe substrate leading toan increase of 54 and 32% in Cmax and AUC, respectively. This might be clinically relevant forpatients who are treated concomitantly with therapeutic agents with a narrow therapeutic windowwhose absorption involves P-gp transporters in the gastrointestinal tract (e.g. digoxin, colchicine,dabigatran, phenytoin, statins, cyclosporine, everolimus, sirolimus, tacrolimus). They should becarefully monitored (see sections 4.4 and 5.2).
Breast cancer resistance protein efflux transporter
Neratinib may inhibit breast cancer resistance protein (BCRP) at intestinal level as suggested by invitro studies. A clinical study with BCRP substrates has not been conducted. As co-administration ofneratinib with BCRP substrates may lead to an increase of their exposure, patients who are treatedwith BCRP substrates (e.g., rosuvastatin, sulfasalazine and irinotecan) should be monitored carefully(see 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 endingtreatment. Therefore, women of child-bearing potential must use highly effective contraceptivemeasures while taking Nerlynx and for 1 month after stopping treatment.
It is currently unknown whether neratinib may reduce the effectiveness of systemically actinghormonal contraceptives, and therefore women using systemically acting hormonal contraceptivesshould add a barrier method.
Men should use a barrier method of contraception during treatment and for 3 months after stoppingtreatment.
PregnancyThere are no data from the use of Nerlynx in pregnant women. Studies in animals have shownembryo-foetal lethality and foetal morphological anomalies (see section 5.3). The potential risk forhumans is unknown. Nerlynx should not be used during pregnancy unless the clinical condition of thewoman requires treatment with neratinib.
If neratinib is used during pregnancy, or if the patient becomes pregnant while taking Nerlynx, thepatient should be informed of the potential hazard to the foetus.
Breast-feedingIt is not known whether neratinib is excreted in human milk. A risk to the breast-fed infant cannot beexcluded. A decision must be made whether to discontinue breast-feeding or to discontinue Nerlynx,taking into account the importance of Nerlynx to the mother and the benefit of breast-feeding to thechild.
FertilityNo fertility studies in women or men have been conducted. No significant changes in fertilityparameters 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 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 patientshould be considered when assessing the patient’s ability to perform tasks that require judgment,motor, or cognitive skills.
4.8 Undesirable effects
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 aminotransferaseincreased (0.4%), abdominal pain (0.3%), fatigue (0.3%) and decreased appetite (0.2%).
Tabulated list of adverse reactionsThe table below lists adverse reactions observed with neratinib based on the assessment of pooleddata from 1 710 patients.
The MedDRA frequency convention and system organ class database has been utilised for theclassification 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 cancerstudies
System Organ Class Frequency Adverse Drug Reaction
Infections and infestations Common Urinary tract infection
Metabolism and nutrition Very Common Decreased appetitedisorders Common Dehydration
Nervous system disorders Common Syncope
System Organ Class Frequency Adverse Drug Reaction
Respiratory, thoracic andmediastinal disorders Common Epistaxis
Diarrhoea, vomiting, nausea, abdominal
Very Common pain, abdominal pain upper, and
Gastrointestinal disorders stomatitis1
Common Abdominal distension, dry mouth anddyspepsia
Common Alanine aminotransferase increased, and
Hepatobiliary disorders aspartate aminotransferase increased
Uncommon Blood bilirubin increased
Skin and subcutaneous tissue Very Common Rashdisorders Common Nail disorder , skin fissures and dryskin
Musculoskeletal and connectivetissue disorders Very Common Muscle spasms
Renal and urinary disorders Common Blood creatinine increased
Uncommon Renal failure
General disorders andadministration site conditions Very common Fatigue
Investigations Common Weight decreased1 Includes stomatitis, aphthous stomatitis, mouth ulceration, oral mucosal blistering, and mucosalinflammation.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 reactionsDiarrhoea
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 Nerlynxpatients. 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 thefirst week, 46.9% in the second week, 40.2% in the third week and 43.2% in the fourth week (mediantime to first onset was 2 days).
The median duration of a single episode of any grade diarrhoea was 2 days. The median cumulativeduration of any grade diarrhoea was 59 days and the median cumulative duration of Grade 3 diarrhoeawas 5 days.
Diarrhoea was also the most common adverse reaction leading to discontinuation, 14.4 % of patientstreated with Nerlynx without loperamide prophylaxis discontinued treatment due to diarrhoea. Dosereductions occurred in 24.7% of Nerlynx-treated patients.
RashIn 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 3rash.
Nail disorders
In the Nerlynx monotherapy group, 7.8% patients experience nail disorders. The incidence of Grade 1and Grade 2 was 6.2% and 1.4% respectively. There were 0.2% of Nerlynx treated patients whoexperienced Grade 3 nail disorder.
Both rash and nail disorders led to treatment discontinuation in 0.6% of Nerlynx-treated patients.
HepatotoxicityHepatic-associated adverse reactions in the pivotal phase III study, ExteNET (3004), were reportedmore frequently in the Nerlynx arm compared to the placebo arm (12.4% vs. 6.6%), due primarily toalanine 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 adversereactions 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 in1.1% 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 increasedwas reported in 0.2% vs 0.0%, of Nerlynx- vs placebo-treated patients. There was no Grade 3 or 4adverse reactions of blood bilirubin increased.
Other special populationsElderly
In the pivotal phase III study, ExteNET (3004), the mean age was 52 years in the Nerlynx arm,1 236 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 yearsage 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 frequentlyreported in the ≥65 years-old group were vomiting (2.3%), diarrhoea (1.7%), dehydration (1.2%), andrenal failure (1.2%).
Treatment-emergent adverse reactions leading to hospitalisation in the Nerlynx arms versus theplacebo arm was 6.3% vs 4.9% in the <65 years-old group and 8.7% vs. 8.1% in the ≥65 years-oldgroup.
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 treatedwith Nerlynx was higher than in Caucasian patients (56.4% vs. 34.5%) but comparable in placebopatients (24.9% vs. 22.8%). Pooled safety data of 1 710 patients treated with Nerlynx monotherapyshowed a higher incidence of dermatologic toxicities in Asian patients (57.1%) versus Caucasianpatients (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 1and Grade 2 events was 25.6% and 7.8%, respectively. The frequency of Grade 3 events was similarbetween Asians and Caucasians (1.6% vs. 1.0%). There was no difference in frequency of SAEs inthe Skin SOC between Asian and Caucasian subgroups. The most common TEAEs in the Skin SOCthat 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 (6.0vs. 1.0%).
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.
4.9 Overdose
There is no specific antidote, and the benefit of haemodialysis in the treatment of Nerlynx overdose isunknown. In the event of an overdose, administration should be withheld and general supportivemeasures undertaken.
In the clinical trial setting, adverse reactions associated with overdose were most commonlydiarrhoea, with or without nausea, vomiting and dehydration.
In a dose escalation study in healthy volunteers, single oral doses of Nerlynx up to 800 mg wereadministered. 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 havenot been administered in the clinical studies.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01EH02
Mechanism of actionNeratinib is an irreversible pan-erythroblastic leukaemia viral oncogene homolog (ERBB) tyrosinekinase inhibitor (TKI) that blocks mitogenic growth factor signal transduction through covalent, highaffinity 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 activeheterodimers with HER3 (encoded by ERBB3). This results in sustained inhibition of these growthpromoting 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 safetyIn 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 was52 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 positivedisease (defined as ER-positive and/or PgR-positive), 27.2% were node negative, 41.5% had one tothree 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 IIItumours. 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 ofthe study included disease-free survival (DFS) including ductal carcinoma in situ (DFS-DCIS), timeto distant recurrence (TTDR), distant disease-free survival (DDFS), cumulative incidence of centralnervous system recurrence and overall survival (OS).
The primary analysis of the study after 2 years post-randomisation demonstrated that Nerlynxsignificantly 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.
Table 6: Primary 2-year efficacy results - ITT and hormone receptor positivepopulations who were less than one year from completion of trastuzumabtherapy
Variable Estimated 2 year event Hazardfree rates1 (%) ratio P-value3(95% CI)2
ITT population
Nerlynx Placebo(N=1420) (N=1420)
Invasive disease-free survival 94.2 91.9 0.67 0.011(0.49, 0.91)
Disease-free survival including ductal 94.2 91.3 0.62 0.002carcinoma in situ (0.46, 0.84)
Distant disease-free survival 95.3 94.0 0.75 0.110(0.53, 1.06)
Time to distant recurrence 95.5 94.2 0.74 0.102(0.52, 1.06)
CNS recurrence 0.92 1.16 - 0.586
Hormone receptor positive population who wereless than one year from completion of trastuzumab
Nerlynx Placebo Hazard(N=671) (N=668) ratio P-value5(95% CI)4
Invasive disease-free survival 95.3 90.9 0.50 0.003(0.31, 0.78)
Disease-free survival including ductal 95.3 90.1 0.45 <0.001carcinoma in situ (0.28, 0.71)
Distant disease-free survival 96.1 93.0 0.53 0.015(0.31, 0.88)
Time to distant recurrence 96.3 93.3 0.53 0.018(0.30, 0.89)
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 model3 Stratified 2-sided log-rank test for all endpoints, except for CNS recurrence for which Gray’s method wasused.4 Unstratified Cox proportional hazards model5 Unstratified 2-sided log-rank test for all endpoints, except for CNS recurrence for which Gray’s method wasused.
Figure 1: Kaplan-Meier plot of invasive disease-free survival - hormone receptorpositive population who were less than one year from completion oftrastuzumab therapy
For hormone receptor positive patients who were less than one year from completion of trastuzumabtherapy, the relative treatment benefit of Nerlynx within pre-specified patient subgroups is presentedin Figure 2.
Figure 2: Hormone receptor positive patients who were less than one year fromcompletion of trastuzumab therapy, invasive disease-free survival bypatient subgroup
Note: Patients (n = 30) who had an unknown nodal status are not shown because the HR could not be estimated
In patients that were hormone receptor negative, regardless of time from trastuzumab therapy, thehazard ratio for iDFS at 2 years was 0.94, with 95% CI (0.61, 1.46). In this population, efficacy hasnot been demonstrated.
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 treatmentbenefit of Nerlynx over placebo was maintained at five years, the effect size cannot be reliablyestimated.
The median OS follow-up time for the ITT population was 8.06 years, 8.03 years in the neratinib armand 8.10 years in the placebo arm, with a total of 1542 (54.3%) patients followed up for survival for 8or more years, 746 (52.5%) in the neratinib arm and 796 (56.1%) in the placebo arm. The number ofdeaths was 264 (9.3%), with 127 (8.9%) in the patients treated with neratinib and 137 (9.6%) in thepatients treated with placebo.
There was no statistically significant difference in overall survival between the Nerlynx and theplacebo arm [HR 0.96 (95% CI: 0.75, 1.22)] in the ITT population at a median follow-up of8.06 years.
In the hormone receptor positive population who were less than one year from completion oftrastuzumab therapy, the median follow-up was 8.0 years in the neratinib arm and 8.1 years in theplacebo arm, with a total of 1 339 (47.1%) patients followed up for survival for 8 or more years, 671(23.6%) in the neratinib arm and 668 (23.5%) in the placebo arm. In this subpopulation the number ofdeaths was 55 (8.2%) in the patients treated with neratinib and 68 (10.2%) in the patients treated withplacebo [HR 0.83 (95% CI, 0.58, 1.18)].
Paediatric populationThe European Medicines Agency has waived the obligation to submit the results of studies in allsubsets 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 sixhealthy subjects.
AbsorptionFollowing oral administration of 240 mg neratinib, absorption was slow and peak plasmaconcentrations of neratinib occurred around 7 hours after administration. A single dose of 240 mgneratinib taken with food increased Cmax and AUC by approximately 17% and 13%, respectively,compared with administration in the fasting state. A single oral dose of 240 mg neratinib taken with ameal high in fat increased both Cmax and AUC by approximately 100%. In a mass balance study, thetotal recovery (urinary and fecal excretion) of intact neratinib and metabolites demonstrates that thefraction absorbed for neratinib is at least 10% and likely more than 20%. Moreover, model-basedpredictions suggested an overall absorbed fraction from the gut (fa) of 26%.
In vitro neratinib solubility is pH-dependent. Treatments that increase gastrointestinal pH may lowerthe absorption of neratinib, thus decreasing systemic exposure.
DistributionBinding of neratinib to human plasma proteins, including covalent binding to human serum albumin(HSA), was greater than 98% and independent of the tested neratinib concentration. Neratinib boundpredominantly to HSA and human alpha-1 acid glycoprotein (AAG). Binding of M6 main metabolite(M6) to human plasma proteins was greater than 99% and independent of the tested M6concentrations.
In vitro studies demonstrated that neratinib is a substrate for P-glycoprotein (P-gp) (see sections 4.2,4.3, pct. 4.4 and 4.5) and BCRP. In vitro studies demonstrated that neratinib and its main metabolite M6are not substrates of hepatic uptake transporters OATP1B1*1a and OATP1B3 at relevant clinicalconcentration.
BiotransformationNeratinib 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, neratinibundergoes oxidative metabolism through CYP3A4. Circulating metabolites include neratinib pyridine
N-oxide (M3), N-desmethyl neratinib (M6), neratinib dimethylamine N-oxide (M7) and traces ofhydroxyl neratinib N-oxide and neratinib bis-N-oxide (M11). Neratinib represents the most prominentcomponent in plasma and amongst circulating metabolites (M2, M3, M6, M7 and M11) none is above8% of neratinib plus metabolite total exposure after oral administration of neratinib. The neratinibmetabolites M3, M6, M7 and M11 were shown to have similar potencies to neratinib in either in vitroenzyme (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.
EliminationFollowing single doses of neratinib, the mean apparent plasma half-life of neratinib was 17 hours inpatients.
Excretion of neratinib is primarily 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 and96.5% of total radioactivity recovered in excreta after 8 days.
Unchanged neratinib was the most abundant species in excreta accounting for 62.1% of total doserecovered in excreta. The most abundant metabolites in faeces were M6 (19.7% of administereddose), followed by M2, M3 and M7, all below 10% of administered dose.
Medicinal product interactionsEffect 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 sections 4.3 and 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 systemicexposure by 3.2- and 4.8-fold for Cmax and AUC, respectively, compared with neratinib administeredalone.
Model-based predictions suggested that co-administration of a single oral dose of 240 mg of neratinibin 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 withneratinib administered alone.
Model-based predictions suggested that co-administration of a single oral dose of 240 mg of neratinibin the presence of verapamil (120 mg twice daily for 8 days), a moderate CYP3A4/strong P-gpinhibitor, increased neratinib systemic exposure by 3.0- and 4.0-fold for Cmax and AUC, comparedwith neratinib administered alone (see sections 4.2, pct. 4.4 and 4.5).
Effect of gastric pH modifiers on neratinib
Co-administration of lansoprazole or ranitidine (1x300 mg) with a 240 mg single dose of neratinib inhealthy 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 staggeringthe administration of ranitidine (2x150 mg) 2 hours after neratinib administration (see sections 4.2,4.4 and 4.5).
Effect of other treatment on neratinib
There were no apparent clinically relevant drug-drug interactions observed for neratinib whenadministered concomitantly with capecitabine, paclitaxel, trastuzumab, vinorelbine, or antidiarrhoeals(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 and no time-dependent inhibition is expected.
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 areported IC50 value of > 10 µM. Neratinib at 10 µM appeared to inhibit the BCRP efflux transporterwhich 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 wasfurther confirmed in a clinical study. Multiple oral doses of neratinib 240 mg increased digoxinexposures (54 and 32% increase in Cmax and AUC, respectively) with no impact on its renal clearancelevel (see sections 4.4 and 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 inhibitoryactivity in OCT1 uptake transporter, with an IC50 of 2.9 µM.
Special populationsRenal impairment
Pharmacokinetic studies in patients with renal impairment or undergoing dialysis have not beencarried out. Population pharmacokinetic modelling revealed that creatinine clearance did not explainthe variability between patients, hence, no dose modifications are recommended for patients with mildto moderate renal impairment (see sections 4.2 and 4.4).
Hepatic impairmentNeratinib is extensively metabolised in the liver. In subjects with severe pre-existing hepaticimpairment (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 sections4.2 and 4.3).
5.3 Preclinical safety data
Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar toclinical 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 vitrogenotoxicity studies.
A 6-month carcinogenicity study in Tg.rasH2 transgenic mice and the rat 2-year data showed no signsof carcinogenic potential.
Reproductive toxicityIn 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 andmisshapen anterior fontanelles and enlarged anterior and/or posterior fontanelles) were observed atdoses that may be considered to be clinically relevant.
Environmental risk assessment (ERA)Environmental risk assessment studies have shown that neratinib has an evident potential to bepersistent, bioaccumulative, and toxic to the environment (see section 6.6).
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Mannitol (E421)
Microcrystalline cellulose
Crospovidone
Povidone
Silica, colloidal anhydrous
Magnesium stearate
Tablet coatingPolyvinyl 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
60 mL white high density polyethylene (HDPE) round bottle with child-resistant, polypropyleneclosure, 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 and other handling
This medicinal product may pose a risk to the environment (see section 5.3).
Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.
10. DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines
Agency https://www.ema.europa.eu.