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.

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.

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. intolerable toxicities, persistent Grade 2 adverse reactions, etc.).

Table 1:          Nerlynx dose modifications for adverse reactions

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

* 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

* 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

ULN=Upper Limit Normal; ALT= Alanine Aminotransferase

* Per CTCAE v4.0

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 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 well tolerated, increase to 80 mg for at least 1 week, then to 120 mg for at least 1 week, and to 160 mg as a maximal daily dose. Patient should be monitored carefully, especially GI effects including 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 after the intake of the H2-receptor antagonist. Separate dosing of Nerlynx and antacids by at least 3 hours should be applied (see sections 4.4, 4.5 and 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 of 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. The tablets should be taken with food, preferably in the morning (see section 5.2).

Diarrhoea

Diarrhoea has been reported during treatment with Nerlynx (see sections 4.2 and 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 sections 4.2 and 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 intravenous 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 sections 4.5 and 5.2).

In case of H2-receptor antagonists or antacids, modalities of administration should be adapted (see sections 4.2, 4.5 and 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).

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 cannot be avoided, Nerlynx dose adjustment should 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 during treatment 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 lead to 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 window whose absorption involves P-gp transporters in the gastrointestinal tract should be carefully monitored (see sections 4.5 and 5.2).

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 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 loss of efficacy (e.g. moderate inducers: bosentan, efavirenz, etravirine, phenobarbital, primidone, dexamethasone) (see sections 4.3 and 5.2).

CYP3A4/P-gp inhibitors

A 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, cyclosporin, diltiazem, fluconazole, erythromycin, fluvoxamine and verapamil). If the inhibitor can not be avoided, Nerlynx dose adjustment shoud be applied (see sections 4.2, 4.4 and 5.2).

Grapefruit/pomegranate or grapefruit/pomegranate juice may also increase neratinib plasma concentrations and should be avoided (see sections 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 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 sections 4.4 and 5.2).

Nerlynx should be taken at least 2 hours before or 10 hours after the intake of the H2-receptor antagonist (see sections 4.2, 4.4 and 5.2).

Separate dosing of Nerlynx and antacids by at least 3 hours (see sections 4.2, 4.4 and 5.2).

Antidiarrhoeal loperamide

A clinical study has 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 a 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 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 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 (see section 5.2).

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,

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).

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 patient should be considered when assessing the patient’s ability to perform tasks that require judgment, motor, or cognitive skills.

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

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 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, 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 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 1 710 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:

The National Pharmacovigilance Centre (NPC):

Fax: +966-11-205-7662

SFDA Call Center: 19999

E-mail: npc.drug@sfda.gov.sa Website: https://ade.sfda.gov.sa Other GCC States:

- Please contact the relevant competent authority

By reporting side effects, you can help provide more information on the safety of this medicine.

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.

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.

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01EH02 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.

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

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.

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

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.

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

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.

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.

The median OS follow-up time for the ITT population was 8.06 years, 8.03 years in the neratinib arm and 8.10 years in the placebo arm, with a total of 1 542 (54.3%) patients followed up for survival for 8 or more years, 746 (52.5%) in the neratinib arm and 796 (56.1%) in the placebo arm. The number of deaths was 264 (9.3%), with 127 (8.9%) in the patients treated with neratinib and 137 (9.6%) in the patients treated with placebo.

There was no statistically significant difference in overall survival between the Nerlynx and the placebo arm [HR 0.96 (95% CI: 0.75, 1.22)] in the ITT population at a median follow-up of 8.06 years.

In the hormone receptor positive population who were less than one year from completion of trastuzumab therapy, the median follow-up was 8.0 years in the neratinib arm and 8.1 years in the placebo 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 of deaths was 55 (8.2%) in the patients treated with neratinib and 68 (10.2%) in the patients treated with placebo [HR 0.83 (95% CI, 0.58, 1.18)].

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.

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 13%, 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 independent 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 independent of the tested M6 concentrations.

In vitro studies demonstrated that neratinib is a substrate for P-glycoprotein (P-gp) (see sections 4.2, 4.3, 4.4 and 4.5) and BCRP. In vitro studies demonstrated that neratinib and its main metabolite M6 are not substrates of hepatic uptake transporters OATP1B1*1a and OATP1B3 at relevant clinical concentration.

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 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 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 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 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 sections 4.2, 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 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 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 when administered 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 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 increased digoxin exposures (54 and 32% increase in Cmax and AUC, respectively) with no impact on its renal clearance level (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 inhibitory activity in OCT1 uptake transporter, with an IC50 of 2.9 µM 

Special populations

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 sections 4.2 and 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 sections 4.2 and 4.3).

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.

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.

Environmental risk assessment (ERA)

Environmental risk assessment studies have shown that neratinib has an evident potential to be persistent, bioaccumulative, and toxic to the environment (see section 6.6).

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)

Not applicable.

Keep the bottle tightly closed in order to protect from moisture. Store below 30°C.

60 mL white 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.

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 local requirements.