Neratinib

Neratinib is an irreversible pan-ERBB tyrosine kinase inhibitor. It binds covalently and with high affinity to the ATP-binding site of three epidermal growth factor receptors (EGFR, HER2 and HER4) and of their active heterodimers with HER3. This gives sustained inhibition of growth-promoting signalling in HER2-amplified, HER2-overexpressing or HER2-mutant breast cancers.

Mechanism of Action

• Target receptors: EGFR (encoded by ERBB1), HER2 (ERBB2) and HER4 (ERBB4), and their active heterodimers with HER3 (ERBB3).
• Signalling: neratinib reduces EGFR and HER2 autophosphorylation and the downstream MAPK and AKT pathways, and strongly inhibited tumour cell proliferation in vitro (cellular IC50 below 100 nM in EGFR- and/or HER2-expressing carcinoma cell lines).
• Clinical basis: in the randomised, double-blind, placebo-controlled phase III ExteNET study, 2,840 women with early-stage HER2-positive breast cancer who had completed adjuvant trastuzumab received neratinib or placebo daily for one year.

Pharmacokinetics

• Absorption: slow, with peak plasma concentrations about 7 hours after a 240 mg dose. A single dose taken with food raised Cmax and AUC by about 17% and 13% compared with fasting, and a high-fat meal roughly doubled both. The fraction absorbed is at least 10% and probably above 20% (26% by model-based prediction). Solubility depends on pH, so medicines that raise gastric pH can lower absorption.
• Distribution: more than 98% bound to plasma proteins, mainly albumin (including covalent binding) and alpha-1 acid glycoprotein; the main metabolite M6 is more than 99% bound. Neratinib is a substrate of P-glycoprotein (P-gp) and of BCRP.
• Metabolism: mainly in the liver by CYP3A4, and to a lesser extent by flavin-containing monooxygenase. Circulating metabolites include M3, M6 and M7, with traces of M11; neratinib is the most prominent compound in plasma and no metabolite exceeds 8% of the total exposure.
• Elimination: mostly in the faeces (about 97% of a dose) and about 1% in the urine. The mean half-life after repeated dosing is about 14.6 hours for neratinib (7 to 17 hours after a single dose).
• Special populations: see Administration and Dosage for renal and hepatic impairment and for elderly patients.

• Early breast cancer (extended adjuvant treatment): adults with early-stage hormone receptor-positive, HER2-overexpressed/amplified breast cancer who completed adjuvant trastuzumab-based therapy less than one year ago.

• Hypersensitivity to neratinib or to any of the excipients (SmPC section 6.1).
• Co-administration with strong inducers of CYP3A4 and P-gp: carbamazepine and phenytoin (antiepileptics), St John’s wort (herbal product) and rifampicin (antimycobacterial).
• Severe hepatic impairment (Child-Pugh C).

The reactions below come from pooled data of 1,710 patients. The most common 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%), upper abdominal pain (13.2%), stomatitis (11.2%) and muscle spasms (10.0%). The most common grade 3–4 reactions were diarrhoea (grade 3, 36.9%; grade 4, 0.2%) and vomiting (grade 3, 3.4%; grade 4, 0.1%). Reactions reported as serious included diarrhoea (1.9%), vomiting (1.3%), dehydration (1.1%), nausea (0.5%), increased alanine and aspartate aminotransferase (0.4% each), abdominal pain (0.3%), fatigue (0.3%) and decreased appetite (0.2%).

Very common (≥1/10): decreased appetite, diarrhoea, vomiting, nausea, abdominal pain, upper abdominal pain, stomatitis, rash, muscle spasms, fatigue.

Common (≥1/100 to <1/10): urinary tract infection, dehydration, syncope, epistaxis, abdominal distension, dry mouth, dyspepsia, increased alanine aminotransferase, increased aspartate aminotransferase, nail disorder, skin fissures, dry skin, increased blood creatinine, decreased weight.

Uncommon (≥1/1,000 to <1/100): increased blood bilirubin, renal failure.

Diarrhoea is the reaction to plan for. Among 1,660 patients on neratinib alone who did not receive loperamide prophylaxis, 94.6% had at least one episode, grade 3 diarrhoea occurred in 37.5%, and 1.9% were hospitalised. Most cases began in the first month (83.6% of patients reported it in the first week), and diarrhoea was the most common reason for stopping treatment (14.4%). Doses had to be reduced in 24.7% of patients. Hepatic reactions were more frequent than with placebo in the ExteNET study (12.4% against 6.6%), mainly raised ALT and AST.

Neratinib is metabolised mainly by CYP3A4 and is a P-gp substrate; it also inhibits P-gp and possibly BCRP.

• Strong CYP3A4/P-gp inducers (phenytoin, carbamazepine, rifampicin, St John’s wort): exposure to neratinib falls significantly; the combination is contraindicated.
• Moderate CYP3A4/P-gp inducers (for example bosentan, efavirenz, etravirine, phenobarbital, primidone, dexamethasone): not recommended, because efficacy may be lost.
• Strong CYP3A4/P-gp inhibitors (for example atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, lopinavir, ketoconazole, itraconazole, clarithromycin, troleandomycin, voriconazole, cobicistat) and moderate inhibitors (for example ciprofloxacin, ciclosporin, diltiazem, fluconazole, erythromycin, fluvoxamine, verapamil): exposure rises significantly and the combination is not recommended. If the inhibitor cannot be avoided, the neratinib dose is reduced (see Administration and Dosage).
• Grapefruit and pomegranate (or their juices): may raise neratinib levels and should be avoided.
• Acid-reducing medicines: neratinib dissolves less well at higher gastric pH. Proton pump inhibitors (for example omeprazole, lansoprazole) are not recommended. Take Nerlynx at least 2 hours before or 10 hours after an H2-receptor antagonist, and separate it from antacids by at least 3 hours.
• Loperamide: a clinical study found no clinically significant difference in neratinib exposure with or without loperamide.
• P-gp substrates: neratinib raised digoxin Cmax by 54% and AUC by 32%. Monitor carefully patients on medicines with a narrow therapeutic window whose absorption depends on gut P-gp (for example digoxin, colchicine, dabigatran, phenytoin, statins, ciclosporin, everolimus, sirolimus, tacrolimus).
• BCRP substrates (for example rosuvastatin, sulfasalazine, irinotecan): neratinib may raise their exposure at gut level; monitor carefully.
• Hormonal contraceptives: it is unknown whether neratinib reduces their effectiveness, so users of systemic hormonal contraceptives should add a barrier method.

Treatment should be started and supervised by a physician experienced in the use of anti-cancer medicinal products. The tablets are swallowed whole, preferably with water, with food and preferably in the morning; they must not be crushed or dissolved.

Recommended Dose

• 240 mg (six 40 mg tablets) once daily, taken continuously for one year.
• Treatment should start within 1 year after completing trastuzumab therapy.

Diarrhoea Prophylaxis

• Patients are told to start prophylactic treatment with an anti-diarrhoeal medicine (loperamide is the one named in the SmPC) with the first dose of Nerlynx, and to keep taking it regularly during the first 1–2 months, titrating to 1–2 bowel movements per day.
• Managing diarrhoea needs the correct use of an anti-diarrhoeal medicine, dietary changes and the dose modifications below; a fluid intake of about 2 L per day should be kept up to avoid dehydration.

Dose Reduction

• Dose levels: 240 mg daily (starting dose), then 200 mg (first reduction), 160 mg (second) and 120 mg (third).
• Grade 3 toxicity: stop until recovery to grade 1 or lower (or baseline) within 3 weeks, then resume at the next lower dose level; if there is no recovery within 3 weeks, discontinue permanently. Grade 4: discontinue permanently.
• Nerlynx is also discontinued in patients who do not recover to grade 0–1 from treatment-related toxicity, whose toxicity causes a delay of more than 3 weeks, or who cannot tolerate 120 mg daily.

Dose Modification for Diarrhoea

• Grade 1; grade 2 (4–6 stools per day over baseline) lasting under 5 days; grade 3 (7 or more stools per day over baseline, incontinence, hospitalisation indicated, limiting self-care) lasting 2 days or less: adjust the anti-diarrhoeal treatment, change the diet, keep up fluids, and once the event is grade 1 or lower consider restarting anti-diarrhoeal prophylaxis with each later dose.
• Any grade with complicated features (dehydration, fever, hypotension, renal failure, or grade 3–4 neutropenia); grade 2 lasting 5 days or longer; grade 3 lasting between 2 days and 3 weeks (the last two despite optimal medical therapy): interrupt Nerlynx. If diarrhoea resolves to grade 1 or lower within one week, resume at the same dose; if it takes longer, resume at a reduced dose. If grade 3 diarrhoea lasts longer than 3 weeks, discontinue permanently.
• Grade 4 diarrhoea, or diarrhoea that returns at grade 2 or higher at 120 mg daily: discontinue permanently.

Dose Modification for Hepatotoxicity

• Grade 3 ALT (5–20 times the upper limit of normal) or grade 3 bilirubin (3–10 times): stop Nerlynx until recovery to grade 1 or lower and look for other causes. Resume at the next lower dose level if recovery occurs within 3 weeks; if grade 3 ALT or bilirubin recurs despite one dose reduction, discontinue permanently. Grade 3 hepatotoxicity lasting longer than 3 weeks also means permanent discontinuation.
• Grade 4 ALT (above 20 times the upper limit) or grade 4 bilirubin (above 10 times): discontinue permanently and look for other causes.

Dose Escalation After a CYP3A4/P-gp Inhibitor

• If a strong or moderate CYP3A4/P-gp inhibitor cannot be avoided, the dose is reduced to 40 mg (one tablet) once daily.
• With a moderate inhibitor, if 40 mg is well tolerated, the dose can be increased to 80 mg for at least 1 week, then to 120 mg for at least 1 week, and to 160 mg as the maximal daily dose, with careful monitoring, especially of gastrointestinal effects including diarrhoea and hepatotoxicity.
• After a strong or moderate inhibitor is stopped, the previous dose of 240 mg is resumed.

Timing With Other Medicines

Take Nerlynx at least 2 hours before or 10 hours after an H2-receptor antagonist, and at least 3 hours apart from antacids. Grapefruit, pomegranate and their juices are not recommended.

Special Populations

• Renal impairment: no adjustment in mild to moderate impairment. Not studied in severe impairment, including dialysis; treatment is not recommended there.
• Hepatic impairment: no adjustment in Child-Pugh A or B; Child-Pugh C is a contraindication.
• Elderly: no dose adjustment; there are no data in patients aged 85 years and older.
• Children and adolescents: no relevant use in breast cancer.

Missed Dose

Missed doses should not be made up. Treatment resumes with the next scheduled daily dose.

Diarrhoea

Diarrhoea may be severe and associated with dehydration. It usually starts in the first or second week of treatment and may recur. Prophylactic anti-diarrhoeal treatment is started with the first dose (see Administration and Dosage). Patients aged 65 and older are at higher risk of renal insufficiency and dehydration as a complication, as are patients with renal impairment, and all should be monitored carefully. Patients with a significant chronic gastrointestinal disorder with diarrhoea as a major symptom were not included in the pivotal study and should also be monitored carefully.

Liver Function

Hepatotoxicity has been reported. ALT, AST and total bilirubin are monitored at 1 week, then monthly for the first 3 months and every 6 weeks after that during treatment, or as clinically indicated. Patients with grade 3 or worse diarrhoea needing intravenous fluids, or any sign or symptom of hepatotoxicity (worsening fatigue, nausea, vomiting, jaundice, right upper quadrant pain or tenderness, fever, rash or eosinophilia), should have liver function tests checked, with fractionated bilirubin and prothrombin time.

Left Ventricular Function

Left ventricular dysfunction has been linked to HER2 inhibition. Nerlynx has not been studied in patients whose left ventricular ejection fraction (LVEF) is below the lower limit of normal or who have a significant cardiac history. In patients with known cardiac risk factors, cardiac monitoring including LVEF assessment should be done as clinically indicated.

Acid-Reducing Medicines

Treatments that raise gastrointestinal pH may lower the absorption of neratinib. Proton pump inhibitors are not recommended; H2-receptor antagonists and antacids need adapted timing (see Administration and Dosage).

Skin and Subcutaneous Tissue Disorders

Nerlynx is associated with skin and subcutaneous tissue disorders, and patients with symptoms should be monitored carefully.

CYP3A4, P-gp and Transporter Interactions

Strong or moderate CYP3A4/P-gp inhibitors are not recommended because of higher neratinib exposure; if unavoidable, adjust the dose. Moderate CYP3A4/P-gp inducers are not recommended because efficacy may be lost. Grapefruit and pomegranate juice should be avoided. Patients taking medicines with a narrow therapeutic window that depend on gut P-gp should be monitored carefully.

Pregnancy, Breastfeeding and Fertility

• Contraception: neratinib may cause foetal harm. Women of childbearing potential must use highly effective contraception during treatment and for 1 month after stopping. Women using systemic hormonal contraceptives should add a barrier method. Men should use a barrier method during treatment and for 3 months after stopping.
• Pregnancy: there are no human data. Animal studies showed embryo-foetal lethality and foetal morphological anomalies. Nerlynx should not be used in pregnancy unless the woman’s clinical condition requires it, and a patient who becomes pregnant should be told of the potential hazard to the foetus.
• Breastfeeding: it is not known whether neratinib passes into human milk and a risk to the infant cannot be excluded. A decision must be made whether to stop breast-feeding or Nerlynx, weighing its importance to the mother against the benefit of breast-feeding.
• Fertility: no fertility studies have been done in women or men. No significant changes in fertility parameters were found in male and female rats at doses up to 12 mg/kg/day.

Effect on Driving

Nerlynx has a minor influence on the ability to drive and use machines. Fatigue, dizziness, dehydration and syncope have been reported, and the patient’s clinical status should be considered when judging their ability to do tasks that need judgement, motor or cognitive skills.

Keep the bottle tightly closed to protect from moisture. No special temperature storage conditions are required. Each white high-density polyethylene bottle has a child-resistant closure and foil induction seal, holds 180 tablets, and contains a canister with 1 g of silica gel desiccant.

3 years.

Prescription only (Rx); a medicinal product subject to restricted medical prescription (Annex II B), started and supervised by a physician experienced in the use of anti-cancer medicinal products. Nerlynx tablets are taken at home, so the medicine is supplied to the patient or to the treating clinic on prescription.