Neratinib

Registered South African indications:

• 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

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Coadministration with the following medicines that are strong or moderate inducers of the CYP3A4/P gp isoform of cytochrome P450, such as
  • Carbamazepine, phenobarbital, phenytoin (antiepileptics)
  • St John’s wort (Hypericum perforatum) (herbal product)
  • Rifampicin (antimycobacterial)
• Severe hepatic impairment (Child-Pugh C)

South African recommendations

Caution in the following patient groups

• Pregnancy
• Women of childbearing potential
• Breastfeeding
• Renal impairment
• Mild to moderate hepatic impairment

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

Diarrhoea

• Diarrhoea has been reported during treatment with neratinib. The diarrhoea may be severe and associated with dehydration
• Diarrhoea generally occurs early during the first or second week of treatment with neratinib and may be recurrent
• Patients should be instructed to initiate prophylactic treatment with an anti-diarrhoeal medicine with the first dose of neratinib, and maintain regular dosing of the anti-diarrhoeal medicine during the first 1-2 months of neratinib treatment, titrating to 1-2 bowel movements per day

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

Hepatic function

• Hepatotoxicity has been reported in patients treated with neratinib
• 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
• Patients who experience ≥ Grade 3 diarrhoea requiring IV fluid treatment or any signs or symptoms of hepatotoxicity, such as worsening of fatigue, nausea, vomiting, jaundice, right upper quadrant pain or tenderness, fever, rash, or eosinophilia, should be evaluated for changes in liver function tests
• Fractionated bilirubin and prothrombin time should also be collected during hepatotoxicity evaluation

Left ventricular function

• Left ventricular dysfunction has been associated with HER2 inhibition
• Neratinib 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
• In case of H2 receptor antagonists or antacids, modalities of administration should be adapted

Skin and subcutaneous tissue disorders

• Neratinib is associated with skin and subcutaneous tissue disorders
• Patients with symptomatic skin and subcutaneous tissue disorders should be carefully monitored

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, neratinib dose adjustment should be applied
• Grapefruit or pomegranate juice should be avoided during treatment with neratinib

Concomitant treatment with moderate inducers of CYP3A4 and P-gp

• Concomitant treatment with moderate CYP3A4 and P-gp inducer is not recommended as it may lead to a loss of neratinib efficacy

Concomitant treatment with substrates of P-gp

• Patients who are treated concomitantly with therapeutic medicines with a narrow therapeutic window whose absorption involves P-gp transporters in the gastrointestinal tract should be carefully monitored

Effects on ability to drive and use machines

• Neratinib has minor or moderate influence on the ability to drive and use machines. Fatigue, dizziness, dehydration, and syncope have been reported as adverse reactions with neratinib. The clinical status of the patient should be considered when assessing the patient’s ability to perform tasks that require judgment, motor, or cognitive skills

Forms avail. in SA and covered in this monograph: fct

South African registered indications and dosages

Therapy should be initiated and supervised by a medical practitioner experienced in the administration of anti-cancer medicines

Used for the treatment of

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

• Oral (fct): 240mg (six 40mg tabs), once dly; Treatment duration: Taken continuously for one year

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Neratinib should be taken with food, preferably in the morning. Patients should initiate treatment within 1 year after completion of trastuzumab therapy

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Dose modifications for adverse reactions
Dose modification is recommended based on individual safety and tolerability. Management of some adverse reactions may require dose interruption and/or dose reduction. See additional prescribing points

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Missed doses
Missed doses should not be replaced and treatment should resume with the next scheduled daily dose

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Use of CYP3A4/P-gp inhibitors
If the inhibitor cannot be avoided, reduce neratinib dose to 40mg (one 40mg tablet), once daily with a moderate to strong CYP3A4/P-gp inhibitor. If well tolerated, increase to 80mg for at least 1 week, then to 120mg for at least 1 week, and to 160mg as a maximal daily dose. Patient should be monitored carefully, especially GI effect including diarrhoea and hepatotoxicity. After discontinuation of a strong or moderate CYP3A4/P-gp inhibitor, resume previous dose of neratinib 240mg

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Use of H2 receptor antagonists and antacids
If H2 receptor antagonists are used, neratinib should be taken at least 2 hours before or 10 hours after the intake of the H2 receptor antagonist. Separate dosing of neratinib and antacids by at least 3 hours should be applied

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Method of administration

Neratinib is for oral use. The tablets should be swallowed whole preferably with water and should not be crushed or dissolved, and should be taken with food, preferably in the morning

Not indicated for use in children

Pregnancy 

South African recommendations

• Caution; positive evidence of risk in animal studies
• There are no data from the use of neratinib in pregnant women. Studies in animals have shown embryo-foetal lethality and foetal morphological anomalies
• The potential risk for humans is unknown. Neratinib 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 neratinib, the patient should be informed of the potential hazard to the foetus
• Neratinib may cause foetal harm when administered to pregnant women

Women of childbearing potential/contraception in males and females

• Based on findings in animals, neratinib may cause foetal harm when administered to pregnant women. Women should avoid becoming pregnant while taking neratinib and for up to 1 month after ending treatment
• Therefore, women of child-bearing potential must use highly effective contraceptive measures while taking neratinib 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

Breastfeeding

South African recommendations

• Caution; not recommended
• 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 neratinib, taking into account the importance of neratinib to the mother and the benefit of breast feeding to the child

Fertility

South African recommendations

• 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

South African recommendations

• Mild to moderate: Caution; no dose adjustment recommended
  Patients with renal impairment are at a higher risk of complications of dehydration if they develop diarrhoea, and these patients should be carefully monitored
• Severe: Caution; not recommended
  Neratinib 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

South African recommendations

• Mild to moderate (Child-Pugh A or B): Caution; no dose adjustment recommended
• Severe: Contraindicated

South African recommendations

• ≥ 65 years: Caution; no dose adjustment recommended
• ≥ 85 years: Caution; no information available

Infections and Infestations

Common

• Urinary tract infection

Metabolism and Nutrition Disorders

Very Common

• Decreased appetite

Common

• Dehydration

Nervous System Disorders

Common

• Syncope

Respiratory, Thoracic and Mediastinal Disorders

Common

• Epistaxis

Gastrointestinal Disorders

Very Common

• Diarrhoea
• Vomiting
• Nausea
• Abdominal pain
• Abdominal pain upper
• Stomatitis
  • Aphthous stomatitis
  • Mouth ulceration
  • Oral mucosal blistering
  • Mucosal inflammation

Common

• Abdominal distension
• dry mouth
• dyspepsia

Hepatobiliary Disorders

Common

• Increased alanine aminotransferase
• Increased aspartate aminotransferase

Uncommon

• Increased blood bilirubin

Skin and Subcutaneous Tissue Disorders

Very Common

• Rash
  • Erythematous rash
  • Follicular rash
  • Generalised rash
  • Pruritic rash
  • Pustular rash

Common

• Nail disorder
  • Paronychia
  • Onychoclasis
  • Nail discolouration
• Skin fissures
• Dry skin

Musculoskeletal and Connective Tissue Disorders

Very Common

• Muscle spasms

Renal and Urinary Disorders

Common

• Increased blood creatinine

Uncommon

• Renal failure

General Disorders and Administration Site Conditions

Very Common

• Fatigue

Investigations

Common

• Weight decreased

• Strong Cytochrome P450 3A4 / P-glycoprotein inducers
• Phenytoin
• Carbamazepine
• Rifampicin
• Moderate Cytochrome P450 3A4 / P-glycoprotein inducers
• Bosentan
• Efavirenz
• Etravirine
• Phenobarbital (phenobarbitone)
• Primidone
• Dexamethasone
• Strong Cytochrome P450 3A4 / P-glycoprotein inhibitors
• Atazanavir
• Indinavir
• Nefazodone
• Nelfinavir
• Ritonavir
• Saquinavir
• Lopinavir
• Ketoconazole
• Itraconazole
• Clarithromycin
• Troleandomycin
• Voriconazole
• Cobicistat
• Moderate Cytochrome P450 3A4 / P-glycoprotein inhibitors
• Ciprofloxacin
• Cyclosporine
• Diltiazem
• Fluconazole
• Erythromycin
• Fluvoxamine
• Verapamil
• Proton pump inhibitors
• Omeprazole
• Lansoprazole
• Histamine-2 receptor antagonists
• Antacids
• Systemically acting hormonal contraceptives
• Narrow therapeutic window agents whose absorption involves P-glycoprotein transporters in the gastrointestinal tract
• Digoxin
• Colchicine
• Dabigatran
• Phenytoin
• Statins
• Ciclosporin
• Everolimus
• Sirolimus
• Tacrolimus
• Breast cancer resistance protein substrates
• Rosuvastatin
• Sulfasalazine
• Irinotecan

Other interactions

• Herbal preparations containing St John’s wort (Hypericum perforatum)
• Grapefruit
• Pomegranate
• Grapefruit juice
• Pomegranate juice

• Hepatic function (at 1 week after starting treatment, then monthly for the first 3 months, and every 6 weeks thereafter, or as clinically indicated)
  • Alanine aminotransferase (ALT)
  • Aspartate aminotransferase (AST)
  • Total bilirubin
  • Fractionated bilirubin
  • Prothrombin time

Specific cases may require

• Cardiac function
  • Left Ventricular Ejection Fraction (LVEF)

Dose modifications for adverse reactions

Discontinue Neratinib 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: Neratinib dose modifications for adverse reactions

Dose level	Neratinib dose
Recommended starting dose	240mg, dly
First dose reduction	200mg, dly
Second dose reduction	160mg, dly
Third dose reduction	120mg, dly

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Table 2: Neratinib dose modifications and management - general toxicities (Refer to Table 3 and Table 4 below for management of diarrhoea and hepatotoxicity)

Severity of toxicity (Per CTCAE v4.0)	Action
Grade 3	Stop neratinib until recovery to Grade 0 – 1 or baseline within 3 weeks of stopping treatment. Then resume neratinib at the next lower dose level. If grade 3 toxicity does not recover within 3 weeks, discontinue neratinib permanently
Grade 4	Discontinue neratinib permanently

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Table 3: Dose modifications for diarrhoea

Severity of diarrhoea (Per CTCAE v4.0)	Action
Grade 1 diarrhoea (increase of < 4 stools per day over baseline) Grade 2 diarrhoea [increase of 4 – 6 stools per day over baseline] lasting < 5 days Grade 3 diarrhoea [increase of ≥ 7 stools per day over baseline; incontinence; hospitalisation indicated; limiting self-care activities of daily living] lasting ≤ 2 days	Adjust anti-diarrhoeal treatment Diet modifications Fluid intake of ~2 L should be maintained to avoid dehydration Once event resolves to Grade 0 – 1 or baseline, consider restarting anti-diarrhoeal prophylaxis, if appropriate with each subsequent neratinib administration
Any grade with complicated features (Complicated features include dehydration, fever, hypotension, renal failure, or Grade 3 or 4 neutropenia) Grade 2 diarrhoea lasting 5 days or longer (Despite being treated with optimal medical therapy) Grade 3 diarrhoea lasting between 2 days and 3 weeks (Despite being treated with optimal medical therapy)	Interrupt neratinib treatment Diet modifications Fluid intake of ~2 L should be maintained to avoid dehydration If diarrhoea resolves to Grade 0 – 1 in one week or less, then resume neratinib treatment at the same dose If diarrhoea resolves to Grade 0 – 1 in longer than one week, then resume neratinib treatment at reduced dose (see Table 1) Once event resolves to Grade 0 – 1 or baseline, consider restarting anti-diarrhoeal prophylaxis, if appropriate with each subsequent neratinib administration If grade 3 diarrhoea persists longer than 3 weeks, discontinue neratinib permanently
Grade 4 diarrhoea (life-threatening consequences; urgent intervention indicated)	Permanently discontinue neratinib treatment
Diarrhoea recurs to Grade 2 or higher at 120mg per day	Permanently discontinue neratinib treatment

• Diarrhoea management requires the correct use of an anti-diarrhoeal medicine dietary changes, and appropriate dose modifications of neratinib

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Table 4: Dose modifications for hepatotoxicity

Severity of hepatotoxicity (Per CTCAE v4.0)	Action
Grade 3 ALT (> 5 – 20 x ULN) OR Grade 3 bilirubin (>3 - 10 x ULN)	Stop neratinib until recovery to Grade 0 – 1 Evaluate alternative causes Resume neratinib at the next lower dose level if recovery to Grade 0 – 1 occurs within 3 weeks. If Grade 3 ALT or bilirubin occurs again despite one dose reduction, permanently discontinue neratinib
Grade 4 ALT (> 20 x ULN) OR Grade 4 bilirubin (> 10 x ULN)	Permanently discontinue neratinib Evaluate alternative causes

ULN = upper limit normal
ALT = alanine aminotransferase

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 signalling 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.