Neratinib

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.

Concurrent use of neratinib with moderate CYP3A4/P-gp inducers is not recommended as it may lead to loss of efficacy (e.g. moderate inducers: bosentan, efavirenz, etravirine, phenobarbital, primidone, dexamethasone).

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 cannot be avoided, reduce neratinib 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 neratinib 240 mg.

Concomitant administration of neratinib with grapefruit or pomegranate/grapefruit or pomegranate juice is not recommended.

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 C_max 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.

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.

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).

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.

It is currently unknown whether neratinib reduces the effectiveness of systemically acting hormonal contraceptives. Therefore, women using systemically acting hormonal contraceptives should add a barrier method.

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.

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.

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.

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.

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 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.

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.

Neratinib 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.

Adverse drug reactions due to neratinib 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 neratinib monotherapy without loperamide prophylaxis, 94.6% experienced at least 1 episode of diarrhoea. Grade 3 diarrhoea was reported in 37.5% of neratinib patients. 0.2% of patients had diarrhoea classified as Grade 4. Diarrhoea led to hospitalisation in 1.9% of neratinib-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 neratinib without loperamide prophylaxis discontinued treatment due to diarrhoea. Dose reductions occurred in 24.7% of neratinib-treated patients.

Rash

In the neratinib 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 neratinib-treated patients experienced Grade 3 rash.

Nail disorders

In the neratinib 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 neratinib treated patients who experienced Grade 3 nail disorder.

Both rash and nail disorders led to treatment discontinuation in 0.6% of neratinib-treated patients.

Hepatotoxicity

Hepatic-associated adverse reactions in the pivotal phase III study, ExteNET (3004), were reported more frequently in the neratinib 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%, neratinib- 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 neratinib- vs placebotreated 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 neratinib- 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 neratinib 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 neratinib arm, the respective percentages were 44.8% compared with 25.2%, respectively.

The incidence of serious adverse reactions in the neratinib 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 neratinib 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 neratinib 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 neratinib 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%).