Nerlynx · 4.5 Interaction with other medicinal products and other forms of interaction · 1

HOS-217125 · has-adverse-reaction-information · PDF-Seite 9

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 System Organ Class Frequency Adverse Drug Reaction Infections and infestations Common Urinary tract infection Metabolism and nutrition Very Common Decreased appetite disorders Common Dehydration Nervous system disorders Common Syncope 9  System Organ Class Frequency Adverse Drug Reaction Respiratory, thoracic and Common Epistaxis mediastinal disorders Diarrhoea, vomiting, nausea, abdominal Very Common pain, abdominal pain upper, and Gastrointestinal disorders stomatitis1 Abdominal distension, dry mouth and Co

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HOS-217121 · has-contraindication-information · PDF-Seite 5

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-gp isoform 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) 5 Severe hepatic impairment (Child-Pugh C) (see section 5.2).

HOS-217120 · has-indication-information · PDF-Seite 2

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.

HOS-217123 · has-interaction-information · PDF-Seite 7

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 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 that increase gastric pH may lower the absorption of neratinib, thus decreasing systemic exposure. Co- 7 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 lo

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HOS-217124 · has-pregnancy-information · PDF-Seite 8

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. 8 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).

HOS-217122 · has-warning-information · PDF-Seite 6

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 intraveinous 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

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