Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: PIERRE FABRE MEDICAMENT, Les Cauquillous, 81500 Lavaur, France
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):
Severe hepatic impairment (Child-Pugh C) (see section 5.2).
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 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 with diarrhoea as a major symptom were not included in the pivotal study, and should be carefully monitored.
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).
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 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.
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).
Neratinib may cause foetal harm when administered to pregnant women (see section 4.6).
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 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 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 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).
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).
Neratinib is primarily metabolized by CYP3A4 and is a P-gp substrate.
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).
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).
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).
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).
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).
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).
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).
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.
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.
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.
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.
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%).
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 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, and stomatitis1 |
| Common | Abdominal distension, dry mouth and dyspepsia | |
| Hepatobiliary disorders | Common | Alanine aminotransferase increased, and aspartate aminotransferase increased |
| Uncommon | Blood bilirubin increased | |
| Skin and subcutaneous tissue disorders | Very Common | Rash2 |
| Common | Nail disorder3, skin fissures and dry skin | |
| Musculoskeletal and connective tissue disorders | Very Common | Muscle spasms |
| Renal and urinary disorders | Common | Blood creatinine increased |
| Uncommon | Renal failure | |
| General disorders and administration site conditions | Very common | Fatigue |
| Investigations | Common | Weight decreased |
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.
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.
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.
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.
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 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 Nerlynx- vs placebo-treated patients. There was no Grade 3 or 4 adverse reactions of blood bilirubin increased.
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.
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 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 listed in Appendix V.
Not applicable.
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