Nerlynx

Nerlynx

Manufacturer:

CANbridge

Distributor:

DKSH
Full Prescribing Info
Contents
Neratinib.
Description
Each film-coated tablet contains neratinib maleate, equivalent to 40 mg neratinib.
Excipients/Inactive Ingredients: Tablet core: Mannitol (E421), Microcrystalline cellulose, Crospovidone, Povidone, Colloidal anhydrous silica, Magnesium stearate.
Tablet coating: Polyvinyl alcohol, Titanium dioxide (E171), Macrogol, Talc, Iron oxide red (E172).
Action
Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, protein kinase inhibitors. ATC code: L01XE45.
Pharmacology: Pharmacodynamics: Mechanism of action: 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 signaling 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.
Clinical efficacy and safety: In the multicentre, randomised, double-blind, placebo-controlled, pivotal phase III study, ExteNET (3004), 2,840 women with early-stage HER2-positive breast cancer (as confirmed locally by assay) who had completed adjuvant treatment with trastuzumab were randomised 1:1 to receive either Nerlynx or placebo daily for one year. The median age in the intention-to-treat (ITT) population was 52.3 years (59.9% was ≥50 years old, 12.3% was ≥65 years old); 81.0% were Caucasian, 2.6% black or African American, 13.6% Asian and 2.9% other. At baseline, 57.4% had hormone receptor positive disease (defined as ER-positive and/or PgR-positive), 23.6% were node negative, 46.8% had one to three positive nodes and 29.6% had four or more positive nodes. Approximately 10% of patients had Stage I tumours, approximately 40% had Stage II tumours and approximately 30% had Stage III tumours. Median time from the last adjuvant trastuzumab treatment to randomization was 4.5 months.
The primary endpoint of the study was invasive disease-free survival (iDFS). Secondary endpoints of the study included disease-free survival (DFS) including ductal carcinoma in situ (DFS-DCIS), time to distant recurrence (TTDR), distant disease-free survival (DDFS), cumulative incidence of central nervous system recurrence and overall survival (OS).
The primary analysis of the study after 2 years post-randomization demonstrated that Nerlynx significantly reduced the risk of invasive disease recurrence or death by 34% (HR=0.66 with 95% CI (0.49, 0.90), two-sided p = 0.008) in the ITT population. (See Table 1 and Figure 1.)

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Approximately 75% of patients were re-consented for extended follow-up beyond 24 months. Observations with missing data were censored at the last date of assessment. While the treatment benefit of Nerlynx over placebo was maintained at five years, the effect size cannot be reliably estimated.
In patients that were hormone receptor negative, regardless of time from trastuzumab therapy, the hazard ratio for iDFS at 2 years was 0.93, with 95% CI (0.60, 1.43). In this population, efficacy has not been demonstrated.
For hormone receptor positive patients, the relative treatment benefit of Nerlynx within pre-specified patient subgroups is presented in Figure 2. (See Figure 2.)

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Paediatric population: The European Medicines Agency has waived the obligation to submit the results of studies in all subsets of the paediatric population in the treatment of breast carcinoma.
Pharmacokinetics: The mass balance after administration of a single oral dose of 200 mg of neratinib was studied in six healthy subjects.
Absorption: Following oral administration of 240 mg neratinib, absorption was slow and peak plasma concentrations of neratinib occurred around 7 hours after administration. A single dose of 240 mg neratinib taken with food increased Cmax and AUC by approximately 17% and 23%, respectively, compared with administration in the fasting state. A single oral dose of 240 mg neratinib taken with a meal high in fat increased both Cmax and AUC by approximately 100%.
Distribution: Binding of neratinib to human plasma proteins, including covalent binding to human serum albumin (HSA), was greater than 98% and independent of concentration. Neratinib bound predominantly to HSA and human alpha-1 acid glycoprotein (AAG). In vitro studies demonstrated that neratinib is a substrate for P-glycoprotein (P-gp). Neratinib was not a potent inhibitor of human BSEP efflux transporter activity in vitro, with a reported IC50 value of > 10μM. Neratinib at 10 μM appeared to inhibit the BCRP efflux transporter. Neratinib produced no inhibitory activity towards the uptake transporters, OATP1B1*1a, OATP1B3, OAT1, OAT3 and OCT2, with reported IC50 values were > 10μM. Neratinib produced inhibitory activity in OCT1 uptake transporter, with an IC50 of 2.9 μM.
Biotransformation: Neratinib is metabolised primarily in liver microsomes by CYP3A4 and to a lesser extent by flavin-containing monooxygenase (FMO).
Preliminary metabolite profiling in human plasma indicates that after oral administration, neratinib undergoes oxidative metabolism through CYP3A4. Circulating metabolites include neratinib pyridine N-oxide (M3), N-desmethyl neratinib (M6), neratinib dimethylamine N-oxide (M7) and traces of hydroxyl neratinib N-oxide and neratinib bis-N-oxide (M11). Neratinib represents the most prominent component in plasma and systemic exposure to the metabolites (M3, M6, M7 and M11) after oral administration of neratinib is between 10% and 33% lower than parent in healthy subjects. The neratinib metabolites M3, M6, M7 and M11 were shown to have similar potencies to neratinib in either in vitro enzyme (binding assays) or cell based assays against cells expressing ERBB1, ERBB2 (HER2) and ERBB4.
Elimination: Following single doses of neratinib, the mean apparent plasma half-life of neratinib was 17 hours in patients.
Excretion of neratinib is primary via the faeces: Following the administration of a single radiolabelled dose of 200 mg neratinib oral solution, 97.1% and 1.1% of the administered dose was recovered in the faeces and urine, respectively. The excretion was rapid and complete, with the majority of the radioactivity (61%) recovered within 96 hours and 98% recovered after 10 days. It is not known if elimination is as unchanged drug or metabolites.
Pharmacokinetic/pharmacodynamic relationship(s): Renal impairment: Pharmacokinetic studies in patients with renal impairment or undergoing dialysis have not been carried out. Population pharmacokinetic modelling revealed that creatinine clearance did not explain the variability between patients, hence, no dose modifications are recommended for patients with mild to moderate renal impairment.
Hepatic impairment: Neratinib is extensively metabolised in the liver. In subjects with severe pre-existing hepatic impairment (Child Pugh Class C) without cancer, the clearance of neratinib was decreased by 36% and exposure to neratinib increased by about 3-fold as compared to healthy volunteers.
Toxicology: Preclinical safety data: Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were as follows: Carcinogenesis, mutagenesis: Nerlynx was neither clastogenic nor mutagenic in the standard battery of genotoxicity studies.
Neratinib metabolites M3, M6, M7 and M11 are negative in the standard battery of in vitro genotoxicity studies.
A 6-month carcinogenicity study in Tg.rasH2 transgenic mice and the rat 2-year data showed no signs of carcinogenic potential.
Reproductive toxicity: In rabbits, there were no effects on mating or the ability of animals to become pregnant, but embryo-foetal lethality and foetal morphologic anomalies (e.g. domed head, dilation of brain ventricles and misshapen anterior fontanelles and enlarged anterior and/or posterior fontanelles) were observed at doses that may be considered to be clinically relevant.
Indications/Uses
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.
Dosage/Direction for Use
Nerlynx treatment should be initiated and supervised by a physician experienced in the administration of anti-cancer medicinal products.
Posology: The recommended dose of Nerlynx is 240 mg (six 40 mg tablets) taken orally once daily, continuously for one year. Nerlynx should be taken with food, preferably in the morning. Patients should initiate treatment within 1 year after completion of trastuzumab therapy.
Dose modifications for adverse reactions: Nerlynx dose modification is recommended based on individual safety and tolerability. Management of some adverse reactions may require dose interruption and/or dose reduction as shown in Table 2, Table 3, Table 4, and Table 5.
Discontinue Nerlynx 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.). (See Tables 2 and 3.)

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Dose modifications for diarrhoea: Diarrhoea management requires the correct use of an anti-diarrhoeal medicinal product, dietary changes, and appropriate dose modifications of Nerlynx. Guidelines for adjusting doses of Nerlynx in the setting of diarrhoea are shown in Table 4. (See Table 4.)

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Missed dose: Missed doses should not be replaced and treatment should resume with the next scheduled daily dose (see Overdosage).
Use of CYP3A4/Pgp inhibitors: If the inhibitor cannot be avoided, reduce Nerlynx dose to 40 mg (one 40 mg tablet) taken once daily with a strong CYP3A4/Pgp inhibitor. After discontinuation of a strong CYP3A4/Pgp inhibitor, resume previous dose of Nerlynx 240 mg (see Precautions and Interactions).
Patients with renal impairment: No dose adjustment is necessary in patients with mild to moderate renal impairment. Nerlynx 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 (see Pharmacology: Pharmacokinetics under Actions).
Patients with hepatic impairment: No dose adjustment is required in patients with Child Pugh A or B (mild to moderate) hepatic impairment. Treatment of patients with Child Pugh C hepatic impairment is not recommended (see Pharmacology: Pharmacokinetics under Actions).
Dose modifications for hepatotoxicity: Guidelines for dose adjustment of Nerlynx in the event of liver toxicity are shown in Table 5. (See Precautions.) (See Table 5.)

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Elderly: No dose adjustment is required. There is no data in patients ≥85 years of age.
Paediatric population: There is no relevant use of Nerlynx in the paediatric population in the indication breast cancer.
Method of administration: Nerlynx 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 (see Pharmacology: Pharmacokinetics under Actions).
Overdosage
There is no specific antidote, and the benefit of haemodialysis in the treatment of Nerlynx overdose is unknown. In the event of an overdose, administration should be withheld and general supportive measures undertaken.
In the clinical trial setting, adverse reactions associated with overdose were most commonly diarrhoea, with or without nausea, vomiting and dehydration.
In a dose escalation study in healthy volunteers, single oral doses of Nerlynx up to 800 mg were administered. The frequency and severity of gastrointestinal disorders (diarrhoea, abdominal pain, nausea and vomiting) appeared to be dose-related. Single doses of Nerlynx greater than 800 mg have not been administered in the clinical studies.
Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in Description.
Co-administration with the following medical products that are strong inducers of the CYP3A4/Pgp isoform of cytochrome P450: carbamazepine, phenobarbital, phenytoin (antiepileptics); St John's wort (Hypericum perforatum) (herbal product); rifampicin (antimycobacterial).
Co-administration with moderate CYP3A4/P-gp inhibitors: fluconazole (antifungal); diltiazem, verapamil (calcium-channel blockers); erythromycin (antibiotic).
Severe hepatic impairment (Child-Pugh C).
Special Precautions
Diarrhoea: Diarrhoea has been reported during treatment with Nerlynx (see Dosage & Administration and Adverse Reactions). 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.
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 Dosage & Administration).
Hepatic impairment: In patients with severe hepatic impairment (Child-Pugh C) there is a 2.8-fold increase of exposure to neratinib (see Pharmacology: Pharmacokinetics under Actions).
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 Dosage & Administration).
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. 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: Co-administration with proton pump inhibitors (PPIs) and H2-receptor antagonists are not recommended. If an antacid is taken, separate the dosing of Nerlynx and the antacid by at least 3 hours.
Skin and subcutaneous tissue disorders: Nerlynx is associated with skin and subcutaneous tissue disorders. Patients with symptomatic skin and subcutaneous tissue disorders should be carefully monitored (see Adverse Reactions).
Concomitant treatment with inhibitors of CYP3A4 and P-gp: Concomitant treatment with strong CYP3A4 and P-gp inhibitors should be avoided due to risk of increased exposure to neratinib (see Dosage & Administration and Interactions).
Grapefruit juice should be avoided during treatment with Nerlynx (see Interactions).
Effects on ability to drive and use machines: Nerlynx 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.
Use in 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.
Use in Pregnancy: Neratinib may cause foetal harm when administered to pregnant women (see Use in Pregnancy & Lactation).
Use In Pregnancy & Lactation
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 Pharmacology: Toxicology: Preclinical safety data under Actions). 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.
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 Pharmacology: Toxicology: Preclinical safety data under Actions).
Adverse Reactions
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 following table 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. (See Table 6.)

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Description of selected adverse reactions: Diarrhoea: 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.
Rash: 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.
Nail disorders: 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.
Hepatotoxicity: 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 placebo-treated 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.
Other special populations: Elderly: In the pivotal phase III study, ExteNET (3004), the mean age was 52 years in the Nerlynx arm, 1236 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.
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 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 1710 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 of suspected adverse reactions: 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.
Drug Interactions
Effects of other substances on neratinib: CYP3A4/Pgp inhibitors: Co-administration of a single oral dose of 240 mg of neratinib in the presence of ketoconazole (400 mg once daily for 5 days), a strong CYP3A4/Pgp inhibitor, increased neratinib systemic exposure. The Cmax of neratinib increased by 3.2 fold and AUC increased by 4.8 fold when co-administered with ketoconazole, compared with neratinib administered alone.
Concomitant use of strong CYP3A4/Pgp inhibitors (e.g. atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, ketoconazole, itraconazole, clarithromycin, telithromycin, and voriconazole) should be avoided. Grapefruit or grapefruit juice may also increase neratinib plasma concentrations and should be avoided.
Proton pump inhibitors, H2-receptor antagonists and antacids: The solubility of neratinib is pH-dependent. Concomitant treatment with substances that increase gastric pH should be avoided, as neratinib solubility and absorption may decrease. A single 240 mg dose of neratinib combined with lansoprazole decreased AUC by up to 70%. Co-administration with proton pump inhibitors (PPIs) and H2-receptor antagonists is not recommended. Separate dosing of Nerlynx and antacids by at least 3 hours.
CYP3A4/Pgp inducers: Following concomitant administration with repeated doses of 600 mg rifampicin, a strong CYP3A4/Pgp inducer, neratinib exposures were significantly decreased with mean values that were 24% and 13% of reference values (neratinib administered alone) for Cmax and AUC, respectively.
Concurrent use of neratinib with potent CYP3A4/Pgp inducers (e.g. phenytoin, carbamazepine, rifampicin, phenobarbital or herbal preparations containing St John's Wort/Hypericum perforatum) should be avoided.
Effects of neratinib on other substances: Hormonal contraceptives: 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 Use in Pregnancy & Lactation).
Breast cancer resistance protein inhibitors: Neratinib may inhibit breast cancer resistance protein (BCRP) moderately as suggested by in vitro studies. Clinical studies with BCRP substrates have not been conducted. Patients who are treated with BCRP inhibitors (e.g., rosuvastatin and sulfasalazine) should be monitored carefully.
P-glycoprotein transporters: In in-vitro studies, neratinib is an inhibitor of P-glycoprotein (P-gp) substrates. In healthy subjects, digoxin increased Cmax by 54% and AUC increased by 32% when co-administered with multiple oral doses of neratinib 240 mg compared with exposures of digoxin alone. The clearance values of digoxin were equivalent following digoxin and digoxin plus neratinib. It appeared that the inhibitory effect of neratinib was primarily on P-gp activity in the gastrointestinal tract as a result of pre-systemic inhibition. This pre-systemic interaction of neratinib with digoxin might be clinically relevant for P-gp substrates with a narrow therapeutic window (e.g. dabigatran, digoxin, and fexofenadine). Patients who are treated concomitantly with therapeutic agents whose metabolism involves P-gp substrates in the gastrointestinal tract should be monitored carefully.
Caution For Usage
Special precautions for disposal: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Incompatibilities: Not applicable.
Storage
Storage under 25°C.
Keep the bottle tightly closed in order to protect from moisture.
Shelf life: 24 months.
ATC Classification
L01EH02 - neratinib ; Belongs to the class of human epidermal growth factor receptor 2 (HER2) tyrosine kinase inhibitors. Used in the treatment of cancer.
Presentation/Packing
Tab 40 mg (oval, red, with 'W104' debossed on one side, dimensions are 10.5 mm x 4.3 mm with thickness of 3.1 mm) x 180's.
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