Version May 2024
Note: If not utilizing neratinib dose escalation, administer antidiarrheal prophylaxis during the first 56 days of therapy; initiate with the first neratinib dose (see "Premedications").
Breast cancer, HER2-positive, advanced or metastatic: 240 mg once daily on days 1 to 21 of a 21-day cycle (in combination with capecitabine [on days 1 to 14 only]) until disease progression or unacceptable toxicity (Saura 2020).
Breast cancer, HER 2-positive, early stage, extended adjuvant therapy: Oral: 240 mg once daily (as a single agent) until disease recurrence or for up to 1 year (Chan 2016).
Dose escalation strategy: To improve neratinib tolerability and decrease the rate, severity, and duration of neratinib-induced diarrhea, a dose escalation strategy may be utilized for patients with early stage and metastatic breast cancer (Barcenas 2020). If diarrhea occurs, manage with antidiarrheal medications, fluid, and electrolytes, as clinically indicated; may also require neratinib treatment interruption and dosage reduction.
Week 1 (days 1 to 7): Neratinib 120 mg once daily.
Week 2 (days 8 to 14): Neratinib 160 mg once daily.
Week 3 (day 15 and thereafter): Neratinib 240 mg once daily.
Missed dose: If a dose is missed, resume neratinib with the next scheduled daily dose; do not replace the missed dose.
Premedication (manufacturer's labeling): If not utilizing neratinib dose escalation, administer antidiarrheal prophylaxis during the first 56 days of neratinib therapy (beginning with the first neratinib dose). After day 56, titrate loperamide to achieve 1 to 2 bowel movements/day. Additional antidiarrheal medication, fluids, and electrolytes may be required for loperamide-refractory diarrhea.
Neratinib weeks 1 to 2 (days 1 to 14): Loperamide 4 mg orally 3 times daily.
Neratinib weeks 3 to 8 (days 15 to 56): Loperamide 4 mg orally twice daily.
Neratinib week 9 to neratinib discontinuation: Loperamide 4 mg as needed (maximum: 16 mg/day; titrate loperamide dose to achieve 1 to 2 bowel movements per day).
Note: The addition of budesonide or colestipol to loperamide prophylaxis has also been described to decrease the rate, severity, and duration of neratinib-induced diarrhea (Barcenas 2020):
Budesonide 9 mg orally once daily in the morning for the first 28 days, in addition to loperamide prophylaxis as described above.
Colestipol 2 g orally twice daily for the first 28 days, in addition to loperamide prophylaxis as described above.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling; however, renal function does not have a clinically significant effect on neratinib pharmacokinetics.
Preexisting hepatic impairment:
Mild to moderate (Child-Pugh class A or B) impairment: No initial neratinib dosage adjustment is necessary.
Severe (Child-Pugh class C) impairment: Reduce initial neratinib dose to 80 mg once daily.
Hepatotoxicity during treatment:
ALT or AST >5 to 20 times ULN (grade 3) or bilirubin >3 to 10 times ULN (grade 3): Interrupt neratinib until recovery to ≤ grade 1 (evaluate for alternative hepatotoxic causes); resume neratinib at the next lower dose level (see tables in "Dosage Adjustment for Toxicity") if recovery to ≤ grade 1 occurs within 3 weeks.
Recurrent grade 3 ALT, AST, or bilirubin elevation despite one dose reduction: Permanently discontinue neratinib.
ALT or AST >20 times ULN (grade 4) or bilirubin >10 times ULN (grade 4): Permanently discontinue neratinib and evaluate for alternative hepatotoxic causes.
Discontinue neratinib if adverse reaction does not recover to ≤ grade 1 or baseline, or for toxicities that result in a treatment delay of >3 weeks.
|
Dose level |
Neratinib dose |
|---|---|
|
Recommended starting dose |
240 mg once daily |
|
First dose reduction |
200 mg once daily |
|
Second dose reduction |
160 mg once daily |
|
Third dose reduction |
120 mg once daily |
|
Discontinue if unable to tolerate neratinib 120 mg once daily. | |
|
Dose level |
Neratinib dose |
|---|---|
|
a Capecitabine may also require dose adjustment due to toxicity; refer to Capecitabine monograph for further information. | |
|
Recommended neratinib starting dose |
240 mg once daily |
|
First neratinib dose reduction |
160 mg once daily |
|
Second neratinib dose reduction |
120 mg once daily |
|
Discontinue if unable to tolerate neratinib 120 mg once daily. | |
|
Adverse reaction |
Severity |
Management |
|---|---|---|
|
a Complicated features include dehydration, fever, hypotension, renal failure, or grade 3 or 4 neutropenia. | ||
|
b Despite being treated with optimal medical therapy. | ||
|
Diarrhea |
• Grade 1 diarrhea (increase of <4 stools/day over baseline) • Grade 2 diarrhea (increase of 4 to 6 stools/day over baseline) lasting ≤5 days • Grade 3 diarrhea (increase of ≥7 stools/day over baseline; incontinence; hospitalization indicated; limiting self-care activities of daily living) lasting ≤2 days |
• Adjust antidiarrheal treatment. • Diet modifications. • Maintain fluid intake of ~2 L/day to avoid dehydration. • Once diarrhea improves to ≤ grade 1 or baseline, initiate loperamide 4 mg with each subsequent neratinib dose. |
|
• Any grade diarrhea with complicated featuresa • Grade 2 diarrhea lasting >5 daysb • Grade 3 diarrhea lasting >2 daysb |
• Interrupt neratinib treatment. • Diet modifications. • Maintain fluid intake of ~2 L/day to avoid dehydration. • If diarrhea improves to ≤ grade 1 in 1 week or less, resume neratinib at the same dose. • If diarrhea improves to ≤ grade 1 in longer than 1 week, resume neratinib at the next lower dose level. • Once diarrhea improves to ≤ grade 1 or baseline, initiate loperamide 4 mg with each subsequent neratinib dose. | |
|
• Grade 4 diarrhea (life-threatening consequences; urgent intervention indicated) |
• Permanently discontinue neratinib. | |
|
• Recurrent ≥ grade 2 diarrhea occurring at 120 mg once daily neratinib dose |
• Permanently discontinue neratinib. | |
|
Other adverse reactions |
Grade 3 |
• Interrupt neratinib until recovery to ≤ grade 1 or baseline within 3 weeks of stopping treatment. Upon recovery, resume neratinib at the next lower dose level. |
|
Grade 4 |
• Permanently discontinue neratinib. | |
|
Adverse reaction |
Severity |
Management |
|---|---|---|
|
Diarrhea |
• Grade 1 diarrhea (increase of <4 stools/day over baseline) • Grade 2 diarrhea (increase of 4 to 6 stools/day over baseline) lasting ≤5 days • Grade 3 diarrhea (increase of ≥7 stools/day over baseline; incontinence; hospitalization indicated; limiting self-care activities of daily living) lasting ≤2 days |
• Adjust antidiarrheal treatment. • Continue neratinib and capecitabine at full doses. • Diet modifications. • Maintain fluid intake of ~2 L/day to avoid dehydration. • Once diarrhea improves to ≤ grade 1 or baseline, initiate loperamide 4 mg with each subsequent neratinib dose. |
|
• Persisting and intolerable grade 2 diarrhea lasting >5 days • Grade 3 diarrhea lasting >2 days • Grade 4 diarrhea (life-threatening consequences; urgent intervention indicated) |
• Adjust antidiarrheal treatment. • Hold neratinib and capecitabine until recovery to ≤ grade 1 or baseline. • Diet modifications. • Maintain fluid intake of ~2 L/day to avoid dehydration. • If recovery occurs: 1. ≤1 week after withholding treatment, resume same doses of neratinib and capecitabine. 2. Within 1 to 3 weeks after withholding treatment, reduce neratinib dose to 160 mg, and maintain the same dose of capecitabine. • If event occurs a second time and the neratinib dose has not already been decreased, reduce neratinib dose to 160 mg (maintain the same dose of capecitabine). If neratinib dose has already been reduced, then reduce the dose of capecitabine to ~550 mg/m2 twice daily (maintain the same dose of neratinib). • If subsequent events occur, reduce the dose of neratinib or capecitabine to the next lower dose level in an alternate fashion (ie, reduce capecitabine to ~375 mg/m2 twice daily if neratinib was previously reduced, or reduce neratinib to 120 mg if capecitabine was previously reduced). • Once diarrhea improves to ≤ grade 1 or baseline, initiate loperamide 4 mg with each subsequent neratinib dose. | |
|
Other adverse reactions |
Grade 3 |
• Interrupt neratinib until recovery to ≤ grade 1 or baseline within 3 weeks of stopping treatment. Upon recovery, resume neratinib at the next lower dose level. |
|
Grade 4 |
Permanently discontinue neratinib. |
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Dermatologic: Skin rash (18%)
Gastrointestinal: Abdominal pain (36%; severe abdominal pain: <1%), decreased appetite (12%), diarrhea (95%; severe diarrhea: 2%), nausea (43%; severe nausea: <1%), stomatitis (14%; grade 3: <1%), vomiting (26%; severe vomiting: <1%)
Nervous system: Fatigue (27%; severe fatigue: <1%)
Neuromuscular & skeletal: Muscle spasm (11%)
1% to 10%:
Dermatologic: Nail disease (8%), skin fissure (2%), xeroderma (6%)
Endocrine & metabolic: Dehydration (4%; severe dehydration: <1%), weight loss (5%)
Gastrointestinal: Abdominal distension (5%), dyspepsia (10%), xerostomia (3%)
Genitourinary: Urinary tract infection (5%)
Hepatic: Increased serum alanine aminotransferase (9% to 10%; severely increased serum alanine aminotransferase: <1%), increased serum aspartate aminotransferase (5% to 7%; severely increased serum aspartate aminotransferase: <1%)
Respiratory: Epistaxis (5%)
<1%:
Dermatologic: Cellulitis, erysipelas
Renal: Renal failure syndrome
Frequency not defined: Hepatic: Hepatotoxicity
There are no contraindications listed in the manufacturer's US labeling.
Canadian labeling: Hypersensitivity to neratinib or any component of the formulation.
Concerns related to adverse effects:
• GI toxicity: Severe diarrhea, which may result in dehydration, hypotension, and renal failure, has been observed commonly with neratinib (both as monotherapy and in combination with capecitabine) treatment. The majority of patients receiving neratinib in clinical trials experienced diarrhea; most developed diarrhea during the first month of treatment (antidiarrhea prophylaxis was not required in one trial, although was required during cycle one in another trial). The median time to onset of ≥ grade 3 diarrhea was 8 to 11 days (range: 1 day to 728 days); the median cumulative duration of toxicity was 3 to 5 days (range: 1 day to 139 days). When patients initiated neratinib therapy utilizing a dose escalation strategy, the median time to onset of ≥ grade 3 diarrhea was 45 days (range: 15 to 132 days); the median cumulative duration of toxicity was 2.5 days (range: 1 to 6 days).
• Hepatoxicity: Hepatotoxicity characterized by elevated liver enzymes has been reported with neratinib therapy. ALT and AST elevations have been observed; transaminase elevations and hepatotoxicity have led to treatment discontinuation in some patients.
Disease related concerns:
• Hepatic impairment: Neratinib clearance is reduced and exposure is increased in patients with severe preexisting hepatic impairment.
Special populations:
• Older adult: The incidence of serious adverse reactions and treatment discontinuation was higher in patients ≥65 years of age (compared to patients <65 years of age) in clinical trials. The most commonly reported serious adverse reactions in elderly patients included vomiting, diarrhea, acute kidney injury, renal failure, and dehydration.
Other warnings/precautions:
• Appropriate use: Guidelines from the American Society of Clinical Oncology (ASCO) for selection of optimal adjuvant chemotherapy and targeted therapy in early breast cancer supports the use of extended adjuvant neratinib therapy in patients with early-stage human epidermal growth receptor type 2-positive, hormone receptor-positive, and node-positive breast cancer, with patients beginning neratinib within 1 year of completion of trastuzumab therapy deriving the most benefit (ASCO [Denduluri 2018]).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral, as maleate [strength expressed as base]:
Nerlynx: 40 mg
No
Tablets (Nerlynx Oral)
40 mg (per each): $147.65
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral, as maleate [strength expressed as base]:
Nerlynx: 40 mg
Neratinib is available through select specialty pharmacies. Refer to http://www.nerlynx.com for further information.
Oral: Administer orally with food at approximately the same time each day. Swallow tablets whole; do not crush, chew, or split tablets. Antidiarrheal prophylaxis is recommended during the first 8 weeks (if not utilizing neratinib dose escalation). Maintain adequate hydration.
This medication is not on the NIOSH (2016) list; however, it may meet the criteria for a hazardous drug. Neratinib may cause teratogenicity, reproductive toxicity, and has a structural or toxicity profile similar to existing hazardous agents.
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.
An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208051s002lbl.pdf#page=19, must be dispensed with this medication.
Breast cancer:
Extended adjuvant treatment (as a single agent) of early-stage HER2-positive breast cancer in adults (following adjuvant trastuzumab-based therapy).
Treatment of advanced or metastatic HER2-positive breast cancer (in combination with capecitabine) in adults who have received 2 or more prior anti-HER2 based regimens in the metastatic setting.
Neratinib may be confused with afatinib, binimetinib, ceritinib, dasatinib, enasidenib, erlotinib, imatinib, lapatinib, lenvatinib, nilotinib, nintedanib, niraparib, ponatinib, regorafenib, SUNItinib, vandetanib.
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.
Substrate of CYP3A4 (major), P-glycoprotein/ABCB1 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits P-glycoprotein/ABCB1
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Afatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: If combined, administer the P-gp inhibitor simultaneously with, or after, the dose of afatinib. Monitor closely for signs and symptoms of afatinib toxicity and if the combination is not tolerated, reduce the afatinib dose by 10 mg. Risk D: Consider therapy modification
Aliskiren: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Aliskiren. Risk C: Monitor therapy
Antacids: May decrease the serum concentration of Neratinib. Specifically, antacids may reduce neratinib absorption. Management: Separate the administration of neratinib and antacids by giving neratinib at least 3 hours after the antacid. Risk D: Consider therapy modification
Berotralstat: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Berotralstat. Management: Decrease the berotralstat dose to 110 mg daily when combined with P-glycoprotein (P-gp) inhibitors. Risk D: Consider therapy modification
Bilastine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bilastine. Risk X: Avoid combination
Celiprolol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Celiprolol. Risk C: Monitor therapy
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
Colchicine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Colchicine. Colchicine distribution into certain tissues (e.g., brain) may also be increased. Management: This combination is often contraindicated, but combined use may be permitted with dose adjustment and monitoring. Recommendations vary based on brand, indication, use of CYP3A4 inhibitors, and hepatic/renal function. See interaction monograph for details. Risk D: Consider therapy modification
CycloSPORINE (Systemic): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Neratinib. Risk X: Avoid combination
CYP3A4 Inducers (Strong): May decrease the serum concentration of Neratinib. Risk X: Avoid combination
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Neratinib. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Neratinib. Risk X: Avoid combination
Dabigatran Etexilate: P-glycoprotein/ABCB1 Inhibitors may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Risk C: Monitor therapy
Digoxin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Digoxin. Management: Measure digoxin serum concentrations before initiating treatment with these P-glycoprotein (P-gp) inhibitors. Reduce digoxin concentrations by either reducing the digoxin dose by 15% to 30% or by modifying the dosing frequency. Risk D: Consider therapy modification
DOXOrubicin (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Conventional). Risk X: Avoid combination
DOXOrubicin (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Liposomal). Risk C: Monitor therapy
Edoxaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban. Risk C: Monitor therapy
Etoposide: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Etoposide. Risk C: Monitor therapy
Etoposide Phosphate: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Etoposide Phosphate. Risk C: Monitor therapy
Everolimus: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Everolimus. Risk C: Monitor therapy
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Glecaprevir and Pibrentasvir: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Glecaprevir and Pibrentasvir. Risk C: Monitor therapy
Histamine H2 Receptor Antagonists: May decrease the serum concentration of Neratinib. Specifically, histamine H2 receptor antagonists may reduce neratinib absorption. Management: Administer neratinib at least 2 hours before or 10 hours after administration of a histamine H2 receptor antagonist to minimize the impact of this interaction. Risk D: Consider therapy modification
Inhibitors of CYP3A4 (Moderate) and P-glycoprotein: May increase the serum concentration of Neratinib. Risk X: Avoid combination
Inhibitors of the Proton Pump (PPIs and PCABs): May decrease the serum concentration of Neratinib. Specifically, proton pump inhibitors may reduce neratinib absorption. Risk X: Avoid combination
Lapatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Lapatinib. Risk C: Monitor therapy
Larotrectinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Larotrectinib. Risk C: Monitor therapy
Lefamulin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Lefamulin. Management: Avoid concomitant use of lefamulin tablets with P-glycoprotein/ABCB1 inhibitors. If concomitant use is required, monitor for lefamulin adverse effects. Risk D: Consider therapy modification
Morphine (Systemic): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Morphine (Systemic). Risk C: Monitor therapy
Nadolol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Nadolol. Risk C: Monitor therapy
Naldemedine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naldemedine. Risk C: Monitor therapy
Naloxegol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naloxegol. Risk C: Monitor therapy
PAZOPanib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of PAZOPanib. Risk X: Avoid combination
Pralsetinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Pralsetinib. Management: If this combo cannot be avoided, decrease pralsetinib dose from 400 mg daily to 300 mg daily; from 300 mg daily to 200 mg daily; and from 200 mg daily to 100 mg daily. Risk D: Consider therapy modification
Ranolazine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ranolazine. Risk C: Monitor therapy
Relugolix: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Relugolix. Management: Avoid coadministration of relugolix with oral P-gp inhibitors whenever possible. If combined, take relugolix at least 6 hours prior to the P-gp inhibitor and monitor patients more frequently for adverse reactions. Risk D: Consider therapy modification
Relugolix, Estradiol, and Norethindrone: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Relugolix, Estradiol, and Norethindrone. Management: Avoid use of relugolix/estradiol/norethindrone with P-glycoprotein (P-gp) inhibitors. If concomitant use is unavoidable, relugolix/estradiol/norethindrone should be administered at least 6 hours before the P-gp inhibitor. Risk D: Consider therapy modification
Repotrectinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Repotrectinib. Risk X: Avoid combination
RifAXIMin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RifAXIMin. Risk C: Monitor therapy
Rimegepant: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Rimegepant. Management: Avoid administration of another dose of rimegepant within 48 hours if given concomitantly with a P-glycoprotein (P-gp) inhibitor. Risk D: Consider therapy modification
RisperiDONE: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RisperiDONE. Risk C: Monitor therapy
RomiDEPsin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RomiDEPsin. Risk C: Monitor therapy
Silodosin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Silodosin. Risk C: Monitor therapy
Sirolimus (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Sirolimus (Conventional). Management: Avoid concurrent use of sirolimus with P-glycoprotein (P-gp) inhibitors when possible and alternative agents with lesser interaction potential with sirolimus should be considered. Monitor for increased sirolimus concentrations/toxicity if combined. Risk D: Consider therapy modification
Sirolimus (Protein Bound): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Sirolimus (Protein Bound). Risk X: Avoid combination
Tacrolimus (Systemic): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
Talazoparib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Talazoparib. Risk C: Monitor therapy
Tegaserod (Withdrawn from US Market): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Tegaserod (Withdrawn from US Market). Risk C: Monitor therapy
Teniposide: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Teniposide. Risk C: Monitor therapy
Tenofovir Disoproxil Fumarate: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Tenofovir Disoproxil Fumarate. Risk C: Monitor therapy
Topotecan: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Topotecan. Risk X: Avoid combination
Ubrogepant: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ubrogepant. Management: Use an initial ubrogepant dose of 50 mg and second dose (at least 2 hours later if needed) of 50 mg when used with a P-gp inhibitor. Risk D: Consider therapy modification
Venetoclax: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring concomitant treatment with P-glycoprotein (P-gp) inhibitors. Resume the previous venetoclax dose 2 to 3 days after discontinuation of a P-gp inhibitor. Risk D: Consider therapy modification
VinCRIStine (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of VinCRIStine (Liposomal). Risk X: Avoid combination
A high-fat meal (~55% fat, 31% carbohydrate, and 14% protein) increases neratinib Cmax and AUCinf by 70% and 120%, respectively. A standard breakfast (~50% carbohydrate, 35% fat, and 15% protein) increased neratinib Cmax by 20% and AUCinf by 10%. Management: Administer with food.
Grapefruit juice may increase neratinib exposure. Management: Avoid grapefruit juice.
Patients who can become pregnant should have a pregnancy test prior to treatment; effective contraception should be used during therapy and for at least 1 month after the last neratinib dose.
Patients with partners who can become pregnant should also use effective contraception during therapy and for 3 months after the last neratinib dose.
Based on the mechanism of action and data from animal reproduction studies, use of neratinib in pregnancy may cause fetal harm.
It is not known if neratinib is present in breast milk.
According to the manufacturer, breastfeeding is not recommended during therapy or for at least 1 month after the last neratinib dose.
Monitor LFTs (ALT, AST, bilirubin, and alkaline phosphatase) prior to treatment initiation, monthly for the first 3 months, then every 3 months thereafter or as clinically indicated; fractionated bilirubin and prothrombin time if clinically necessary. Also assess LFTs in patients with ≥ grade 3 diarrhea requiring IV fluids or in those with signs/symptoms of hepatotoxicity (worsening fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or eosinophilia). Evaluate pregnancy status prior to therapy initiation (in patients who can become pregnant). Monitor closely for diarrhea (and subsequent complications); stool cultures may be needed to exclude infectious etiologies for diarrhea. Monitor for signs/symptoms of dehydration and hepatotoxicity. Monitor adherence.
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
Cardiovascular monitoring: Comprehensive assessment prior to treatment including a history and physical examination, screening for cardiovascular disease risk factors such as hypertension, diabetes, dyslipidemia, obesity, and smoking (ASCO [Armenian 2017]; ESC [Lyon 2022]).
Neratinib is an irreversible tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and HER4 (Chan 2016). Neratinib reduces EGFR and HER2 autophosphorylation and downstream MAPK and AKT signaling pathways and demonstrates antitumor activity in EGFR and/or HER2 expressing cancer cell lines.
Distribution: Vss/F: 6,433 L.
Protein binding: >99% to serum albumin and alpha-1 acid glycoprotein.
Metabolism: Primarily hepatic via CYP3A4 (major) and flavin-containing monooxygenase (minor) to active metabolites M3, M6, M7, and M11.
Half-life elimination: 7 to 17 hours.
Time to peak: 2 to 8 hours (parent drug and active metabolites M3, M6, and M7).
Excretion: Feces (~97%); urine (~1%).
Clearance: 216 L/hour (following a single dose); 281 L/hour (at steady state).
Hepatic function impairment: Neratinib Cmax and AUC were increased by 173% and 181%, respectively, in patients with severe (Child-Pugh class C) hepatic impairment compared to subjects with normal hepatic function.
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