Neratinib
Looking up MedlinePlus…
From MedlinePlus, U.S. National Library of Medicine
Dosing in kidney impairment
Advise patients of potential risk to a fetus and to use effective contraception. ( 5.3 , 8.1 , 8.3 ) 5.1 Diarrhea Severe diarrhea and sequelae, such as dehydration, hypotension, and renal failure occurred during treatment with NERLYNX. Diarrhea was reported in 95% of NERLYNX-treated patients in ExteNET, a randomized placebo-controlled trial in the extended adjuvant setting who were not required to receive antidiarrheal prophylaxis.
| Adverse Reaction | Severity† | Action/Dose Modification |
|---|---|---|
| ALT=Alanine Aminotransferase; AST=Aspartate Aminotransferase; ULN=Upper Limit Normal | ||
| † Per CTCAE v4.0 | ||
| * Complicated features include dehydration, fever, hypotension, renal failure, or Grade 3 or 4 neutropenia. | ||
| ‡ Despite being treated with optimal medical therapy | ||
| Diarrhea [see Warnings and Precautions ( 5.1)] | Grade 1 diarrhea [increase of <4 stools per day over baseline]Grade 2 diarrhea [increase of 4–6 stools per day over baseline] lasting ≤5 daysGrade 3 diarrhea [increase of ≥7 stools per day over baseline; incontinence; hospitalization indicated; limiting self-care activities of daily living] lasting ≤2 days | Adjust antidiarrheal treatmentDiet modificationsFluid intake of ~2 L/day should be maintained to avoid dehydrationOnce event resolves to ≤Grade 1 or baseline, start loperamide 4 mg with each subsequent NERLYNX administration |
| Any grade with complicated features*Grade 2 diarrhea lasting longer than 5 days ‡Grade 3 diarrhea lasting longer than 2 days ‡ | Interrupt NERLYNX treatmentDiet modificationsFluid intake of ~2 L/day should be maintained to avoid dehydrationIf diarrhea resolves to ≤Grade 1 in one week or less, then resume NERLYNX treatment at the same doseIf diarrhea resolves to ≤Grade 1 in longer than one week, then resume NERLYNX treatment at reduced dose (see Table 3) Once event resolves to ≤Grade 1 or baseline, start loperamide 4 mg with each subsequent NERLYNX administration | |
| Grade 4 diarrhea [life-threatening consequences; urgent intervention indicated] | Permanently discontinue NERLYNX treatment | |
| Diarrhea recurs to Grade 2 or higher at 120 mg per day | Permanently discontinue NERLYNX treatment | |
| Hepatotoxicity [see Warnings and Precautions ( 5.2)] | Grade 3 ALT or AST (>5–20× ULN) OR Grade 3 bilirubin (>3–10× ULN) | Hold NERLYNX until recovery to ≤Grade 1Evaluate alternative causesResume NERLYNX at the next lower dose level if recovery to ≤Grade 1 occurs within 3 weeks. If Grade 3 ALT or AST, or bilirubin occurs again despite one dose reduction, permanently discontinue NERLYNX. |
| Grade 4 ALT or AST (>20× ULN) OR Grade 4 bilirubin (>10× ULN) | Permanently discontinue NERLYNXEvaluate alternative causes | |
| Other [see Adverse Reactions ( 6.1)] | Grade 3 | Hold NERLYNX until recovery to ≤Grade 1 or baseline within 3 weeks of stopping treatment. Then resume NERLYNX at the next lower dose level. |
| Grade 4 | Discontinue NERLYNX permanently | |
Dosing in liver impairment
Dosage Modifications for Hepatic Impairment Reduce the NERLYNX starting dose to 80 mg in patients with severe hepatic impairment (Child Pugh C). No dose modifications are recommended for patients with mild to moderate hepatic impairment (Child Pugh A or B) [see Use in Specific Populations and Clinical Pharmacology] .
Preparation and administration
Premedication for Diarrhea When not using dose escalation [see Dosage and Administration], administer antidiarrheal prophylaxis during the first 56 days of treatment and initiate with the first dose of NERLYNX [see Warnings and Precautions and Adverse Reactions] . Instruct patients to take loperamide as directed in Table 1 .
Titrate loperamide to 1–2 bowel movements per day. [See table below.] If diarrhea occurs despite prophylaxis, treat with additional antidiarrheals, fluids and electrolytes as clinically indicated. NERLYNX dose interruptions and dose reductions may also be required to manage diarrhea [see Dosage and Administration] .
Drug interactions
Check neratinib against a medication listLabel text (5 paragraphs)
Gastric acid reducing agents: Avoid concomitant use with proton pump inhibitors. Separate NERLYNX by at least 2 hours before or 10 hours after H 2 -receptor antagonists. Or separate NERLYNX by at least 3 hours after antacids. ( 2.5 , 7.1 ) Strong CYP3A4 inhibitors: Avoid concomitant use. ( 7.1 ) P-gp and moderate CYP3A4 dual inhibitors: Avoid concomitant use. ( 7.1 ) Strong or moderate CYP3A4 inducers: Avoid concomitant use. ( 7.1 ) Certain P-gp substrates: Monitor for adverse reactions of P-gp substrates for which minimal concentration change may lead to serious adverse reactions when used concomitantly with NERLYNX. ( 7.2 )
7.1 Effect of Other Drugs on NERLYNX Table 10 includes drug interactions that affect the pharmacokinetics of neratinib. Table 10: Drug Interactions that Affect NERLYNX AUC=Area Under Curve; C max =Maximum Concentration Gastric Acid Reducing Agents Clinical Impact Concomitant use of NERLYNX with a proton pump inhibitor (PPI), H 2 -receptor antagonist, or antacid may decrease neratinib AUC [see Clinical Pharmacology ( 12.3 )], which may reduce NERLYNX activity. Prevention or Management [see Dosage and Administration ( 2.5 )] Avoid concomitant use of PPIs. Separate administration of NERLYNX at least 2 hours before or 10 hours after the H 2 -receptor antagonist dose.
Separate administration of NERLYNX by at least 3 hours after antacids. Strong CYP3A4 Inhibitors Clinical Impact Concomitant use of NERLYNX with a strong CYP3A4 inhibitor increased neratinib C max and AUC [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of NERLYNX toxicity. Prevention or Management Avoid concomitant use of NERLYNX with strong CYP3A4 inhibitors. P-gp and Moderate CYP3A4 Dual Inhibitors Clinical Impact Concomitant use of NERLYNX with a P-gp and moderate CYP3A4 dual inhibitor may increase neratinib C max and AUC [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of NERLYNX toxicity.
Prevention or Management Avoid concomitant use of NERLYNX with P-gp and moderate CYP3A4 dual inhibitors. Strong or Moderate CYP3A4 Inducers Clinical Impact Concomitant use of NERLYNX with a strong CYP3A4 inducer reduced neratinib C max and AUC [see Clinical Pharmacology ( 12.3 )] , which may reduce NERLYNX activity. Prevention or Management Avoid concomitant use of NERLYNX with strong or moderate CYP3A4 inducers.
7.2 Effect of NERLYNX on Other Drugs Certain P-glycoprotein (P-gp) Substrates Concomitant use of NERLYNX increased concentrations of a P-gp substrate [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of adverse reactions of these substrates. Monitor for adverse reactions of certain P-gp substrates for which minimal concentration changes may lead to serious adverse reactions.
Contraindications
None. None. ( 4 )
Pregnancy and lactation
Pregnancy
8.1 Pregnancy Risk Summary Based on findings from animal studies and the mechanism of action, NERLYNX can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1 )] . There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of neratinib to pregnant rabbits during organogenesis resulted in abortions, embryo-fetal death and fetal abnormalities in rabbits at maternal exposures (AUC) approximately 0.2 times exposures in patients at the recommended dose ( see Data ). Advise pregnant women of the potential risk to a fetus.
The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk of major birth defects is 2%–4% and of miscarriage is 15%–20% of clinically recognized pregnancies in the U.S. general population. Data Animal Data In a fertility and early embryonic development study in female rats, neratinib was administered orally for 15 days before mating to Day 7 of pregnancy, which did not cause embryonic toxicity at doses up to 12 mg/kg/day in the presence of maternal toxicity. A dose of 12 mg/kg/day in rats is approximately 0.5 times the maximum recommended dose of 240 mg/day in patients on a mg/m 2 basis.
In an embryo-fetal development study in rats, pregnant animals received oral doses of neratinib up to 15 mg/kg/day during the period of organogenesis. No effects on embryo-fetal development or survival were observed. Maternal toxicity was evident at 15 mg/kg/day (approximately 0.6 times the AUC in patients receiving the maximum recommended dose of 240 mg/day). In an embryo-fetal development study in rabbits, pregnant animals received oral doses of neratinib up to 9 mg/kg/day during the period of organogenesis. Administration of neratinib at doses ≥6 mg/kg/day resulted in maternal toxicity, abortions, and embryo-fetal death (increased resorptions).
Neratinib administration resulted in increased incidence of fetal gross external (domed head), soft tissue (dilation of the brain ventricles and ventricular septal defect), and skeletal (misshapen anterior fontanelles and enlarged anterior and/or posterior fontanelles) abnormalities at ≥3 mg/kg/day. The AUC (0-t) at 6 mg/kg/day and 9 mg/kg/day in rabbits were approximately 0.5 and 0.8 times, respectively, the AUCs in patients receiving the maximum recommended dose of 240 mg/day. In a peri- and postnatal development study in rats, oral administration of neratinib from gestation day 7 until lactation day 20 resulted in maternal toxicity at ≥10…
For breastfeeding, also see LactMed (National Library of Medicine), which summarizes milk levels and infant effects.
Supply and cost
Drug shortage status
Recalls (last 24 months)
Therapeutic equivalence (Orange Book)
Price ladder
Not the price at the counterThese are not what a patient pays at the pharmacy counter. They are what pharmacies, health plans, and government buyers pay, before manufacturer rebates. A patient's cost depends on their insurance (copay, coinsurance, or deductible) or the pharmacy's cash price.