Nerlynx
(neratinib)Dosage & Administration
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Nerlynx Prescribing Information
Extended Adjuvant Treatment of Early-Stage Breast Cancer
NERLYNX as a single agent is indicated for the extended adjuvant treatment of adult patients with early-stage human epidermal growth factor receptor 2 (HER2)-positive breast cancer, to follow adjuvant trastuzumab based therapy [see Clinical Studies ( 14.1)] .
Advanced or Metastatic Breast Cancer
NERLYNX in combination with capecitabine is indicated for the treatment of adult patients with advanced or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 based regimens in the metastatic setting [see Clinical Studies ( 14.2)] .
Premedication for Diarrhea
When not using dose escalation [see Dosage and Administration ( 2.2)], administer antidiarrheal prophylaxis during the first 56 days of treatment and initiate with the first dose of NERLYNX [see Warnings and Precautions ( 5.1) and Adverse Reactions ( 6.1)] .
Instruct patients to take loperamide as directed in Table 1. Titrate loperamide to 1–2 bowel movements per day.
| Time on NERLYNX | Loperamide Dose and Frequency |
|---|---|
| Weeks 1–2 (days 1–14) | 4 mg three times daily |
| Weeks 3–8 (days 15–56) | 4 mg twice daily |
| Weeks 9–Discontinuation of NERLYNX | 4 mg as needed, not to exceed 16 mg per day; titrate dosing to achieve 1–2 bowel movements per day |
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 ( 2.3)] .
Recommended Dose and Schedule
Extended Adjuvant Treatment of Early-Stage Breast Cancer
The recommended dose of NERLYNX is 240 mg (six tablets) given orally once daily, with food, continuously until disease recurrence or for up to one year.
Advanced or Metastatic Breast Cancer
The recommended dose of NERLYNX is 240 mg (six tablets) given orally once daily with food on Days 1–21 of a 21-day cycle plus capecitabine (750 mg/m 2given orally twice daily) on Days 1–14 of a 21-day cycle until disease progression or unacceptable toxicities.
Dose Escalation
A two-week dose escalation for NERLYNX may be considered instead of starting at the 240 mg daily dose for patients with early-stage breast cancer and metastatic breast cancer, as described in Table 2[see Warnings and Precautions ( 5.1) and Adverse Reactions ( 6.1)] .
| Time on NERLYNX | NERLYNX Dose |
|---|---|
| Week 1 (days 1–7) | 120 mg daily (three 40 mg tablets) |
| Week 2 (days 8–14) | 160 mg daily (four 40 mg tablets) |
| Week 3 and onwards | 240 mg daily (six 40 mg tablets, recommended dose) |
If diarrhea occurs, treat with antidiarrheal medications, fluids, and electrolytes as clinically indicated. NERLYNX dose interruptions and dose reductions may also be required to manage diarrhea [see Dosage and Administration ( 2.3)] .
Administration Instructions
Instruct patients to take NERLYNX at approximately the same time every day. NERLYNX tablets should be swallowed whole (tablets should not be chewed, crushed, or split prior to swallowing).
If a patient misses a dose, do not replace missed dose, and instruct the patient to resume NERLYNX with the next scheduled daily dose.
Dosage 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 3to Table 6.
Discontinue NERLYNX for patients with adverse reactions that fail to recover to Grade 0–1 or baseline, with toxicities that result in a treatment delay >3 weeks, or if 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.).
When NERLYNX is used in combination with capecitabine, refer to the capecitabine prescribing information for dose modifications of capecitabine.
| Dose Level | NERLYNX Dose |
|---|---|
| Recommended starting dose | 240 mg daily (six 40 mg tablets) |
| First dose reduction | 200 mg daily (five 40 mg tablets) |
| Second dose reduction | 160 mg daily (four 40 mg tablets) |
| Third dose reduction | 120 mg daily (three 40 mg tablets) |
| 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)] |
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| Hepatotoxicity [see Warnings and Precautions ( 5.2)] |
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| Other [see Adverse Reactions ( 6.1)] |
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| Dose Level | NERLYNX Dose |
|---|---|
| Recommended starting dose | 240 mg daily (six 40 mg tablets) |
| First dose reduction | 160 mg daily (four 40 mg tablets) |
| Second dose reduction | 120 mg daily (three 40 mg tablets) |
ALT=Alanine Aminotransferase; AST=Aspartate Aminotransferase; ULN=Upper Limit Normal | ||
† Per CTCAE v4.0 | ||
aSince capecitabine is provided as 150 mg or 500 mg tablets, it is recommended that the capecitabine dose reduction(s) is(are) rounded down to the nearest 500 mg or multiple of 150 mg for the twice daily dose. If the patient's body surface area is >2.0, the standard of care for the study center can be utilized for capecitabine mg/m 2dosing. | ||
| Adverse Reaction | Severity† | Action/Dose Modification |
| Diarrhea [see Warnings and Precautions ( 5.1)] |
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| Hepatotoxicity [see Warnings and Precautions ( 5.2)] |
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| Other [see Adverse Reactions ( 6.1)] |
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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 ( 8.6) and Clinical Pharmacology ( 12.3)] .
Dosage Modifications for Gastric Acid Reducing Agents
Proton pump inhibitors (PPI):Avoid concomitant use with NERLYNX [see Drug Interactions ( 7.1)] .
H2-receptor antagonists:Take NERLYNX at least 2 hours before the next dose of the H 2-receptor antagonist or 10 hours after the H 2-receptor antagonist [see Drug Interactions ( 7.1)] .
Antacids:Separate dosing of NERLYNX by 3 hours after antacids [see Drug Interactions ( 7.1)] .
Tablets: 40 mg neratinib (equivalent to 48.31 mg of neratinib maleate).
Film-coated, red, oval shaped and debossed with 'W104' on one side and plain on the other side.
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 2basis.
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 mg/kg/day (approximately 0.4 times the maximum recommended dose of 240 mg/day in patients on a mg/m 2basis) including decreased body weights, body weight gains, and food consumption. Effects on long-term memory were observed in male offspring at maternal doses ≥5 mg/kg/day (approximately 0.2 times the maximum recommended dose of 240 mg/day in patients on a mg/m 2basis).
Lactation
Risk Summary
No data are available regarding the presence of neratinib or its metabolites in human milk or its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in breastfed infants from NERLYNX, advise lactating women not to breastfeed while taking NERLYNX and for at least 1 month after the last dose.
Females and Males of Reproductive Potential
Pregnancy
Based on animal studies, NERLYNX can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1)] . Females of reproductive potential should have a pregnancy test prior to starting treatment with NERLYNX.
Contraception
Females
Based on animal studies, NERLYNX can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1)] . Advise females of reproductive potential to use effective contraception during treatment with NERLYNX and for at least 1 month after the last dose.
Males
Based on findings in animal reproduction studies, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of NERLYNX [see Use in Specific Populations ( 8.1)] .
Pediatric Use
The safety and efficacy of NERLYNX in pediatric patients has not been established.
Geriatric Use
In the ExteNET trial, in the NERLYNX arm; 1236 patients were <65 years, 172 patients were ≥65 years, of whom 25 patients were 75 years or older. There was a higher frequency of treatment discontinuations due to adverse reactions in the ≥65 years age group than in the <65 years age group; in the NERLYNX arm, the percentages were 45% compared with 25%, respectively, and in the placebo arm 6% and 5%, respectively. The incidence of serious adverse reactions in the NERLYNX arm vs placebo arm was 7% vs 6% (<65 years old) and 10% vs 8% (≥65 years old). The serious adverse reactions most frequently reported in the ≥65 years old group were vomiting (2.3%), diarrhea (1.7%), renal failure (1.7%), and dehydration (1.2%).
In the NALA trial, in the NERLYNX plus capecitabine arm; 242 patients were <65 years, 61 patients were ≥65 years, of whom 12 patients were 75 years or older. The incidence of serious adverse reactions in the NERLYNX plus capecitabine arm in the ≥65 years age group was 36% and in the <65 years age group was 34%. The serious adverse reactions most frequently reported in the ≥65 years age group were diarrhea (16%), acute kidney injury (8%), and dehydration (7%). No overall differences in effectiveness were observed between patients ≥65 years old and patients <65 years old.
Hepatic Impairment
No dosage modifications are recommended for patients with mild to moderate hepatic impairment (Child Pugh A or B).
Neratinib clearance is reduced, and C maxand AUC increase in patients with severe, pre-existing hepatic impairment (Child Pugh C). Reduce the NERLYNX dosage for patients with severe hepatic impairment [see Dosage and Administration ( 2.4) and Clinical Pharmacology ( 12.3)] .
None.
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. In the NERLYNX arm, Grade 3 diarrhea occurred in 40% and Grade 4 diarrhea occurred in 0.1% of patients. The majority of patients (93%) had diarrhea in the first month of treatment, the median time to first onset of Grade ≥3 diarrhea was 8 days (range, 1–350), and the median cumulative duration of Grade ≥3 diarrhea was 5 days (range, 1–139) [see Adverse Reactions ( 6.1)] .
Diarrhea was reported in 83% of NERLYNX plus capecitabine treated patients in NALA, a randomized placebo-controlled trial in the metastatic breast cancer setting who were required to receive anti-diarrheal prophylaxis in the first 21-day cycle. The majority of patients (70%) had diarrhea in the first 21 days of treatment, the median time to first onset of Grade ≥3 diarrhea was 11 days (range, 2–728) and the median cumulative duration of Grade ≥3 diarrhea was 3 days (range, 1–21). In the NERLYNX plus capecitabine arm, Grade 3 diarrhea occurred in 24% of patients [see Adverse Reactions ( 6.1)] .
Antidiarrheal prophylaxis has been shown to lower the incidence and severity of diarrhea. Instruct patients to initiate antidiarrheal prophylaxis with loperamide along with the first dose of NERLYNX and continue during the first 56 days of treatment; after day 56, titrate dose to achieve 1–2 bowel movements per day and not to exceed 16 mg loperamide per day [see Dosage and Administration ( 2.1)]. Consider adding other agents to loperamide as clinically indicated [see Adverse Reactions ( 6.1)] .
Alternatively, a 2-week NERLYNX dose escalation approach prior to initiation of the recommended treatment regimen with NERLYNX can also be considered for diarrhea management [see Dosage and Administration ( 2.2)]. For patients who used NERLYNX dose escalation, the median time to first onset of Grade ≥3 diarrhea was 45 days (range, 15–132) and the median cumulative duration of Grade ≥3 diarrhea was 2.5 days (range, 1–6). Grade 3 diarrhea occurred in 13% of patients who used NERLYNX dose escalation [see Adverse Reactions ( 6.1)].
Monitor patients for diarrhea and treat with additional antidiarrheals as needed. When severe diarrhea with dehydration occurs, administer fluid and electrolytes as needed, interrupt NERLYNX, and reduce subsequent doses [see Dosage and Administration ( 2.3)]. Perform stool cultures as clinically indicated to exclude infectious causes of Grade 3 or 4 diarrhea or diarrhea of any grade with complicating features (dehydration, fever, neutropenia).
Hepatotoxicity
NERLYNX has been associated with hepatotoxicity characterized by increased liver enzymes. In ExteNET, 10% of patients experienced an alanine aminotransferase (ALT) increase ≥2× ULN, 5% of patients experienced an aspartate aminotransferase (AST) increase ≥2× ULN, and 1.7% of patients experienced an AST or ALT increase >5× ULN (≥Grade 3). Hepatotoxicity or increases in liver transaminases led to drug discontinuation in 1.7% of NERLYNX-treated patients.
In the NALA study, in NERLYNX and capecitabine-treated patients, 7% experienced an ALT or AST increase >3× ULN, 2% experienced an ALT or AST increase >5× ULN, 7% experienced a bilirubin increase >1.5× ULN, and 1.3% experienced a bilirubin increase >3× ULN. Hepatotoxicity or increases in liver transaminases led to drug discontinuation in 0.3% of NERLYNX and capecitabine-treated patients.
Total bilirubin, AST, ALT, and alkaline phosphatase should be measured prior to starting treatment with NERLYNX monthly for the first 3 months of treatment, then every 3 months while on treatment and as clinically indicated. These tests should also be performed in patients experiencing Grade 3 diarrhea or any signs or symptoms of hepatotoxicity, such as worsening of fatigue, nausea, vomiting, right upper quadrant tenderness, fever, rash, or eosinophilia [see Dosage and Administration ( 2.3) and Adverse Reactions ( 6.1)] .
Embryo-Fetal Toxicity
Based on findings from animal studies and its mechanism of action, NERLYNX can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of neratinib to pregnant rabbits during organogenesis caused abortions, embryo-fetal death, and fetal abnormalities in rabbits at maternal AUCs approximately 0.2 times the AUC in patients receiving the recommended dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for at least 1 month after the last dose. [see Use in Specific Populations ( 8.1, 8.3) and Clinical Pharmacology ( 12.1)] .