Nerlynx

2 DOSAGE AND ADMINISTRATION Premedication for diarrhea: When not using dose escalation, initiate loperamide with the first dose of NERLYNX and continue during the first 56 days of treatment. After day 56, use loperamide to maintain 1–2 bowel movements per day. ( 2.1 , 2.2 ) Extended adjuvant treatment of early-stage breast cancer: 240 mg (6 tablets) given orally once daily, with food, continuously until disease recurrence or for up to one year. ( 2.2 ) Advanced or metastatic breast cancer: 240 mg (6 tablets) given orally once daily with food on Days 1–21 of a 21-day cycle plus capecitabine (750 mg/m 2 given orally twice daily) on Days 1–14 of a 21-day cycle until disease progression or unacceptable toxicities. ( 2.2 ) Dose escalation: A two-week dose escalation for NERLYNX may also be initiated. ( 2.2 ) Dose interruptions and/or dose reductions are recommended based on individual safety and tolerability. ( 2.3 ) Hepatic impairment: Reduce starting dose to 80 mg in patients with severe hepatic impairment. ( 2.4 ) 2.1 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. Table 1: Loperamide Prophylaxis 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 )] . 2.2 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 2 given 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 )] . Table 2: NERLYNX Dose Escalation and Treatment Schedule 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. 2.3 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 3 to 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. Table 3: NERLYNX Monotherapy Dose Modifications for Adverse Reactions 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) Table 4: Recommended Dosage Modifications for Adverse Reactions with NERLYNX Monotherapy 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 5–20× ULN) OR Grade 3 bilirubin (>3–10× ULN) Hold NERLYNX until recovery to ≤Grade 1 Evaluate alternative causes Resume 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 NERLYNX Evaluate 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 Table 5: NERLYNX in Combination with Capecitabine Dose Modifications for Adverse Reactions 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) Table 6: Recommended Dosage Modifications for Adverse Reactions with NERLYNX in Combination with Capecitabine ALT=Alanine Aminotransferase; AST=Aspartate Aminotransferase; ULN=Upper Limit Normal † Per CTCAE v4.0 a Since 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 2 dosing. Adverse Reaction Severity † Action/Dose Modification Diarrhea [see Warnings and Precautions ( 5.1 )] Grade 1 Diarrhea [Increase of 5 days Grade 3 Diarrhea lasting >2 days Grade 4 Diarrhea [Life-threatening consequences; urgent intervention indicated] Adjust antidiarrheal treatment Hold NERLYNX and capecitabine until recovery to Grade ≤1 or baseline Diet modifications Fluid intake of ~2 L/day should be maintained intravenously, if needed If recovery occurs: ≤1 week after withholding treatment, resume same doses of NERLYNX and capecitabine Within 1–3 weeks after withholding treatment, reduce NERLYNX dose to 160 mg and maintain the same dose of capecitabine If event occurs a second time and the NERLYNX dose has not already been decreased, reduce NERLYNX dose to 160 mg (maintain the same dose of capecitabine). If NERLYNX dose has already been reduced, then reduce the dose of capecitabine to 550 mg/m 2 given twice daily a (maintain the same dose of NERLYNX). If subsequent events occur, reduce the dose of NERLYNX or capecitabine to the next lower dose level in an alternate fashion (i.e., reduce capecitabine to 375 mg/m 2 given twice daily a if NERLYNX was previously reduced, or reduce NERLYNX to 120 mg if capecitabine was previously reduced) Once the event resolves to Grade ≤1 or baseline, start loperamide 4 mg with each subsequent NERLYNX administration 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 1 Evaluate alternative causes Resume 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 NERLYNX Evaluate 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 2.4 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 )] . 2.5 Dosage Modifications for Gastric Acid Reducing Agents Proton pump inhibitors (PPI): Avoid concomitant use with NERLYNX [see Drug Interactions ( 7.1 )] . H 2 -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 )] .

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1 INDICATIONS AND USAGE NERLYNX is a kinase inhibitor indicated: As a single agent, for the extended adjuvant treatment of adult patients with early-stage HER2-positive breast cancer, to follow adjuvant trastuzumab-based therapy.