Nerlynx

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. (
  
  
  1.1 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 ]

  .
  )
  
• In combination with capecitabine, 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. (
  
  
  1.2 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 ]

  .
  )
  

• 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 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 (

  5.1

  ) and Adverse Reactions ]

  .

  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 ]

  .
  ,
  
  
  2.2 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/m²given 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 ]

  .

  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 ]

  .

  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.
  )
  
• 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 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/m²given 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 ]

  .

  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 ]

  .

  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.
  )
  
• 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
  
  ²given orally twice daily) on Days 1–14 of a 21-day cycle until disease progression or unacceptable toxicities. (
  
  
  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/m²given 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 ]

  .

  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 ]

  .

  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.
  )
  
• Dose escalation: A two-week dose escalation for NERLYNX may also be initiated. (
  
  
  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/m²given 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 ]

  .

  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 ]

  .

  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.
  )
  
• Dose interruptions and/or dose reductions are recommended based on individual safety and tolerability. (
  
  
  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 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.

  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 ]	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 days Grade 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 treatment Diet modifications Fluid intake of ~2 L/day should be maintained to avoid dehydration Once 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 treatment Diet modifications Fluid intake of ~2 L/day should be maintained to avoid dehydration If diarrhea resolves to ≤Grade 1 in one week or less, then resume NERLYNX treatment at the same dose If 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 ]	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 ]	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
  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/m2dosing.
  Adverse Reaction	Severity †	Action/Dose Modification
  Diarrhea [see Warnings and Precautions ]	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 days Grade 3 Diarrhea [Increase of ≥7 stools per day over baseline; incontinence; hospitalization indicated; limiting self-care and activities of daily living] lasting ≤2 days	Adjust antidiarrheal treatment Continue NERLYNX and capecitabine at full doses Diet modifications Fluid intake of ~2 L/day should be maintained to avoid dehydration Once the event resolves to Grade ≤1 or baseline, start loperamide 4 mg with each subsequent NERLYNX administration
  	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 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/m2given twice dailya(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/m2given twice dailyaif 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 ]	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 ]	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
  )
  
• Hepatic impairment: Reduce starting dose to 80 mg in patients with severe hepatic impairment. (
  
  
  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 and Clinical Pharmacology ]

  .
  )
  

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.

Lactation: Advise women not to breastfeed. (

• Diarrhea: Manage diarrhea through either NERLYNX dose escalation or loperamide prophylaxis (
  
  
  2.1 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 (

  5.1

  ) and Adverse Reactions ]

  .

  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 ]

  .
  ,
  
  
  2.2 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/m²given 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 ]

  .

  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 ]

  .

  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.
  ). If diarrhea occurs despite recommended prophylaxis, treat with additional antidiarrheals, fluids, and electrolytes as clinically indicated. Withhold NERLYNX in patients experiencing severe and/or persistent diarrhea. Permanently discontinue NERLYNX in patients experiencing Grade 4 diarrhea or Grade ≥2 diarrhea that occurs after maximal dose reduction. (
  
  
  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 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.

  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 ]	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 days Grade 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 treatment Diet modifications Fluid intake of ~2 L/day should be maintained to avoid dehydration Once 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 treatment Diet modifications Fluid intake of ~2 L/day should be maintained to avoid dehydration If diarrhea resolves to ≤Grade 1 in one week or less, then resume NERLYNX treatment at the same dose If 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 ]	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 ]	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
  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/m2dosing.
  Adverse Reaction	Severity †	Action/Dose Modification
  Diarrhea [see Warnings and Precautions ]	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 days Grade 3 Diarrhea [Increase of ≥7 stools per day over baseline; incontinence; hospitalization indicated; limiting self-care and activities of daily living] lasting ≤2 days	Adjust antidiarrheal treatment Continue NERLYNX and capecitabine at full doses Diet modifications Fluid intake of ~2 L/day should be maintained to avoid dehydration Once the event resolves to Grade ≤1 or baseline, start loperamide 4 mg with each subsequent NERLYNX administration
  	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 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/m2given twice dailya(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/m2given twice dailyaif 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 ]	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 ]	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
  ,
  
  
  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. 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 ]

  .

  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 ]

  .

  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 ]

  .

  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 ].

  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 ].

  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: Monitor liver function tests monthly for the first 3 months of treatment, then every 3 months while on treatment and as clinically indicated. Withhold NERLYNX in patients experiencing Grade 3 liver abnormalities and permanently discontinue NERLYNX in patients experiencing Grade 4 liver abnormalities. (
  
  
  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 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.

  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 ]	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 days Grade 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 treatment Diet modifications Fluid intake of ~2 L/day should be maintained to avoid dehydration Once 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 treatment Diet modifications Fluid intake of ~2 L/day should be maintained to avoid dehydration If diarrhea resolves to ≤Grade 1 in one week or less, then resume NERLYNX treatment at the same dose If 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 ]	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 ]	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
  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/m2dosing.
  Adverse Reaction	Severity †	Action/Dose Modification
  Diarrhea [see Warnings and Precautions ]	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 days Grade 3 Diarrhea [Increase of ≥7 stools per day over baseline; incontinence; hospitalization indicated; limiting self-care and activities of daily living] lasting ≤2 days	Adjust antidiarrheal treatment Continue NERLYNX and capecitabine at full doses Diet modifications Fluid intake of ~2 L/day should be maintained to avoid dehydration Once the event resolves to Grade ≤1 or baseline, start loperamide 4 mg with each subsequent NERLYNX administration
  	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 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/m2given twice dailya(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/m2given twice dailyaif 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 ]	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 ]	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
  ,
  
  
  5.2 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 and Adverse Reactions ]

  .
  )
  
• Embryo-Fetal Toxicity: NERLYNX can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception. (
  
  
  5.3 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 and Clinical Pharmacology ]

  .
  ,
  
  
  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 ]

  .

  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/m²basis.

  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/m²basis) 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/m²basis).
  ,
  
  
  8.3 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 ]

  . 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 ]

  . 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 ]

  .
  )