ne-RA-ti-nib

• Extended adjuvant treatment of early stage human epidermal receptor type 2 (HER2)-overexpressed/amplified breast cancer following adjuvant trastuzumab-based therapy.
• Advanced or metastatic HER2-positive breast cancer in patients who have received 2 prior anti-HER2 based regimens in the metastatic setting (in combination with capecitabine).

• Irreversibly binds to epidermal growth factor receptor (EGFR), HER2, and HER4 to inhibit growth of tumors that express HER2 and EGFR.

• Decreased progression of breast cancer and improved survival.

Absorption: Blood levels ↑ by high-fat foods.

Distribution: Extensively distributed to tissues.

Protein Binding: >99%.

Metabolism/Excretion: Primarily metabolized in liver via the CYP3A4 isoenzyme into active metabolites (M3, M6, M7, and M11); 97% excreted in feces, <2% excreted by kidneys.

Half-life: 7–17 hr.

Contraindicated in:

• OB: Pregnancy (may cause fetal harm)
• Lactation: Lactation.

Use Cautiously in:

• Severe hepatic impairment (Child-Pugh C) (↓ dose)
• Rep: Women of reproductive potential and men with female partners of reproductive potential
• Pedi: Safety and effectiveness not established in children
• Geri: ↑risk of adverse reactions/side effects in older adults.

CV: hypotension.

Derm: rash, dry skin, nail disorder.

EENT: epistaxis.

GI: diarrhea, HEPATOTOXICITY, abdominal pain, ↓appetite, dyspepsia, nausea, stomatitis, vomiting, abdominal distention, dry mouth.

GU: renal failure, urinary tract infection.

Metab: ↓weight.

MS: muscle spasms.

Neuro: fatigue.

Drug-Drug:

• ↓levels with proton pump inhibitors, H₂ blockers, and antacids; avoid concurrent use with proton pump inhibitors; take 2 hr before next dose of H₂ antagonist or 10 hr after the H₂ antagonist; take 3 hr after antacids.
• Strong or moderate CYP3A4 inhibitors, including aprepitant, cimetidine, ciprofloxacin, clarithromycin, clotrimazole, cobicistat, conivaptan, crizotinib, cyclosporine, diltiazem, dronedarone, erythromycin, fluconazole, fluvoxamine, idelalisib, imatinib, indinavir, itraconazole, ketoconazole, lopinavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, tipranavir, verapamil, and voriconazole may ↑ levels/toxicity of neratinib; avoid concurrent use.
• Strong or moderate CYP3A4 inducers, including bosentan, carbamazepine, efavirenz, enzalutamide, mitotane, modafanil, phenytoin, and rifampin may ↓ levels of neratinib and its effectiveness; avoid concurrent use.
• May ↑ digoxin levels.

Drug-Natural Products:

• St. John's wort may ↓ levels of neratinib and its effectiveness; avoid concurrent use.

Extended Adjuvant Treatment of Early Stage Breast Cancer

• PO (Adults): Non-dose escalation strategy (administer antidiarrheal prophylaxis for the first 56 days of treatment on scheduled basis) — 240 mg once daily until disease recurrence or for up to 1 yr ORDose escalation strategy (use antidiarrheals only as needed for diarrhea) — 120 mg once daily for 7 days, then 160 mg once daily for 7 days, then 240 mg once daily thereafter until disease recurrence or for up to 1 yr.

Advanced or Metastatic Breast Cancer

• PO (Adults): Non-dose escalation strategy (administer antidiarrheal prophylaxis for the first 56 days of treatment on scheduled basis) — 240 mg once daily on Days 1–21 of a 21-day cycle; continue until disease recurrence or unacceptable toxicity. ORDose escalation strategy (use antidiarrheals only as needed for diarrhea) — 120 mg once daily for 7 days, then 160 mg once daily for 7 days, then 240 mg once daily for 7 days, then 240 mg once daily on Day 1–21 of a 21-day cycle; continue until disease recurrence of unacceptable toxicity.

• Do not confuse neratinib with nilotinib or niraparib.
• Premedication for Diarrhea: When not using dose escalation, use antidiarrheal prophylaxis for first 56 days of therapy, starting with first dose of neratinib. For Weeks 1–2 (days 1–14), administer loperamide 4 mg three times daily.For Weeks 3–8 (days 15–56), administer loperamide 4 mg twice daily. For Week 9– discontinuation of neratinib, administer 4 mg loparamide as needed, not to exceed 16 mg/day; titrate to achieve 1–2 bowel movements/day. If diarrhea occurs despite prophylaxis, treat with additional antidiarrheals, fluids and electrolytes as indicated. Neratinib interruptions and dose reductions may also be required to manage diarrhea.
• PO: Administer once daily, at same time each day, with food, continuously for 1 yr; 240-mg dose = 6 tabletsDNC: Swallow tablets whole; do not crush, break, or chew.

Nerlynx

Therapeutic Classification: antineoplastics

Pharmacologic Classification: enzyme inhibitors, kinase inhibitors

• Tablets: 40 mg;

(blood levels)

• Monitor for diarrhea. Use antidiarrheal prophylaxis with first dose and for first 2 cycles (56 days). If 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 occurs, modify antidiarrheal therapy, modify diet, and maintain fluid intake of 2 L to avoid dehydration. Once event resolves to Grade 1 or baseline, start loperamide 4 mg with each subsequent neratinib administration. If any grade diarrhea with dehydration, fever, hypotension, renal failure, neutropenia, Grade 2 diarrhea lasting 5 days, Grade 3 diarrhea lasting >2 days despite medical therapy occurs, hold therapy, modify diet, and maintain fluid intake of 2 L to avoid dehydration. If diarrhea resolves to Grade 0-1 in 1 wk, resume therapy at same dose. If diarrhea resolves to Grade 0-1 in >1 wk, resume therapy at reduced dose. Once diarrhea resolves to Grade 1 or baseline, start loperamide 4 mg with each subsequent neratinib administration. If Grade 4 diarrhea (Life-threatening consequences; urgent intervention indicated) occurs, permanently discontinue neratinib. If diarrhea recurs to Grade 2 at 120 mg neratinib per day, permanently discontinue neratinib. Obtain stool cultures to determine infectious causes of Grade 3 or 4 or with dehydration, fever, or neutropenia.
• Monitor or signs and symptoms of hepatotoxicity (worsening of fatigue, nausea, vomiting, right upper quadrant tenderness, fever, rash, eosinophilia, Grade 3 diarrhea) periodically during therapy. If symptoms occur, obtain liver function test levels to measure changes.

• Verify negative pregnancy test in women of reproductive potential before starting therapy.
  • Monitor total bilirubin, AST, ALT, and alkaline phosphatase before starting therapy, monthly for first 3 mo, and every 3 mo during therapy. If evaluating hepatotoxicity, also obtain fractionated bilirubin and prothrombin time. If Grade 3 ALT (>5–20 × upper limit of normal (ULN)) or Grade 3 bilirubin (>3–10 × ULN), withhold dose until recovery to Grade 1, evaluate alternative causes, resume neratinib at next lower dose if recovery to Grade 1 occurs within 3 wk. If Grade 3 ALT or bilirubin occurs again despite one dose reduction, permanently discontinue neratinib. If Grade 4 ALT (>20 × ULN) or Grade 4 bilirubin (>10 × ULN), discontinue neratinib permanently and evaluate alternative causes.

• Instruct patient to take neratinib as directed. If dose is missed, omit and take next scheduled dose next day. Advise patient to read Patient Information before starting therapy and with each Rx refill in case of changes.
• Advise patient to avoid taking grapefruit or grapefruit juice during therapy.
• Instruct patient to take loperamide according to schedule and titrate to 1–2 bowel movements/day: For days 1–14 (wk 1–2), take 4 mg three times daily. Days 15–56 (wk 3–8), take 4 mg twice daily. Days 57–365 (wk 9–52), take 4 mg as needed up to 16 mg/day. May require additional antidiarrheal agents and dose reduction.
• Caution patient to avoid proton pump inhibitors and H₂ antagonists during therapy and to avoid taking antacids within 3 hrs of neratinib.
• Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care professional before taking any new medications, especially St. John's wort.
• Advise patient to notify health care professional immediately if severe ( Grade 3) diarrhea or diarrhea associated with weakness, dizziness, or fever or if signs and symptoms of liver dysfunction occur.
• Rep: May cause fetal harm. Advise females of reproductive potential to use effective contraception and avoid breast feeding during and for at least 1 mo after last dose. Advise male patients with partners of reproductive potential to use effective contraception during and for 3 mo after last dose.

• Decreased progression of breast cancer.

NDC Code^*

• 70437- Puma Biotechnology, Inc.
  • 70437-240- Nerlynx
    • 70437-240-18- 1 BOTTLE in 1 BOX (70437-240-18) > 180 TABLET in 1 BOTTLE

• 70437- Puma Biotechnology, Inc.
  • 70437-240- Nerlynx
    • 70437-240-26- 1 BOTTLE in 1 BOX (70437-240-26) > 126 TABLET in 1 BOTTLE