SPERANTA

Neratinib was approved in

July for use as an extended adjuvant therapy in Human Epidermal Growth Factor Receptor 2 (HER2) positive breast cancer.

Approval was granted to Puma Biotechnology

Inc. for the tradename Nerlynx.

Neratinib is currently under investigation for use in many other forms of cancer.

For use as an extended adjuvant treatment in adult patients with early stage HER2-overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy.

Neratinib is a tyrosine kinase inhibitor which exhibits antitumor action against Epidermal Growth Factor Receptor (EGFR), HER2, and Human Epidermal Growth Factor Receptor 4 (HER4) postive carcinomas.

Neratinib binds to and irreversibly inhibits

This prevents auotphoshorylation of tyrosine residues on the receptor and reduces oncogenic signalling through the mitogen-activated protein kinase and Akt pathways.

Target Actions Organism U Epidermal growth factor receptor inhibitor Humans U Receptor tyrosine-protein kinase erbB-2 inhibitor Humans U Vascular endothelial growth factor receptor 2 inhibitor Humans.

Neratinib and its major active metabolites

M6, and M7 have a Tmax of 2-8 h.

Administration with a high fat meal increases Cmax by 1.7-fold and total exposure by 2.2-fold.

Administration with a standard meal increases

Cmax by 1.2-fold and total exposure by 1.1-fold.

Administration with gastric acid reducing agents such as proton pump inhibitors reduces Cmax by 71% and total exposure by 65%.

The apparent volume of distribution at steady state is 6433 L.

Neratinib is mainly undergoes metabolism via

It is also metabolized by flavin-containing monooxygenase to a lesser extent.

The systemic exposures of neratinib's active metabolites M3, M6, M7, and M11 are 15%, 33%, 22%, and 4%.

97.1% of the total dose is excreted in the feces and 1.13% in the urine.

The mean half life of elimination ranges from 7-17 h following a single dose.

The mean plasma half life during multiple doses is 14.6 h for neratinib, 21.6 h for M3, 13.8 h for M6, and 10.4 h for M7.

The total clearance during multiple doses is 216 L/h for after the first dose and 281 L/h during steady state.

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Use of neratinib may produce diarrhea and hepatotoxicity as clinically significant adverse effects.

Serious adverse reactions in the neratinib arm of the clinical trials included diarrhea (1.6%), vomiting (0.9%), dehydration (0.6%), cellulitis (0.4%), renal failure (0.4%), erysipelas (0.4%), alanine aminotransferase increase (0.3%), aspartate aminotransferase increase (0.3%), nausea (0.3%), fatigue (0.2%), and abdominal pain (0.2%).

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. 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.

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.

Dose escalation

A two-week dose escalation for NERLYNX may also be initiated.

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

Hepatic impairment

Reduce starting dose to 80 mg in patients with severe hepatic impairment. 2.1 Premedication for Diarrhea When not using dose escalation, administer antidiarrheal prophylaxis during the first 56 days of treatment and initiate with the first dose of NERLYNX.

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. 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.

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 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.

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 to Table 6.

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).

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 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 in one week or less, then resume NERLYNX treatment at the same dose If diarrhea resolves to ≤Grade in longer than one week, then resume NERLYNX treatment at reduced dose 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 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 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.

Severity † Action/Dose Modification Diarrhea 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/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 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.

Grade 4 ALT or AST (>20× ULN) OR Grade 4 bilirubin (>10× ULN) Permanently discontinue NERLYNX Evaluate alternative causes Other Grade 3 Hold NERLYNX until recovery to Grade ≤1 or baseline within 3 weeks of stopping treatment.

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) . 2.5 Dosage Modifications for Gastric Acid Reducing Agents Proton pump inhibitors (PPI): Avoid concomitant use with NERLYNX.

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.

Separate dosing of NERLYNX by 3 hours after antacids.

mg film-coated tablets are red, oval shaped and debossed with 'W104' on one side and plain on the other side.

NERLYNX is available in

Bottles of 180 tablets: NDC 70437-240-18 Bottles of 133 tablets: NDC 70437-240-33 Bottles of 126 tablets: NDC 70437-240-26 Store at controlled room temperature, 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) .

Based on findings from animal studies and the mechanism of action, NERLYNX can cause fetal harm when administered to a pregnant woman.

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.

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.

In a fertility and early embryonic development study in female rats, neratinib was administered orally for 15 days before mating to Day 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 mg/kg/day (approximately 0.4 times the maximum recommended dose of 240 mg/day in patients on a mg/m 2 basis) 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 2 basis).

The safety and efficacy of

NERLYNX in pediatric patients has not been established.

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 than in the <65 years; 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%).

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 was 36% and in the <65 years was 34%.

The serious adverse reactions most frequently reported in the ≥65 years 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.