Neratinib
FDA Drug Information • Also known as: Nerlynx
- Brand Names
- Nerlynx
- Dosage Form
- TABLET
- Product Type
- HUMAN PRESCRIPTION DRUG
Description
11 DESCRIPTION NERLYNX (neratinib) immediate release, film-coated tablets for oral administration contain 40 mg of neratinib, equivalent to 48.31 mg neratinib maleate. Neratinib is a member of the 4-anilino quinolidine class of protein kinase inhibitors. The molecular formula for neratinib maleate is C 30 H 29 ClN 6 O 3
What Is Neratinib Used For?
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. ( 1.1 ) 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 ) 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 ( 14.1 )] . 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 ( 14.2 )] .
Dosage and Administration
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...
Side Effects (Adverse Reactions)
6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Diarrhea [see Warnings and Precautions ( 5.1 )] Hepatotoxicity [see Warnings and Precautions ( 5.2 )] The most common adverse reactions (reported in ≥5% of patients) were: NERLYNX as a single agent: diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, AST or ALT increased, nail disorder, dry skin, abdominal distention, epistaxis, weight decreased, and urinary tract infection. ( 6 ) NERLYNX in combination with capecitabine: diarrhea, nausea, vomiting, decreased appetite, constipation, fatigue/asthenia, weight decreased, dizziness, back pain, arthralgia, urinary tract infection, upper respiratory tract infection, abdominal distention, renal impairment, and muscle spasms. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Puma Biotechnology, Inc. at 1-844-NERLYNX (1-844-637-5969) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Extended Adjuvant Treatment of Early-Stage Breast Cancer ExteNET The data described below reflect the safety data of NERLYNX as a single agent in ExteNET, a multicenter, randomized, double-blind, placebo-controlled study of NERLYNX within 2 years after completion of adjuvant treatment with trastuzumab-based therapy in women with HER2-positive early-stage breast cancer. Patients who received NERLYNX in this trial were not required to receive any prophylaxis with antidiarrheal agents to prevent the NERLYNX-related diarrhea. Patients were treated with 240 mg of NERLYNX given orally once daily with food, continuously until disease recurrence or for up to one year. The median duration of treatment was 11.6 months in the NERLYNX arm and 11.8 months in the placebo arm. The median age was 52 years (60% were ≥50 years old, 12% were ≥65 years old); 81% were Caucasian, 3% Black or African American, 14% Asian, and 3% other. A total of 1408 patients were treated with NERLYNX. NERLYNX dose reduction due to an adverse reaction of any grade occurred in 31% of patients receiving NERLYNX compared to 2.6% of patients receiving placebo. Permanent discontinuation due to any adverse reaction was reported in 28% of NERLYNX-treated patients. The most common adverse reaction leading to discontinuation was diarrhea, accounting for 17% of NERLYNX-treated patients. The most common adverse reactions (≥5%) were diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, AST or ALT increased, nail disorder, dry skin, abdominal distention, epistaxis, weight decreased, and urinary tract infection. The most frequently reported Grade 3 or 4 adverse reactions were diarrhea, vomiting, nausea, and abdominal pain. Serious adverse reactions in the NERLYNX arm included diarrhea (1.6%), vomiting (0.9%), dehydration (0.6%), cellulitis (0.4%), renal failure (0.4%), erysipelas (0.4%), ALT increased (0.3%), AST increased (0.3%), nausea (0.3%), fatigue (0.2%), and abdominal pain (0.2%). Table 7 summarizes the adverse reactions in ExteNET. Table 7: Adverse Reactions Reported in ≥2% of NERLYNX-Treated Patients in ExteNET * Includes abdominal pain, abdominal pain upper, and abdominal pain lower † Includes stomatitis, aphthous stomatitis, mouth ulceration, oral mucosal blistering, mucosal inflammation, oropharyngeal pain, oral pain, glossodynia, glossitis, and cheilitis ‡ Includes rash, rash erythematous, rash follicular, rash generalized, rash pruritic, rash pustular, rash maculo-papular, rash papular, dermatitis, dermatitis acneiform, and toxic skin eruption § Includes nail disorder, paronychia, onychoclasis, nail...
Drug Interactions
7 DRUG INTERACTIONS Gastric acid reducing agents: Avoid concomitant use with proton pump inhibitors. Separate NERLYNX by at least 2 hours before or 10 hours after H 2 -receptor antagonists. Or separate NERLYNX by at least 3 hours after antacids. ( 2.5 , 7.1 ) Strong CYP3A4 inhibitors: Avoid concomitant use. ( 7.1 ) P-gp and moderate CYP3A4 dual inhibitors: Avoid concomitant use. ( 7.1 ) Strong or moderate CYP3A4 inducers: Avoid concomitant use. ( 7.1 ) Certain P-gp substrates: Monitor for adverse reactions of P-gp substrates for which minimal concentration change may lead to serious adverse reactions when used concomitantly with NERLYNX. ( 7.2 ) 7.1 Effect of Other Drugs on NERLYNX Table 10 includes drug interactions that affect the pharmacokinetics of neratinib. Table 10: Drug Interactions that Affect NERLYNX AUC=Area Under Curve; C max =Maximum Concentration Gastric Acid Reducing Agents Clinical Impact Concomitant use of NERLYNX with a proton pump inhibitor (PPI), H 2 -receptor antagonist, or antacid may decrease neratinib AUC [see Clinical Pharmacology ( 12.3 )], which may reduce NERLYNX activity. Prevention or Management [see Dosage and Administration ( 2.5 )] Avoid concomitant use of PPIs. Separate administration of NERLYNX at least 2 hours before or 10 hours after the H 2 -receptor antagonist dose. Separate administration of NERLYNX by at least 3 hours after antacids. Strong CYP3A4 Inhibitors Clinical Impact Concomitant use of NERLYNX with a strong CYP3A4 inhibitor increased neratinib C max and AUC [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of NERLYNX toxicity. Prevention or Management Avoid concomitant use of NERLYNX with strong CYP3A4 inhibitors. P-gp and Moderate CYP3A4 Dual Inhibitors Clinical Impact Concomitant use of NERLYNX with a P-gp and moderate CYP3A4 dual inhibitor may increase neratinib C max and AUC [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of NERLYNX toxicity. Prevention or Management Avoid concomitant use of NERLYNX with P-gp and moderate CYP3A4 dual inhibitors. Strong or Moderate CYP3A4 Inducers Clinical Impact Concomitant use of NERLYNX with a strong CYP3A4 inducer reduced neratinib C max and AUC [see Clinical Pharmacology ( 12.3 )] , which may reduce NERLYNX activity. Prevention or Management Avoid concomitant use of NERLYNX with strong or moderate CYP3A4 inducers. 7.2 Effect of NERLYNX on Other Drugs Certain P-glycoprotein (P-gp) Substrates Concomitant use of NERLYNX increased concentrations of a P-gp substrate [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of adverse reactions of these substrates. Monitor for adverse reactions of certain P-gp substrates for which minimal concentration changes may lead to serious adverse reactions.
Contraindications
4 CONTRAINDICATIONS None. None. ( 4 )
Pregnancy and Breastfeeding
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 ( 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 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...
Overdosage
10 OVERDOSAGE There is no specific antidote, and the benefit of hemodialysis in the treatment of NERLYNX overdose is unknown. In the event of an overdose, administration should be withheld and general supportive measures undertaken. In the clinical trial setting, a limited number of patients reported overdose. The adverse reactions experienced by these patients were diarrhea, nausea, vomiting, and dehydration. The frequency and severity of gastrointestinal disorders (diarrhea, abdominal pain, nausea, and vomiting) appear to be dose related.
How Supplied
16 HOW SUPPLIED/STORAGE AND HANDLING NERLYNX 40 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) [see USP Controlled Room Temperature] .
About This Information
This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.
What are side effects?
Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.
What are drug interactions?
Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.