Neratinib

Neratinib is used to treat a certain type of hormone receptor-positive breast cancer (breast cancer that depends on hormones such as estrogen to grow) in adults after treatment with trastuzumab (Herceptin) and other medications. Neratinib is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal protein that signals cancer cells to multiply. This helps slow or stop the spread of cancer cells.

Follow all directions on your prescription label. Do not use this medicine in larger or smaller amounts or for longer than recommended.

Take the medicine with food, at the same time each day.

The usual dose is 6 tablets taken once daily for 1 year. Follow your doctor's dosing instructions very carefully.

Do not crush, chew, or break a neratinib tablet. Swallow it whole.

Neratinib can cause severe diarrhea, which can be life-threatening if it leads to dehydration. For the first 2 months of treatment with neratinib, you may need to take medication to prevent or quickly treat diarrhea.

Your doctor may recommend you have an anti-diarrhea medicine such as loperamide (Imodium) available at all times while you are taking neratinib. Take the anti-diarrhea medicine as directed on the label, or as prescribed by your doctor.

To best control diarrhea, you may need to follow a special diet. Get familiar with the list of foods you should eat or avoid to help control diarrhea.

Call your doctor if you are sick with severe diarrhea, or you also have weakness, dizziness, or a fever. You may need to stop taking neratinib for a short time.

While using neratinib, you may need frequent blood tests.

Drink plenty of liquids while you are taking neratinib.

Store at room temperature away from moisture and heat.

Grapefruit and grapefruit juice may interact with neratinib and lead to unwanted side effects. Avoid the use of grapefruit products while taking neratinib.

If you also take an antacid: Wait at least 3 hours after taking the antacid before you take neratinib.

Sometimes it is not safe to use certain medications at the same time. Some drugs can affect your blood levels of other drugs you take, which may increase side effects or make the medications less effective.

Tell your doctor about all your current medicines and any you start or stop using, especially:

• a stomach acid reducer--such as Nexium, Prevacid, Prilosec, Tagamet, Zantac, and others.

This list is not complete. Other drugs may interact with neratinib, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

• Store at room temperature.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

Note: Antidiarrheal prophylaxis is recommended during the first 2 cycles of therapy; initiate with the first neratinib dose (see Premedications below)

Breast cancer (HER2-positive), extended adjuvant therapy: Oral: 240 mg once daily for 1 year (Chan 2016)

Missed dose: If a dose is missed, resume therapy with the next scheduled daily dose; do not replace the missed dose.

Premedication: Antidiarrheal prophylaxis is recommended during the first 2 cycles of therapy; initiate with the first neratinib dose. Titrate to 1 to 2 bowel movements/day. Additional antidiarrheal medication may be required for loperamide-refractory diarrhea.

Days 1 to 14: Loperamide 4 mg orally 3 times daily

Days 15 to 56: Loperamide 4 mg orally twice daily

Days 57 to 365: Loperamide 4 mg as needed (maximum: 16 mg/day)

Based on the mechanism of action and data from animal reproduction studies, use of neratinib in pregnancy may cause fetal harm. Women of reproductive potential should have a pregnancy test prior to treatment; effective contraception should be used during therapy and for at least 1 month after the last dose. Male patients with female partners of reproductive potential should also use effective contraception during therapy and for at least 3 months after the last dose.

PRE-EXISTING HEPATIC IMPAIRMENT:
-MILD TO MODERATE HEPATIC IMPAIRMENT (Child-Pugh A or B): No adjustment recommended.
-SEVERE HEPATIC IMPAIRMENT (Child-Pugh C): Initial Dose: Reduce to 80 mg.

HEPATOTOXICITY DURING TREATMENT:
GRADE 3 ALT (greater than 5 to 20 times upper level of normal [ULN]) OR GRADE 3 BILIRUBIN (greater than 3 to 10 x ULN):
-Hold treatment until recovery to Grade 1 or less.
-Evaluate alternative causes.
-Resume treatment at the next lower dose level if recovery to Grade 1 or less occurs within 3 weeks.

GRADE 3 ALT OR GRADE 3 BILIRUBIN RECURRENCE (despite one dose reduction); GRADE 4 ALT (greater than 20 x ULN); OR GRADE 4 BILIRUBIN (greater than 10 x ULN): Permanently discontinue treatment; evaluate alternative causes.

COMMENTS: If Grade 3 or greater diarrhea requiring IV fluid treatment or any signs/symptoms of hepatotoxicity occurs, evaluate for changes in liver function tests, and collect fractionated bilirubin and prothrombin time.

Administration Advice:
-Instruct patients to administer this drug at approximately the same time every day.
-Direct patients to swallow drug tablets whole, and not to chew, crush, or split tablets.
-Advise patients not to replace a missed dose, and to resume treatment with the next scheduled dose.

Storage Requirements:
-Store at controlled room temperature: 20 to 25 Celsius/68 to 77 Fahrenheit; excursions permitted to 15 to 30 C/59 to 86 F.

General:
-Overdosage: No specific antidote; benefit of hemodialysis is unknown.

Monitoring:
-Gastrointestinal: Diarrhea (throughout treatment); stool cultures (as clinically indicated)
-Hepatic: Total bilirubin, AST, ALT, alkaline phosphatase (prior to treatment initiation, monthly for the first 3 months of treatment, then every 3 months during treatment and as clinically indicated); fractionated bilirubin and prothrombin time (as clinically indicated)

Patient Advice:
-Avoid grapefruit products during treatment with this drug.
-This drug may cause side effects including fatigue and muscle spasms; avoid potentially dangerous activities such as driving and operating machinery until you know how this drug affects you.

Administration of this drug in animals during organogenesis caused maternal toxicity, abortions, embryofetal death (increased resorptions), effects on long-term memory in male offspring, and fetal abnormalities (e.g., domed head, dilation of the brain ventricles, ventricular septal defect, misshapen and enlarged anterior fontanelles, enlarged posterior fontanelles) at maternal AUCs approximately 0.2 to 0.5 times the AUC in patients at the recommended human dose (RHD). Findings in animals also revealed tubular hypoplasia of the testes at approximately 0.4 times the RHD AUC; however doses approximately 0.5 times the RHD AUC caused no effects on mating or the ability to become pregnant. There are no controlled data in human pregnancy. US FDA pregnancy category Not Assigned: The US FDA has amended the pregnancy labeling rule for prescription drug products to require labeling that includes a summary of risk, a discussion of the data supporting that summary, and relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy. Pregnancy categories A, B, C, D and X are being phased out.

Safety has not been established during pregnancy. US FDA pregnancy category: Not Assigned Comments: -Based on animal studies and its mechanism of action, this drug can cause fetal harm. -Females of Reproductive Potential: Advise them of the potential fetal risk; perform a pregnancy test prior to treatment initiation; and instruct them to use effective contraception during treatment and for at least 1 month after the last dose. -Males with Female Partners of Reproductive Potential: Advise them to use effective contraception during treatment and for 3 months after the last dose.

Mechanism of Action

Irreversible tyrosine kinase inhibitor (TKI) that blocks signal transduction through the epidermal growth factor receptors (EGFRs), human epidermal growth factor receptor 2 (HER2), and HER4

In vitro, inhibition reduces EGFR and HER2 autophosphorylation, subsequently inhibits signal transduction pathways, and demonstrates antitumor activity in overexpressed EGFR and/or HER2 carcinoma cells; neratinib human metabolites (M3, M6, M7, and M11) inhibit EGFR, HER2, and HER4 activity

Absorption

Peak plasma time: 2-8 hr (active metabolites M3, M6, and M7)

Systemic absorption increased with food

Peak plasma concentration: 1.7-fold (high fat); 1.2-fold (standard breakfast)

AUC: 2.2-fold (high fat); AUC: 1.1-fold (standard breakfast)

Distribution

Vd: 6433 L (steady-state)

Protein bound (in vitro): >99%

Metabolism

Primarily metabolized by CYP3A4 and, to a lesser extent, flavin-containing monooxygenase (FMO)

Metabolites (active): M3, M6, M7, and M11

Elimination

Half-life: 7-17 hr (single dose)

Half-life: 21.6 hr (M3 metabolite); 13.8 hr (M6 metabolite); 10.4 hr (M7 metabolite)

Excretion: Feces (97.1%) and urine (1.13%)

Oral Administration

Take with food at approximately the same time each day

Swallow tablet whole; do not chew, crush, or split

Missed dose: Do not replace missed dose; resume taking with the next scheduled daily dose

Antidiarrheal prophylaxis

• Antidiarrheal prophylaxis is recommended during the first 2 cycles (56 days) of treatment and should be initiated with the first dose
• Loperamide prophylaxis dose
  • Weeks 1-2: 4 mg PO TID
  • Weeks 3-8: 4 mg PO BID
  • Weeks 9-52: 4 mg PO prn; not to exceed 16 mg/day
  • May also require dose interruption and reduction and additional antidiarrheal agents may be required to manage diarrhea in patients with loperamide-refractory diarrhea (also see Dosage Modifications)

Storage

Store at room temperature, 20-25°C (68-77°F); excursions permitted to 15-30°C (59–86°F)