Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

NERLYNX (NDA-208051)

(NERATINIB MALEATE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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06/28/2021 (SUPPL-9)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Diarrhea

(Additions and/or revisions are underlined)

Alternatively, a 2 weeks 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 (2.2)]. For patients who used NERLYNX dose escalation, the median time to first onset of Grade greater than or equal to 3 diarrhea was 45 days (range, 15–132) and the median cumulative duration of Grade greater than or equal 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 (6.1)].

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

Management of Diarrhea

CONTROL

The CONTROL (NCT02400476) study was a multicenter, open-label, multi-cohort trial evaluating patients with early-stage HER2-positive breast cancer treated with NERLYNX 240 mg daily for up to one year receiving loperamide prophylaxis with additional anti-diarrheal treatment as needed or NERLYNX dose escalation with loperamide as needed. All patients in the prophylaxis cohort received loperamide 4 mg loading dose, followed by 4 mg three times a day from days 1-14, followed by 4 mg twice a day on days 15-56, followed by loperamide as needed through 1 year of treatment with NERLYNX [see Dosage and Administration (2.1)]. All patients in the dose escalation cohort received NERLYNX 120 mg for Week 1, followed by NERLYNX 160 mg for Week 2, followed by NERLYNX 240 mg for Week 3 and thereafter [see Dosage and Administration (2.2)].

Table 9 summarizes the diarrhea adverse reactions for NERLYNX with loperamide prophylaxis and NERLYNX dose escalation.

7 Drug Interactions

7.2 Effect of NERLYNX on Other Drugs

(Additions and/or revisions are underlined)

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.

8 Use in Specific Populations

8.6 Hepatic Impairment

(Additions and/or revisions are underlined)

No dosage modifications are recommended for patients with mild to moderate hepatic impairment (Child Pugh A or B).

Neratinib clearance is reduced, and Cmax and AUC increase in patients with severe, pre-existing hepatic impairment (Child Pugh C). Reduce the NERLYNX dosage for patients with severe hepatic impairment. [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Diarrhea

Inform patients that NERLYNX has been associated with diarrhea, which may be severe in some cases.
When not using dose escalation, instruct patients to initiate antidiarrheal prophylaxis with the first dose of NERLYNX.
When using dose escalation, instruct patients to initiate 2 weeks of lower dose NERLYNX prior to receiving the recommended full dose of NERLYNX.

07/29/2020 (SUPPL-7)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Diarrhea

(Additions and/or revisions underlined)

…

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 greater than or equal to 3 diarrhea was 11 days (range, 2–728) and the median cumulative duration of Grade greater than or equal to 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 (6.1)].

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

…

Dosing and Administration

For patients undergoing extended adjuvant treatment for early stage breast cancer, instruct patients to take NERLYNX with food at approximately the same time each day consecutively until disease recurrence or for up to one year.
For patients treatment for metastatic breast cancer, instruct patients to take NERLYNX with food on days 1–21 of a 21-day cycle with capecitabine on Days 1–14 of a 21-day cycle until disease progression or unacceptable toxicities.
If a patient misses a dose, instruct the patient not to replace the missed dose, and to resume NERLYNX with the next scheduled daily dose [see Dosage and Administration (2.2)].

02/25/2020 (SUPPL-5)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Diarrhea

(additions underlined)

…

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 cycle. The majority of patients (70%) had diarrhea in the first cycle of treatment, the median time to first onset of Grade greater than or equal to 3 diarrhea was 11 days (range, 2-728) and the median cumulative duration of Grade greater than or equal to 3 diarrhea was 3 days (range, 1-21). In the NERLYNX plus capecitabine arm, Grade 3 diarrhea occurred in 24% of patients.

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. Consider adding other agents to loperamide as clinically indicated.

…

5.2 Hepatotoxicity

(additions underlined)

…

In the NALA study, in NERLYNX and capecitabine-treated patients, 7% experienced an ALT or AST >3x ULN, 2% experienced ALT or AST >5x ULN, 7% experienced a bilirubin >1.5x ULN, and 1.3% experienced a bilirubin >3x ULN. Hepatotoxicity or increases in liver transaminases led to drug discontinuation in 0.3% of NERLYNX and capecitabine-treated patients.

…

6 Adverse Reactions

6.1 Clinical Trials Experience

(extensive additions; please refer to label for complete information)

8 Use in Specific Populations

8.5 Geriatric Use

(additions and revisions underlined)

In the ExteNET trial, in the NERLYNX arm; 1236 patients were <65 years, 172 patients were greater than or equal to 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 greater than or equal to 65 years age group than in the <65 years age group; 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% (greater than or equal to 65 years old). The serious adverse reactions most frequently reported in the greater than or equal to 65 years old group were vomiting (2.3%), diarrhea (1.7%), renal failure (1.7%), and dehydration (1.2%).

In the NALA trial, in the NERLYNX plus capecitabine arm; 242 patients were <65 years, 61 patients were greater than or equal to 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 greater than or equal to 65 years age group was 36% and in the <65 years age group was 34%. The serious adverse reactions most frequently reported in the greater than or equal to 65 years-old group were diarrhea (16%), acute kidney injury (8%), and dehydration (7%). No overall differences in effectiveness were observed between patients greater than or equal to 65 years old and patients <65 years old.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

(additions underlined)

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Diarrhea

Inform patients that NERLYNX has been associated with diarrhea, which may be severe in some cases.
Advise patients to initiate antidiarrheal prophylaxis with the first dose of NERLYNX.
Instruct patients to maintain 1-2 bowel movements per day and on how to use antidiarrheal treatment regimens.
Advise patients to inform their healthcare provider immediately if severe (greater than or equal to Grade 3) diarrhea or diarrhea associated with weakness, dizziness, or fever occurs during treatment with NERLYNX.
…

PATIENT INFORMATION

(additions underlined)

…

What are the possible side effects of NERLYNX?

NERLYNX may cause serious side effects, including:

…

The most common side effects of NERLYNX when used alone include:

…

nosebleed

…

The most common side effects of NERLYNX when used with capecitabine include:

diarrhea
back pain
nausea
joint pain
vomiting
urinary tract infection
decreased appetite
upper respiratory tract infection
constipation
swelling of your stomach-area
tiredness/weakness
kidney problems
weight loss
muscle spasms
dizziness

…

02/25/2020 (SUPPL-6)

Approved Drug Label (PDF)

7 Drug Interactions

7.1 Effect of Other Drugs on NERLYNX

(addtions and revisions to Table 10, please refer to label for complete information)

04/18/2019 (SUPPL-3)

5 Warnings and Precautions

5.1 Diarrhea

(Additions and/or revisions are underlined)

Severe diarrhea and sequelae, such as dehydration, hypotension, and renal failure, have been reported during treatment with NERLYNX. Diarrhea was reported in 95% of NERLYNX-treated patients in ExteNET, a randomized placebo controlled trial, where no antidiarrheal prophylaxis was used. 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 greater than or equal to 3 diarrhea was 8 days (range, 1-350), and the median cumulative duration of Grade greater than or equal to 3 diarrhea was 5 days (range, 1-139).

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 two cycles (56 days) of treatment. Consider adding other agents to loperamide as clinically indicated.

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

CONTROL

CONTROL (NCT02400476) was a multicenter, open-label, multi-cohort trial evaluating patients with early stage HER2-positive breast cancer treated with neratinib 240 mg daily for up to one year receiving loperamide prophylaxis with/without an additional anti-diarrheal treatment. All patients received loperamide 4 mg loading dose, followed by 4 mg three times a day from days 1-14, followed by 4 mg twice a day on days 15-56, followed by loperamide as needed through 1 year of treatment with neratinib. One cohort of patients received budesonide 9 mg once daily on cycle 1 days 1-28, in addition to loperamide. At the interim analysis, the incidence of all grade diarrhea for patients receiving loperamide alone (n=109) was 78% compared to 86% of patients who received budesonide and loperamide (n=64). The incidence of Grade 2 diarrhea was 25% compared to 33%, respectively. The incidence of Grade 3 diarrhea was 32% compared to 28%, respectively. Diarrhea leading to treatment discontinuation occurred in 18% of patients treated with loperamide alone compared to 11% of the patients who received loperamide and budesonide.

06/28/2018 (SUPPL-2)

Approved Drug Label (PDF)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

(addition underlined)

…

Drug Interactions

NERLYNX may interact with many drugs; therefore, advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products.
NERLYNX may interact with gastric acid reducing agents. Advise patients to avoid concomitant use of proton pump inhibitors. When patients require gastric acid reducing agents, use an H2-receptor antagonist or antacid. Advise patients to separate the dosing of NERLYNX by 3 hours after antacid medicine, and to take NERLYNX at least 2 hours before or 10 hours after a H2-receptor antagonist.

…