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.

NEXLETOL (NDA-211616)

(BEMPEDOIC ACID)

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

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03/22/2024 (SUPPL-12)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:

NEXLETOL is contraindicated in patients with a prior serious hypersensitivity reaction to bempedoic acid or any of the excipients in NEXLETOL. Serious hypersensitivity reactions, such as angioedema, have occurred [see Adverse Reactions (6.2)].

5 Warnings and Precautions

5.1 Hyperuricemia

Additions and/or revisions underlined:

NEXLETOL inhibits renal tubular OAT2 and may increase blood uric acid levels [see Clinical Pharmacology (12.3)]. In the primary hyperlipidemia trials [see Clinical Studies (14.2)], 26% of NEXLETOL-treated patients with normal baseline uric acid values (versus 9.5% placebo) experienced hyperuricemia one or more times, and 3.5% of patients experienced clinically significant hyperuricemia reported as an adverse reaction (versus 1.1% placebo). Increases in uric acid levels usually occurred within the first 4 weeks of treatment initiation, persisted throughout treatment, and returned to baseline following discontinuation of treatment. After 12 weeks of treatment, the mean placebo-adjusted increase in uric acid compared to baseline was 0.8 mg/dL for patients treated with NEXLETOL. In the cardiovascular outcomes trial [see Clinical Studies (14.1)], 16.4% of NEXLETOL-treated patients experienced clinically significant hyperuricemia reported as an adverse reaction (versus 8.2% placebo).

Elevated blood uric acid may lead to the development of gout. In the primary hyperlipidemia trials, gout was reported in 1.5% of patients treated with NEXLETOL and 0.4% of patients treated with placebo. In the cardiovascular outcomes trial, gout was reported in 3.2% of patients treated with NEXLETOL and 2.2% treated with placebo.

…

5.2Tendon Rupture

Additions and/or revisions underlined:

NEXLETOL is associated with an increased risk of tendon rupture or injury. In the primary hyperlipidemia trials [see Clinical Studies (14.2)], tendon rupture occurred in 0.5% of patients treated with NEXLETOL versus 0% of placebo-treated patients and involved the rotator cuff (the shoulder), biceps tendon, or Achilles tendon. Tendon rupture occurred within weeks to months of starting NEXLETOL. In the cardiovascular outcomes trial [see Clinical Studies (14.1)], tendon rupture events occurred in 1.2% of NEXLETOL-treated patients versus 0.9% of placebo- treated patients. Tendon rupture may occur more frequently in patients over 60 years of age, in those taking corticosteroid or fluoroquinolone drugs, in patients with renal failure, and in patients with previous tendon disorders.

6 Adverse Reactions

6.1 Clinical Trials Experience

Extensive changes; please refer to label for complete information.

6.2 Postmarketing Experience

Additions and/or revisions underlined:

Immune System Disorders: Hypersensitivity reactions including: angioedema, wheezing, rash, and urticaria.

7 Drug Interactions

Addition of title to table 3; please refer to label for complete information

Additions and/or revisions underlined:

Table 3 includes a list of drugs with clinically important drug interactions when administered concomitantly with NEXLETOL and instructions for preventing or managing them.

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

Risk Summary

Discontinue NEXLETOL when pregnancy is recognized unless the benefits of therapy outweigh the potential risks to the fetus.

There are insufficient data on NEXLETOL use in pregnant women to evaluate for a drug- associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

…

8.5 Geriatric Use

Additions and/or revisions underlined:

Of the 3,009 adult patients in the primary hyperlipidemia trials of NEXLETOL, 1,753 (58%) were 65 years of age and older, while 478 (16%) were 75 years of age and older.

Of the 13,970 adult patients in the cardiovascular outcomes trial [see Clinical Studies (14.2)], 8,204 (59%) were 65 years of age and older, while 2,107 (15%) were 75 years of age and older.

No overall differences in safety or effectiveness of NEXLETOL have been observed between patients 65 years of age and older and younger adult patients.

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

PATIENT INFORMATION

Extensive changes, please refer to label for complete information

03/22/2024 (SUPPL-13)

Approved Drug Label (PDF)

4 Contraindications

5 Warnings and Precautions

5.1 Hyperuricemia

Additions and/or revisions underlined:

…

5.2Tendon Rupture

Additions and/or revisions underlined:

6 Adverse Reactions

6.1 Clinical Trials Experience

Extensive changes; please refer to label for complete information.

6.2 Postmarketing Experience

Additions and/or revisions underlined:

Immune System Disorders: Hypersensitivity reactions including: angioedema, wheezing, rash, and urticaria.

7 Drug Interactions

Addition of title to table 3; please refer to label for complete information

Additions and/or revisions underlined:

Table 3 includes a list of drugs with clinically important drug interactions when administered concomitantly with NEXLETOL and instructions for preventing or managing them.

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

Risk Summary

Discontinue NEXLETOL when pregnancy is recognized unless the benefits of therapy outweigh the potential risks to the fetus.

There are insufficient data on NEXLETOL use in pregnant women to evaluate for a drug- associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

…

8.5 Geriatric Use

Additions and/or revisions underlined:

Of the 3,009 adult patients in the primary hyperlipidemia trials of NEXLETOL, 1,753 (58%) were 65 years of age and older, while 478 (16%) were 75 years of age and older.

Of the 13,970 adult patients in the cardiovascular outcomes trial [see Clinical Studies (14.2)], 8,204 (59%) were 65 years of age and older, while 2,107 (15%) were 75 years of age and older.

No overall differences in safety or effectiveness of NEXLETOL have been observed between patients 65 years of age and older and younger adult patients.

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

PATIENT INFORMATION

Extensive changes, please refer to label for complete information

09/20/2023 (SUPPL-14)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Newly added subsection:

The following adverse reactions have been identified during postapproval use of NEXLETOL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hypersensitivity: angioedema, wheezing, rash, and urticaria.

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

…

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Report pregnancies to the Esperion Therapeutics, Inc. Adverse Event reporting line at 1-833- 377-7633.

…

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Pregnancy

Advise pregnant women of the potential risk to a fetus based on NEXLETOL’s mechanism of action. Advise females to inform their healthcare provider of a known or suspected pregnancy. Advise patients that there is a pregnancy safety study that monitors pregnancy outcomes in patients exposed to NEXLETOL during pregnancy. Encourage these patients to report their pregnancy to Esperion at 1-833-377-7633 [see Use in Specific Populations (8.1)].

…

PATIENT INFORMATION

Additions and/or revisions underlined:

…

Before you start taking NEXLETOL, tell your healthcare provider about all your medical conditions, including if you:

have or had gout.
have or had tendon problems.
are pregnant. Tell your healthcare provider right away if you become pregnant while taking NEXLETOL. You and your healthcare provider will decide if you should take NEXLETOL while you are pregnant. If you are pregnant during NEXLETOL treatment, you are encouraged to call Esperion at 1-833-377-7633 to share information about the health of you and your baby.
are breastfeeding or plan to breastfeed. It is not known if NEXLETOL passes into your breast milk. You and your healthcare provider should decide if you will take NEXLETOL or breastfeed. You should not do both.
have severe kidney problems.
have severe liver problems.

…

What are possible side effects of NEXLETOL? NEXLETOL may cause serious side effects, including:

…

tendon rupture or injury. Tendon problems can happen in people who take NEXLETOL. Tendons are tough cords of tissue that connect muscles to bones. Symptoms of tendon problems may include pain, swelling, tears, and inflammation of tendons including the arm, shoulder, and back of the ankle (Achilles).
- Tendon rupture can happen while you are taking NEXLETOL. Tendon ruptures can happen within weeks or months of starting NEXLETOL.

…