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.

XTRELUS (NDA-208085)

(GUAIFENESIN; HYDROCODONE BITARTRATE)

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

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12/22/2025 (SUPPL-3)

Approved Drug Label (PDF)

Boxed Warning

Additions and/or revisions underlined:

. . .

Neonatal Opioid Withdrawal Syndrome

Xtrelus is not recommended for use in pregnant women [see Use in Specific Populations (8.1)]. Advise pregnant women using opioids for an extended period of time of the risk of Neonatal Opioid Withdrawal Syndrome, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery [see Warnings and Precautions (5.13)].

5 Warnings and Precautions

5.1 Addiction, Abuse, and Misuse

Additions and/or revisions underlined:

. . .

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Xtrelus. Addiction can occur at recommended dosages and if the drug is misused or abused. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. In postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use [see Adverse Reactions (6)]. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression).

. . .

5.2 Life-Threatening Respiratory Depression

Additions and/or revisions underlined:

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, including hydrocodone, one of the active ingredients in Xtrelus. Hydrocodone produces dose-related respiratory depression by directly acting on the brain stem respiratory center that controls respiratory rhythm and may produce irregular and periodic breathing. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression includes discontinuation of Xtrelus, close observation, supportive measures, and use of opioid overdose reversal agents (e.g., naloxone or nalmefene), depending on the patient’s clinical status [see Overdosage (10)]. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

. . .

5.8 Risks from Concomitant Use with Benzodiazepines or other CNS Depressants

Additions and/or revisions underlined:

Concomitant use of opioids, including Xtrelus, with benzodiazepines, gabapentinoids (gabapentin or pregabalin), or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Because of these risks, avoid use of opioid cough medications in patients taking benzodiazepines, other CNS depressants, or alcohol [see Drug Interactions (7.1, 7.4)].

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. Because of similar pharmacologic properties, it is reasonable to expect similar risk with concomitant use of opioid cough medications and benzodiazepines, gabapentinoids (gabapentin or pregabalin), other CNS depressants, or alcohol.

Advise both patients and caregivers about the risks of respiratory depression and sedation if Xtrelus is used with benzodiazepines, gabapentinoids (gabapentin or pregabalin), alcohol, or other CNS depressants [see Patient Counseling Information (17)].

. . .

5.9 Risks of Gastrointestinal Complications

Subsection title revised

Additions and/or revisions underlined:

. . .

Cases of opioid-induced esophageal dysfunction (OIED) have been reported in patients taking opioids. The risk of OIED may increase as the dose and/or duration of opioids increases. Regularly evaluate patients for signs and symptoms of OIED (e.g., dysphagia, regurgitation, non-cardiac chest pain) and, if necessary, adjust opioid therapy as clinically appropriate [see Clinical Pharmacology (12.2)].

6 Adverse Reactions

Additions and/or revisions underlined:

. . .

Opioid-induced esophageal dysfunction (OIED): Cases of OIED have been reported in patients taking opioids and may occur more frequently in patients taking higher doses of opioids, and/or in patients taking opioids longer term.

7 Drug Interactions

7.4 Benzodiazepines, and Other CNS Depressants

Additions and/or revisions underlined:

Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids (gabapentin or pregabalin), and other opioids, can increase the risk of

hypotension, respiratory depression, profound sedation, coma, and death. Avoid the use of Xtrelus in patients who are taking benzodiazepines, gabapentinoids (gabapentin or pregabalin), or other CNS depressants [see Warnings and Precautions (5.8)], and instruct patients to avoid consumption of alcohol while on Xtrelus [see Warnings and Precautions (5.8), Drug Interactions (7.1), Patient Counseling Information (17)].

7.7 Muscle Relaxants

Additions and/or revisions underlined:

Hydrocodone may enhance the neuromuscular blocking action of skeletal muscle relaxants (e.g., cyclobenzaprine, metaxalone) and produce an increased degree of respiratory depression. Avoid the use of Xtrelus in patients taking muscle relaxants. If concomitant use is necessary, monitor patients for signs of respiratory depression that may be greater than otherwise expected.

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

. . .

Clinical Considerations

. . .

Labor or Delivery

Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid overdose reversal agent, such as naloxone or nalmefene, must be available for reversal of opioid- induced respiratory depression in the neonate. Opioids, including Xtrelus, can prolong labor through actions which temporarily reduce the strength, duration and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor.

Monitor neonates exposed to opioids during labor for signs of excess sedation and respiratory depression.

. . .

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

MEDICATION GUIDE

Additions and/or revisions underlined:

What is the most important information I should know about Xtrelus? Xtrelus is not for children under 18 years of age.

Xtrelus can cause serious side effects, including:

. . .

Severe drowsiness, breathing problems (respiratory depression), coma and death can happen in people who take Xtrelus with benzodiazepines, gabapentinoids (gabapentin or pregabalin), or other central nervous system depressants, including alcohol.

Do not take benzodiazepines or any medicine that can cause drowsiness or sleepiness during treatment with Xtrelus.
Do not drink alcohol or take prescription or over-the-counter medicines that contain alcohol during treatment with Xtrelus.

. . .

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

. . .

Interactions with Benzodiazepines and Other Central Nervous System Depressants, Including Alcohol

Inform patients and caregivers that potentially fatal additive effects may occur if Xtrelus is used with benzodiazepines or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedative/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin], and other opioids). Advise patients to avoid concomitant use of Xtrelus with benzodiazepines or other CNS depressants and instruct patients not to consume alcoholic beverages, as well as prescription and over-the-counter products that contain alcohol, during treatment with Xtrelus [see Warnings and Precautions (5.8), Drug Interactions (7.1, 7.4)].

. . .

12/15/2023 (SUPPL-2)

Approved Drug Label (PDF)

6 Adverse Reactions

(Additions and/or revisions underlined)

The following serious adverse reactions are described, or described in greater detail, in other sections:

…

Other: Drug abuse, drug dependence, opioid withdrawal syndrome.

Hypoglycemia: Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes).