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.

VALTOCO (NDA-211635)

(DIAZEPAM)

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

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04/15/2025 (SUPPL-10)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

VALTOCO (Diazepam Nasal Spray)

Clinical studies of patients with epilepsy 2 years of age and older were conducted to support the safety and tolerability of VALTOCO for the treatment of acute repetitive seizures. A total of 255 patients 2 years of age and older received VALTOCO, of whom 143 received VALTOCO for at least 1 year. Other than adverse reactions related to local nasal administration, the adverse reactions reported in these studies were similar to those seen in the efficacy trials of diazepam rectal gel.

The most commonlocal adverse reactions that occurred in at least 1% of VALTOCO-treated patients were nasal discomfort (5%), dysgeusia (2%), epistaxis (2%), and rhinorrhoea (1%).

…

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

Safety and effectiveness of VALTOCO have been established in pediatric patients 2 years to 16 years of age. Use of VALTOCO in this age group is supported by evidence from adequate and well-controlled studies of diazepam rectal gel in adult and pediatric patients, adult bioavailability studies comparing VALTOCO with diazepam rectal gel, patient pharmacokinetic data, and open-label safety studies of VALTOCO including patients 2 years to 16 years of age [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14)].

Safety and effectiveness of VALTOCO in pediatric patients below the age of 2 years have not been established.

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

MEDICATION GUIDE

Additions and/or revisions underlined:

What is VALTOCO?

VALTOCO is a prescription medicine used for short-term treatment of seizure clusters (also known as “acute repetitive seizures”) that are different from a person’s normal seizure pattern in people 2 years of age and older.
…

01/13/2023 (SUPPL-8)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.7 Neonatal Sedation and Withdrawal Syndrome

Newly added subsection:

Use of VALTOCO late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate [see Use in Specific Populations (8.1)]. Monitor neonates exposed to VALTOCO during pregnancy or labor for signs of sedation and monitor neonates exposed to VALTOCO during pregnancy for signs of withdrawal; manage these neonates accordingly.

6 Adverse Reactions

ADVERSE REACTIONS

Additions and revisions underlined:

The following serious adverse reactions are discussed elsewhere in the labeling:

. . .

Neonatal Sedation and Withdrawal Syndrome [see Warnings and Precautions (5.7)]

8 Use in Specific Populations

8.1 Pregnancy

Extensive changes; please refer to label

8.2 Lactation

Additions and revisions underlined:

Risk Summary

Diazepam is excreted in human milk.

There are reports of sedation, poor feeding, and poor weight gain in infants exposed to benzodiazepines through breast milk. There are no data to assess the effects of diazepam and/or its active metabolite(s) on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for VALTOCO nasal spray and any potential adverse effects on the breastfed infant from VALTOCO or from the underlying maternal condition.

Clinical Considerations

Infants exposed to VALTOCO through breast milk should be monitored for sedation, poor feeding and poor weight gain.

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

MEDICATION GUIDE

Additions and revisions underlined:

Before using VALTOCO, tell your healthcare provider about all of your medical conditions, including if you:

. . .

are pregnant or plan to become pregnant.
- Taking VALTOCO late in pregnancy may cause your baby to have symptoms of sedation (breathing problems, sluggishness, low muscle tone) and/or withdrawal symptoms (jitteriness, irritability, restlessness, shaking, excessive crying, feeding problems).
- Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with VALTOCO.
- If you become pregnant while using VALTOCO, talk to your healthcare provider about registering with the North American Antiepileptic Drug (NAAED) Pregnancy Registry. You can register by calling 1-888-233-2334. For more information about the registry, go to http://www.aedpregnancyregistry.org. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy.
are breastfeeding or plan to breastfeed. VALTOCO passes into your breast milk and may harm your baby.
- Breastfeeding during treatment with VALTOCO may cause your baby to have sleepiness, feeding problems, and decreased weight gain.

PATIENT COUNSELING INFORMATION

Additions and revisions underlined:

Pregnancy

Advise pregnant females that the use of VALTOCO late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in newborns [see Warnings and Precautions (5.7) and Use in Specific Populations (8.1)].

. . .

Lactation

Counsel patients that diazepam, the active ingredient in VALTOCO, is excreted in breast milk. Instruct patients to inform their healthcare provider if they are breastfeeding or intend to breastfeed. Instruct breastfeeding patients who take VALTOCO to monitor their infants for excessive sedation, poor feeding and poor weight gain, and to seek medical attention if they notice these signs [see Use in Specific Populations (8.2)].

02/04/2022 (SUPPL-7)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

VALTOCO (Diazepam Nasal Spray)

Additions and/or revisions underlined:

Clinical studies of patients with epilepsy 6 years of age and older were conducted to support the safety and tolerability of VALTOCO for the treatment of acute repetitive seizures. A total of 220 patients 6 years of age and older received VALTOCO, of whom 134 received VALTOCO for at least 1 year. Other than adverse reactions related to local nasal administration, the adverse reactions reported in these studies were similar to those seen in the efficacy trials of diazepam rectal gel.

The most common local adverse reactions that occurred in VALTOCO-treated patients were nasal discomfort (6%), dysgeusia (3%), and epistaxis (2%).

02/05/2021 (SUPPL-3)

Approved Drug Label (PDF)

Boxed Warning

(Additions and/or revisions underlined)

WARNING: RISKS FROM CONCOMITANT USE WITH

OPIOIDS; ABUSE, MISUSE, AND ADDICTION; and

DEPENDENCE AND WITHDRAWAL REACTIONS

See full prescribing information for complete boxed warning

• Concomitant use of benzodiazepines and opioids may result

in profound sedation, respiratory depression, coma, and

death. (5.1, 7.1)

• The use of benzodiazepines, including VALTOCO, exposes

users to risks of abuse, misuse, and addiction, which can lead

to overdose or death. Before prescribing VALTOCO and

throughout treatment, assess each patient’s risk for abuse,

misuse, and addiction. (5.2)

• Although VALTOCO is indicated only for intermittent use

(1, 2), if used more frequently than recommended, abrupt

discontinuation or rapid dosage reduction of VALTOCO

may precipitate acute withdrawal reactions, which can be

life-threatening. For patients using VALTOCO more

frequently than recommended, to reduce the risk of

withdrawal reactions, use a gradual taper to discontinue

VALTOCO. (5.3)

5 Warnings and Precautions

5.2 Abuse, Misuse, and Addiction

(Newly added section)

The use of benzodiazepines, including VALTOCO, exposes users to the risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death [see Drug Abuse and Dependence (9.2)].

Before prescribing VALTOCO and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction. Use of VALTOCO, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of VALTOCO along with monitoring for signs and symptoms of abuse, misuse, and addiction. Do not exceed the recommended dosing frequency; avoid or minimize concomitant use of CNS depressants and other substances associated with abuse, misuse, and addiction (e.g., opioid analgesics, stimulants); and advise patients on the proper disposal of unused drug. If a substance use disorder is suspected, evaluate the patient and institute (or refer them for) early treatment, as appropriate.

5.3 Dependence and Withdrawal Reactions After Use of VALTOCO More Frequently Than Recommended

(Newly added section)

For patients using VALTOCO more frequently than recommended, to reduce the risk of withdrawal reactions, use a gradual taper to discontinue VALTOCO (a patient-specific plan should be used to taper the dose).

Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages, and those who have had longer durations of use.

Acute Withdrawal Reactions

The continued use of benzodiazepines may lead to clinically significant physical dependence. Although VALTOCO is indicated only for intermittent use [see Indications and Usage (1) and Dosage and Administration (2)], if used more frequently than recommended, abrupt discontinuation or rapid dosage reduction of VALTOCO, or administration of flumazenil (a benzodiazepine antagonist) may precipitate acute withdrawal reactions, which can be life-threatening (e.g., seizures) [see Drug Abuse and Dependence (9.3)].

Protracted Withdrawal Syndrome

In some cases, benzodiazepine users have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months [see Drug Abuse and Dependence (9.3)].

6 Adverse Reactions

(Additions and/or revisions underlined)

The following serious adverse reactions are discussed elsewhere in the labeling:

Risk of Concomitant Use with Opioids [see Warnings and Precautions (5.2)]
Abuse, Misuse, and Addiction [see Warnings and Precautions (5.2)]
Dependence and Withdrawal Reactions After Use of VALTOCO More Frequently Than

Recommended [see Warnings and Precautions (5.3)]

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

Medication Guide

(Extensive changes; please refer to label)

Patient Counseling Information

(Newly added information)

Abuse, Misuse, and Addiction

Inform patients that the use of VALTOCO more frequently than recommended, even at recommended dosages, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose and death, especially when used in combination with other medications (e.g., opioid analgesics), alcohol, and/or illicit substances. Inform patients about the signs and symptoms of benzodiazepine abuse, misuse, and addiction; to seek medical help if they develop these signs and/or symptoms; and on the proper disposal of unused drug [see Warnings and Precautions (5.2) and Drug Abuse and Dependence (9.2)].

Withdrawal Reactions

Inform patients that use of VALTOCO more frequently than recommended may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of VALTOCO may precipitate acute withdrawal reactions, which can be life-threatening. Inform patients that in some cases, patients taking benzodiazepines have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months [see Warnings and Precautions (5.3) and Drug Abuse and Dependence (9.3)].