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.

DORAL (NDA-018708)

(QUAZEPAM)

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

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01/13/2023 (SUPPL-29)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.9 Neonatal Sedation and Withdrawal Syndrome

Newly added subsection:

Use of DORAL 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 DORAL during pregnancy or labor for signs of sedation and monitor neonates exposed to DORAL during pregnancy for signs of withdrawal; manage these neonates accordingly.

6 Adverse Reactions

Newly added information:

Neonatal Sedation and Withdrawal Syndrome [see Warnings and Precautions (5.9)]

8 Use in Specific Populations

8.1 Pregnancy

Extensive changes; please refer to label

8.3 Nursing Mothers

Newly added information:

Risk Summary

Quazepam and its metabolites are present in breast milk. There are reports of sedation, poor feeding and poor weight gain in infants exposed to benzodiazepines through breast milk. The effects of quazepam on milk production are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for DORAL and any potential adverse effects on the breastfed infant from DORAL or from the underlying maternal condition.

Clinical Considerations

Infants exposed to DORAL 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:

Taking DORAL 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 DORAL.
There is a pregnancy registry for women who take DORAL during pregnancy. The purpose of the registry is to collect information about the health of you and your baby. If you become pregnant during treatment with DORAL, talk to your healthcare provider about registering with the National Pregnancy Registry for Psychiatric Medications. You can register by calling 1-866-961-2388 or visiting https://womensmentalhealth.org/pregnancyregistry/.

. . .

Breastfeeding during treatment with DORAL may cause your baby to have sleepiness, feeding problems, and decreased weight gain.

PATIENT COUNSELING INFORMATION

Newly added information:

Advise pregnant females that use of DORAL 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 (5.9), Use in Specific Populations (8.1)]. Instruct patients to inform their healthcare provider if they are pregnant.

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to DORAL during pregnancy [see Use in Specific Populations (8.1)].

Nursing

Instruct patients to notify their healthcare provider if they are breastfeeding or intend to breastfeed. Instruct breastfeeding patients using DORAL to monitor 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 (8.3)].

02/05/2021 (SUPPL-27)

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 informationfor complete boxed warning.

• Concomitant use of benzodiazepines and opioids may result in

profound sedation, respiratory depression, coma, and death.

Reserve concomitant prescribing of these drugs for use in patients

for whom alternative treatment options are inadequate. Limit

dosages and durations to the minimum required.Follow patients

for signs and symptoms of respiratory depression and Sedation

(5.1, 7).

• The use of benzodiazepines, including DORAL, exposes users to

risks of abuse, misuse, and addiction, which can lead to overdose or

death. Before prescribing DORAL and throughout treatment,

assess each patient’s risk for abuse, misuse, and addiction (5.2).

• Abrupt discontinuation or rapid dosage reduction of DORAL after

continued use may precipitate acute withdrawal reactions, which

can be life-threatening. To reduce the risk of withdrawal reactions,

use a gradual taper to discontinue DORAL or reduce the dosage

(2.3, 5.3).

5 Warnings and Precautions

5.2 Abuse, Misuse, and Addiction

(Newly added section)

The use of benzodiazepines, including DORAL, 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 DORAL and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (e.g., using a standardized screening tool). Use of DORAL, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of DORAL along with monitoring for signs and symptoms of abuse, misuse, and addiction. Prescribe the lowest effective dosage; 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

(Newly added section)

To reduce the risk of withdrawal reactions, use a gradual taper to discontinue DORAL or reduce the dosage (a patient-specific plan should be used to taper the dose) [see Dosage and Administration (2.3)].

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, including DORAL, may lead to clinically significant physical dependence. Abrupt discontinuation or rapid dosage reduction of DORAL after continued use, 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 in greater detail in other sections of the label:

Risks from Concomitant Use with Opioids [see Warnings and Precautions (5.1)]
Abuse, Misuse, and Addiction [see Warnings and Precautions (5.2)]
Dependence and Withdrawal Reactions [see Warnings and Precautions (5.3)]

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

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Advise the patient to read the FDA-approved patient labeling (Medication Guide). Risks from Concomitant Use with Opioids

Inform patients and caregivers that potentially fatal additive effects may occur if DORAL is used with opioids and not to use such drugs concomitantly unless supervised by a health care provider [see Warnings and Precautions (5.1), Drug Interactions (7)].

Abuse, Misuse, and Addiction

Inform patients that the use of DORAL 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 the continued use of DORAL may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of DORAL 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. Instruct patients that discontinuation or dosage reduction of DORAL may require a slow taper [see Warnings and Precautions (5.3) and Drug Abuse and Dependence (9.3)].

CNS Depressant Effects and Next-Day Impairment

Tell patients that DORAL can cause next-day impairment, even in the absence of symptoms. Caution patients against driving or engaging in other hazardous activities or activities requiring complete mental alertness when using DORAL. Tell patients that daytime impairment may persist for several days following discontinuation of DORAL. Advise patients that increased drowsiness and decreased consciousness may increase the risk of falls in some patients [see Warnings and Precautions (5.4)].

02/06/2019 (SUPPL-25)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 CNS-Depresant Effects and Daytime Impairment

(additions underlined)

…

Because DORAL can cause drowsiness and a decreased level of consciousness, patients particularly the elderly, are at higher risk of falls.

12/16/2016 (SUPPL-23)

Approved Drug Label (PDF)

Boxed Warning

(new section added)

WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratorydepression, coma, and death.

· Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

· Limit dosages and durations to the minimum required.

· Follow patients for signs and symptoms of respiratory depression and sedation.

5 Warnings and Precautions

5.1 Risks from Concomitant Use with Opioids

(additions underlined)

Concomitant use of benzodiazepines, including TRADENAME, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

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. If a decision is made to prescribe Doral concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of respiratory depression and sedation. In patients already receiving an opioid analgesic, prescribe a lower initial dose of Doral than indicated in the absence of an opioid and titrate based on clinical response. If an opioid is initiated in a patient already taking Doral, prescribe a lower initial dose of the opioid and titrate based upon clinical response.

Advise both patients and caregivers about the risks of respiratory depression and sedation when Doral is used with opioids. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined.

7 Drug Interactions

(additions underlined)

The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at GABAA sites and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists.

Limit dosage and duration of concomitant use of benzodiazepines and opioids, and monitor patients closely for respiratory depression and sedation.

Benzodiazepines, including DORAL, produce additive CNS depressant effects when co-administered with ethanol or other CNS depressants (e.g. psychotropic medications, anticonvulsants, antihistamines). Downward dose adjustment of DORAL and/or concomitant CNS depressants may be necessary because of additive effects.

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

17 PATIENT COUNSELING INFORMATION

(additions underlined)

Inform patients and caregivers that potentially fatal additive effects may occur if Doral is used with opioids and not to use such drugs concomitantly unless supervised by a health care provider.

MEDICATION GUIDE

(additions nderlined)

What is the most important information I should know about DORAL?

· DORAL is a benzodiazepine medicine. Taking benzodiazepines with opioid medicines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, breathing problems (respiratory depression), coma and death.

· DORAL may cause serious side effects that you may not know are happening to you. These side effects include:

· sleepiness during the day

· not thinking clearly

· acting strangely, confused, or upset“sleep-walking”

or doing other activities when you are asleep like:

· eating

· talking

· having sex

· driving a car

Call your healthcare provider right away if you find out that you have done any of the above activities after taking DORAL.

· Do not take DORAL unless you are able to stay in bed a full night (7 to 8 hours) before you must be active again.

· Do not take more DORAL than prescribed.

What is DORAL?

• It is not known if DORAL is safe and effective in children.

Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Taking DORAL with certain other medicines can cause side effects or affect how well DORAL or the other medicines work.

Do not start or stop other medicines without talking to your healthcare provider.

How should I take DORAL?

· If you take too much DORAL or overdose, get emergency treatment right away.

What should I avoid while taking DORAL?

· Do not drive, operate machinery, do other dangerous activities or do anything that needs you to be alert until you know how DORAL affects you. You may still feel drowsy the next day after taking DORAL.

· You should not drink alcohol while you are taking DORAL.

What are the possible side effects of DORAL?

DORAL may cause serious side effects, including:

See “What is the most important information I should know about DORAL?”

· Withdrawal symptoms. You may have withdrawal symptoms if you stop taking DORAL suddenly. Withdrawal symptoms can be serious and include seizures. Mild withdrawal symptoms include a depressed mood and trouble sleeping. Talk to your healthcare provider about slowly stopping DORAL to avoid withdrawal symptoms.

· Other conditions. Call your healthcare provider if your insomnia worsens or is not better within 7 to 10 days. This may mean that there is another condition causing your sleep problem.

· Severe allergic reactions. Symptoms include swelling of the tongue or throat, and trouble breathing. Other symptoms may include nausea and vomiting. Get emergency medical help right away if you have these symptoms after taking DORAL.

· Abnormal thoughts and behavior. Symptoms include more outgoing or aggressive behavior than normal, confusion, agitation, hallucinations, worsening of depression, and suicidal thoughts.

· Depression. Pre-existing depression may emerge or worsen during use of benzodiazepines including DORAL.

· Abuse and dependence. Taking DORAL can cause physical and psychological dependence. Physical and psychological dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical and psychological dependence and drug addiction.