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.

RESTORIL (NDA-018163)

(TEMAZEPAM)

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

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01/13/2023 (SUPPL-71)

Approved Drug Label (PDF)

5 Warnings and Precautions

WARNINGS

Newly added information:

…

Neonatal Sedation and Withdrawal Syndrome

Use of Restoril 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 PRECAUTIONS, Pregnancy). Monitor neonates exposed to Restoril during pregnancy or labor for signs of sedation and monitor neonates exposed to Restoril during pregnancy for signs of withdrawal; manage these neonates accordingly.

PRECAUTIONS

Newly added information:

…

Pregnancy

Advise pregnant females that use of Restoril 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, Neonatal Sedation and Withdrawal Syndrome and Precautions, Pregnancy). 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 Restoril during pregnancy (see Precautions, Pregnancy).

Nursing

Instruct patients to notify their healthcare provider if they are breastfeeding or intend to breastfeed. Instruct breastfeeding patients using Restoril to monitor infants for excessive sedation, poor feeding and poor weight gain, and to seek medical attention if they notice these signs (see Precautions, Nursing Mothers).

…

The benzodiazepines, including temazepam, produce additive CNS-depressant effects when co-administered with other CNS depressants such as alcohol, barbiturates, antipsychotics, sedative/hypnotics, anxiolytics, antidepressants, narcotic analgesics, sedative antihistamines, anticonvulsants, and anesthetics.

…

Pregnancy Exposure Registry

There is a pregnancy registry that monitors pregnancy outcomes in women exposed to psychiatric medications, including Restoril, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/pregnancyregistry/.

Risk Summary

Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal (see WARNINGS, Neonatal Sedation and Withdrawal Syndrome and Clinical Considerations). Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects (see Data).

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia and sedation in neonates. Monitor neonates exposed to Restoril during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to Restoril during pregnancy for signs of withdrawal. Manage these neonates accordingly (see WARNINGS, Neonatal Sedation and Withdrawal Syndrome).

Data

Human Data

Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects. Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted. In addition, the majority of more recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco and other medications, have not confirmed these findings.

Nursing Mothers

Risk Summary

Temazepam is 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 temazepam on milk production are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Restoril and any potential adverse effects on the breastfed infant from Restoril or from the underlying maternal condition.

Clinical Considerations

Infants exposed to Restoril 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/or revisions underlined:

…

Before you take RESTORIL, tell your healthcare provider about all of your medical conditions, including if you:

have a history of depression, mental illness or, suicidal thoughts
have a history of drug or alcohol abuse or addiction
have lung disease or breathing problems
are pregnant or plan to become pregnant.
- Taking RESTORIL 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 RESTORIL.
- There is a pregnancy registry for women who take RESTORIL during pregnancy. The purpose of the registry is to collect information about the health of women and their babies exposed to RESTORIL. If you become pregnant during treatment with RESTORIL, 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/research/pregnancyregistry/.
are breastfeeding, or plan to breastfeed. RESTORIL can pass through your breast milk.

Breastfeeding during treatment with RESTORIL may cause your baby to have sleepiness, feeding problems, and decreased weight gain.
Talk to your healthcare provider about the best way to feed your baby if you take RESTORIL.

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

Taking RESTORIL with certain other medicines can cause side effects or affect how well RESTORIL or the other medicines work. Do not start or stop other medicines without talking to your healthcare provider.

Do not take RESTORIL with other medicines that can make you sleepy unless your healthcare provider tells you to.

…

02/05/2021 (SUPPL-67)

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

• Concomitant use of benzodiazepines and opioids may result in profound

sedation, respiratory depression, coma, and death. Reserve concomitant

prescribing of these drugs 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 (see

WARNINGS and PRECAUTIONS).

• The use of benzodiazepines, including Restoril, exposes users to risks of

abuse, misuse, and addiction, which can lead to overdose or death. Abuse

and misuse of benzodiazepines commonly involve concomitant use of other

medications, alcohol, and/or illicit substances, which is associated with an

increased frequency of serious adverse outcomes. Before prescribing

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

misuse, and addiction (see WARNINGS).

• The continued use of benzodiazepines, including Restoril, may lead to

clinically significant physical dependence. The risks of dependence and

withdrawal increase with longer treatment duration and higher daily dose.

Abrupt discontinuation or rapid dosage reduction of Restoril 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

Restoril or reduce the dosage (see DOSAGE AND ADMINISTRATION and

WARNINGS).

5 Warnings and Precautions

Warnings

(Newly added information)

Abuse, Misuse, and Addiction

The use of benzodiazepines, including Restoril, 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, Abuse).

Before prescribing Restoril and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (e.g., using a standardized screening tool). Use of Restoril, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of Restoril 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.

Dependence and Withdrawal Reactions

To reduce the risk of withdrawal reactions, use a gradual taper to discontinue Restoril or reduce the dosage (a patient-specific plan should be used to taper the dose) (see DOSAGE AND ADMINISTRATION, Discontinuation or Dosage Reduction of Restoril).

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 Restoril, may lead to clinically significant physical dependence. Abrupt discontinuation or rapid dosage reduction of Restoril 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, Dependence).

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, Dependence).

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

Information for Patients

(Newly added information)

Advise the patient to read the FDA approved patient labeling (Medication Guide).

Risks from Concomitant Use with Opioids

Advise both patients and caregivers about the risks of potentially fatal respiratory depression and sedation when Restoril is used with opioids and not to use such drugs concomitantly unless supervised by a healthcare provider. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined (see WARNINGS, Risks from Concomitant Use with Opioids and PRECAUTIONS, Drug Interactions).

Abuse, Misuse, and Addiction

Inform patients that the use of Restoril, 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, Abuse, Misuse, and Addiction and DRUG ABUSE AND DEPENDENCE).

Withdrawal Reactions

Inform patients that the continued use of Restoril may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of Restoril 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 Restoril may require a slow taper (see WARNINGS, Dependence and Withdrawal Reactions and DRUG ABUSE AND DEPENDENCE).

Medication Guide

(Extensive changes; please refer to label)

02/06/2019 (SUPPL-65)

Approved Drug Label (PDF)

5 Warnings and Precautions

WARNINGS

(additions underlined)

…

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

…

PRECAUTIONS

(additions underlined)

…

Advise patients that increased drowsiness and decreased consciousness may increase the risk of falls in some patients.

…

12/16/2016 (SUPPL-64)

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, 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 Warnings and Precautions

WARNINGS

(additions underlined)

Concomitant use of benzodiazepines, including Restoril, 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 Restoril 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 Restoril than indicated in the absence of an opioid and titrate based on clinical response. If an opioid is initiated in a patient already taking Restoril, 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 Restoril 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

(addition 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.

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

MEDICATION GUIDE

(additions underlined)

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

· RESTORIL 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.

· After taking RESTORIL, you may get up out of bed while not being fully awake and do an activity that you do not know you are doing. The next morning, you may not remember that you did anything during the night. You have a higher chance for doing these activities if you drink alcohol or take other medicines that make you sleepy with

RESTORIL. Reported activities include:

· driving a car (“sleep-driving”)

· making and eating food

· talking on the phone

· having sex

· sleep-walking

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

taking RESTORIL.

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

What is RESTORIL?

· It is not known if RESTORIL is safe and effective in children.

· It is not known if RESTORIL is safe and effective for use longer than 2 weeks.

. See the end of this Medication Guide for a complete list of ingredients in RESTORIL.

Before you take RESTORIL, tell your healthcare provider about all of your medical conditions, including if you:

· have a history of depression, mental illness or, suicidal thoughts

· have a history of drug or alcohol abuse or addiction

· lung disease or breathing problems

· are pregnant or plan to become pregnant. RESTORIL may cause birth defects or harm your unborn baby.

· are breastfeeding, or plan to breastfeed. RESTORIL may pass through your breast milk and may harm your baby.

Talk to your healthcare provider about the best way to feed your baby if you take RESTORIL.

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

Do not take RESTORIL with other medicines that can make you sleepy unless your healthcare provider tells you to.

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

· See “What is the most important information I should know about RESTORIL

· Withdrawal symptoms. You may have withdrawal symptoms if you stop taking RESTORIL suddenly. Withdrawal symptoms can be serious and include seizures shakiness, stomach and muscle cramps, vomiting and sweating. Mild

withdrawal symptoms include a depressed mood and trouble sleeping. Talk to your healthcare provider about slowly stopping RESTORIL to avoid withdrawal symptoms.

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

· Abuse and dependence. Taking RESTORIL 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.

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