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.

ATIVAN (NDA-018140)

(LORAZEPAM)

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

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01/13/2023 (SUPPL-51)

Approved Drug Label (PDF)

5 Warnings and Precautions

PRECAUTIONS

Newly added information:

PREGNANCY

Advise pregnant females who are administered ATIVAN Injection late in pregnancy that ATIVAN Injection 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 Ativan Injection during pregnancy (see PRECAUTIONS, Pregnancy).

NURSING

Instruct patients to notify their healthcare provider if they are breastfeeding or intend to breastfeed. Instruct breastfeeding patients who are administered ATIVAN Injection 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).

Pregnancy

Pregnancy Exposure Registry

There is a pregnancy registry that monitors pregnancy outcomes in woman exposed to psychiatric medications including ATIVAN Injection during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychiatric Medication’s 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 recognizable 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 Ativan Injection during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to Ativan Injection during pregnancy for signs of withdrawal. Manage these neonates accordingly (see WARNINGS, Neonatal Sedation and Withdrawal Syndrome).

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

Lorazepam 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 lorazepam on milk production are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ATIVAN Injection and any potential adverse effects on the breastfed infant from ATIVAN Injection or from the underlying maternal condition.

Clinical Considerations

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

WARNINGS

Newly added information:

Neonatal Sedation and Withdrawal Syndrome

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

02/05/2021 (SUPPL-46)

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 ATIVAN Injection, 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 ATIVAN Injection and throughout treatment,

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

• The continued use of benzodiazepines for several days to weeks may lead to clinically

significant physical dependence. The risks of dependence and withdrawal increase

with longer treatment duration and higher daily dose. Although ATIVAN Injection is

indicated only for intermittent use (see INDICATIONS AND USAGE and DOSAGE

AND ADMINISTRATION), if used more frequently than recommended, abrupt

discontinuation or rapid dosage reduction of ATIVAN Injection may precipitate acute

withdrawal reactions, which can be life-threatening. For patients using ATIVAN

Injection more frequently than recommended, to reduce the risk of withdrawal

reactions, use a gradual taper to discontinue ATIVAN Injection (see WARNINGS).

5 Warnings and Precautions

Warnings

(Newly added information)

Abuse, Misuse, and Addiction

The use of benzodiazepines, including ATIVAN Injection, 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 ATIVAN Injection and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction. Use of ATIVAN Injection, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of ATIVAN Injection 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.

Dependence and Withdrawal Reactions After Use of ATIVAN Injection More Frequently Than Recommended

For patients using ATIVAN Injection more frequently than recommended, to reduce the risk of withdrawal reactions, use a gradual taper to discontinue ATIVAN Injection (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 ATIVAN Injection is indicated only for intermittent use (see INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION), if used more frequently than recommended, abrupt discontinuation or rapid dosage reduction of ATIVAN Injection, 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

(Additions and/or revisions underlined)

RISKS FROM CONCOMITANT USE WITH OPIOIDS

Concomitant use of benzodiazepines, including ATIVAN Injection, and opioids may result in profound sedation, respiratory depression, coma, and death (see WARNINGS and PRECAUTIONS, Drug Interactions).

ABUSE, MISUSE, AND ADDICTION

Inform patients that the use of ATIVAN Injection 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 DRUG ABUSE AND DEPENDENCE).

WITHDRAWAL REACTIONS

Inform patients that use of ATIVAN Injection more frequently than recommended may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of ATIVAN Injection 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 DRUG ABUSE AND DEPENDENCE).

EXCESSIVE SEDATION

Patients should be informed of the pharmacological effects of the drug, including sedation, relief of anxiety, and lack of recall, the duration of these effects (about 8 hours), and be apprised of the risks as well as the benefits of therapy.

04/27/2017 (SUPPL-41)

Approved Drug Label (PDF)

4 Contraindications

Addition of the following:

ATIVAN Injection is contraindicated for use in premature infants because the formulation contains benzyl alcohol.

5 Warnings and Precautions

WARNINGS

Addition of the following:

Risks From Concomitant Use with Opioids

Concomitant use of benzodiazepines, including ATIVAN Injection, and opioids may result in profound

sedation, respiratory depression, coma, and death. If a decision is made to use ATIVAN Injection concomitantly with opioids, monitor patients closely for respiratory depression and sedation.

Usage in Preterm Infants and Neonates

ATIVAN Injection contains benzyl alcohol. Exposure to excessive amounts of benzyl alcohol has been associated with toxicity (hypotension, metabolic acidosis), particularly in neonates, and an increased incidence of kernicterus, particularly in small preterm infants. There have been rare reports of deaths, primarily in preterm infants, associated with exposure to excessive amounts of benzyl alcohol. The amount of benzyl alcohol from medications is usually considered negligible compared to that received in flush solutions containing benzyl alcohol. Administration of high dosages of medications (including ATIVAN) containing this preservative must take into account the total amount of benzyl alcohol administered. The recommended dosage range of ATIVAN for preterm and term infants includes amounts of benzyl alcohol well below that associated with toxicity; however, the amount of benzyl alcohol at which toxicity may occur is not known. If the patient requires more than the recommended dosages or other medications containing this preservative, the practitioner must consider the daily metabolic load of benzyl alcohol from these combined sources.

Pediatric Neurotoxicity

Published animal studies demonstrate that the administration of anesthetic and sedation drugs that block

NMDA receptors and/or potentiate GABA activity increase neuronal apoptosis in the developing brain and result in long-term cognitive deficits when used for longer than 3 hours. The clinical significance of these findings is not clear. However, based on the available data, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately three years of age in humans.

Some published studies in children suggest that similar deficits may occur after repeated or prolonged exposures to anesthetic agents early in life and may result in adverse cognitive or behavioral effects. These studies have substantial limitations, and it is not clear if the observed effects are due to the anesthetic/sedation drug administration or other factors such as the surgery or underlying illness.

Anesthetic and sedation drugs are a necessary part of the care of children needing surgery, other procedures, or tests that cannot be delayed, and no specific medications have been shown to be safer than any other. Decisions regarding the timing of any elective procedures requiring anesthesia should take into consideration the benefits of the procedure weighed against the potential risks.

PRECAUTIONS

Information for Patients

Addition of the following:

EFFECT OF ANESTHETIC AND SEDATION DRUGS ON EARLY BRAIN DEVELOPMENT

Studies conducted in young animals and children suggest repeated or prolonged use of general anesthetic or sedation drugs in children younger than 3 years may have negative effects on their developing brains. Discuss with parents and caregivers the benefits, risks, and timing and duration of surgery or procedures requiring anesthetic and sedation drugs.

Drug Interactions

INTERACTION WITH BENZODIAZEPINES AND OTHER CNS DEPRESSANTS

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. Monitor patients closely for respiratory depression and sedation.

Pregnancy

Published studies in pregnant primates demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity during the period of peak brain development increases neuronal apoptosis in the developing brain of the offspring when used for longer than 3 hours. There are no data on pregnancy exposures in primates corresponding to periods prior to the third trimester in humans.

In a published study in primates, administration of an anesthetic dose of ketamine for 24 hours on Gestation Day 122 increased neuronal apoptosis in the developing brain of the fetus. In other published studies, administration of either isoflurane or propofol for 5 hours on Gestation Day 120 resulted in increased neuronal and oligodendrocyte apoptosis in the developing brain of the offspring. With respect to brain development, this time period corresponds to the third trimester of gestation in the human. The clinical significance of these findings is not clear; however, studies in juvenile animals suggest neuroapoptosis correlates with long-term cognitive deficits.

Pediatric Use

Revised as below

STATUS EPILEPTICUS

… (i.e., seizures were not observed for 112 pediatric patients and 18 adults or during approximately 400 doses).

ATIVAN Injection contain benzyl alcohol as a preservative. Benzyl alcohol, a component of this product, has been associated with serious adverse events and death, particularly in pediatric patients. The “gasping syndrome”, (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages greater than 99 mg/kg/day in neonates and low-birth-weight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the “gasping syndrome”, the minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birth-weight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources.

GENERAL

… pediatric patients receiving high doses may be more susceptible to their effects.

Published juvenile animal studies demonstrate that the administration of anesthetic and sedation drugs, such as ATIVAN that either block NMDA receptors or potentiate the activity of GABA during the period of rapid brain growth or synaptogenesis, results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis. Based on comparisons across species, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately 3 years of age in humans.

In primates, exposure to 3 hours of ketamine that produced a light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 5 hours or longer of isoflurane increased neuronal cell loss. Data from isoflurane-treated rodents and ketamine-treated primates suggest that the neuronal and oligodendrocyte cell losses are associated with prolonged cognitive deficits in learning and memory. The clinical significance of these nonclinical findings is not known, and healthcare providers should balance the benefits of appropriate anesthesia in pregnant women, neonates and young children who require procedures with the potential risks suggested by the nonclinical data.

04/27/2017 (SUPPL-42)

Approved Drug Label (PDF)

4 Contraindications

Addition of the following:

ATIVAN Injection is contraindicated for use in premature infants because the formulation contains benzyl alcohol.

5 Warnings and Precautions

WARNINGS

Addition of the following:

Risks From Concomitant Use with Opioids

Concomitant use of benzodiazepines, including ATIVAN Injection, and opioids may result in profound

sedation, respiratory depression, coma, and death. If a decision is made to use ATIVAN Injection concomitantly with opioids, monitor patients closely for respiratory depression and sedation.

Usage in Preterm Infants and Neonates

Pediatric Neurotoxicity

Published animal studies demonstrate that the administration of anesthetic and sedation drugs that block

PRECAUTIONS

Information for Patients

Addition of the following:

EFFECT OF ANESTHETIC AND SEDATION DRUGS ON EARLY BRAIN DEVELOPMENT

Drug Interactions

INTERACTION WITH BENZODIAZEPINES AND OTHER CNS DEPRESSANTS

Pregnancy

Pediatric Use

Revised as below

STATUS EPILEPTICUS

… (i.e., seizures were not observed for 112 pediatric patients and 18 adults or during approximately 400 doses).

GENERAL

… pediatric patients receiving high doses may be more susceptible to their effects.

05/27/2016 (SUPPL-40)

Approved Drug Label (PDF)

8 Use in Specific Populations

Pediatric Use

STATUS EPILEPTICUS

The safety and effectiveness of ATIVAN for status epilepticus have not been established in pediatric patients. A randomized, double-blind, superiority-design clinical trial of ATIVAN versus intravenous diazepam in 273 pediatric patients ages 3 months to 17 years failed to establish the efficacy of ATIVAN for the treatment of status epilepticus. In that trial, assisted ventilation was required in 18% of patients treated with ATIVAN versus 16% of patients treated with diazepam. Patients treated with ATIVAN were also more likely to be reported as sedated (67% for ATIVAN vs. 50% for diazepam), and the time for return to baseline mental status was, on average, 2 hours longer for ATIVAN than for diazepam.
Open-label studies described in the medical literature included 273 pediatric patients; the age range was from a few hours old to 18 years of age. Paradoxical excitation was observed in 10% to 30% of the pediatric patients under 8 years of age and was characterized by tremors, agitation, euphoria, logorrhea, and brief episodes of visual hallucinations. Paradoxical excitation in pediatric patients also has been reported with other benzodiazepines when used for status epilepticus, as an anesthesia, or for pre-chemotherapy treatment.