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.

AMBIEN (NDA-019908)

(ZOLPIDEM TARTRATE)

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

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02/23/2022 (SUPPL-40)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.7 Respiratory Depression

Additions underlined

… Since sedative-hypnotics have the capacity to depress respiratory drive, precautions should be taken if AMBIEN is prescribed to patients with compromised respiratory function or concomitant use with opioids or other CNS depressants. Postmarketing reports of respiratory insufficiency in patients receiving 10 mg of zolpidem tartrate, most of whom had pre- existing respiratory impairment, have been reported. The risk of respiratory depression should be considered prior to prescribing AMBIEN in patients with respiratory impairment including sleep apnea and myasthenia gravis or with concomitant opioid use [see Dosage and Administration (2.3), Drug Interactions (7.1)].

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

MEDICATION GUIDE

Additions underlined

…

AMBIEN and other medicines can interact with each other causing serious side effects. AMBIEN may affect the way other medicines work, and other medicines may affect how AMBIEN works.

Especially tell your healthcare provider if you:

take benzodiazepines
take opioids as it may increase the risk of breathing problems (respiratory depression)
take tricyclic antidepressants
take other medicines that can make you sleepy or affect your breathing (including other zolpidem medicines)
drink alcohol
You can ask your pharmacist for a list of medicines that interact with AMBIEN.
Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.
…

PATIENT COUNSELING INFORMATION

Additions underlined

…

Concomitant Use with Opioids

Inform patients and caregivers that potentially serious additive effects may occur if AMBIEN is used with opioids and not to use such drugs concomitantly unless supervised by a healthcare provider [see Warnings and Precautions (5.2, 5.7), Drug Interactions (7.1)].

…

02/23/2022 (SUPPL-44)

Approved Drug Label (PDF)

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

MEDICATION GUIDE

Additions underlined

…

What is AMBIEN?

AMBIEN is a prescription sleep medicine used for the short-term treatment of adults who have trouble falling asleep (insomnia).

It is not known if AMBIEN is safe and effective in children under the age of 18 years. AMBIEN is not recommended for use in children under the age of 18 years.
AMBIEN is a federally controlled substance (C-IV) because it can be abused or lead to dependence. Keep AMBIEN in a safe place to protect it from theft. Never give your AMBIEN to anyone else because it may cause death or harm them. Selling or giving away this medicine is against the law.

02/23/2022 (SUPPL-47)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 Abnormal Thinking and Behavioral Changes

Additions underlined

…

In controlled trials of AMBIEN 10 mg taken at bedtime <1% of adults with insomnia reported hallucinations. In a clinical trial, 7% of pediatric patients treated with AMBIEN 0.25 mg/kg taken at bedtime reported hallucinations versus 0% treated with placebo [see Use in Specific Populations (8.4)]. There have been postmarketing reports of delirium with zolpidem use [Adverse Reactions (6.2)].

…

6 Adverse Reactions

6.2 Postmarketing Experience

Additions underlined

…

Psychiatric disorders: delirium

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

MEDICATION GUIDE

Additions underlined

…

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

See “What is the most important information I should know about AMBIEN?”
AMBIEN can make you sleepy or dizzy and can slow your thinking and motor skills. Because AMBIEN can make you sleepy or dizzy you are at a higher risk for falls.
- Do not drive, operate heavy machinery, or do other dangerous activities until you know how AMBIEN affects you.
- Do not drink alcohol or take opioids or other medicines that may make you sleepy or dizzy while taking AMBIEN without first talking to your healthcare provider. When taken with alcohol or other medicines that cause sleepiness or dizziness, AMBIEN may make your sleepiness or dizziness much worse.
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 develop any of these symptoms during treatment with AMBIEN.
Abnormal thoughts and behavior. Symptoms include more outgoing or aggressive behavior than normal, confusion (delirium), acting strangely, agitation, hallucinations, worsening of depression, and suicidal thoughts or actions.
Risk of suicide and worsening of depression. Worsening of depression, including suicidal thoughts and actions can happen during treatment with medicines like AMBIEN. Call your healthcare provider right away if you develop any thoughts of suicide, dying, or worsening depression during treatment with AMBIEN.
Breathing problems. See “Before taking AMBIEN, tell your healthcare provider about all of your medical conditions, including if you:” Call your healthcare provider or get emergency medical help right away if you develop breathing problems during treatment with AMBIEN.
Problems with your nervous system caused by severe liver disease (hepatic encephalopathy).
Withdrawal symptoms. You may have withdrawal symptoms if you stop taking AMBIEN suddenly. Withdrawal symptoms can be serious and include stomach and muscle cramps, vomiting, sweating, shakiness, seizures, and confusion (delirium). Talk to your healthcare provider about slowly stopping AMBIEN to avoid withdrawal symptoms.
…

08/18/2019 (SUPPL-46)

Approved Drug Label (PDF)

Boxed Warning

Newly added section:

WARNING: COMPLEX SLEEP BEHAVIORS

Complex sleep behaviors including sleep-walking, sleep-driving, and engaging in other activities while not fully awake may occur following use of AMBIEN. Some of these events may result in serious injuries, including death. Discontinue AMBIEN immediately if a patient experiences a complex sleep behavior.

4 Contraindications

Addition of the following:

who have experienced complex sleep behaviors after taking AMBIEN

5 Warnings and Precautions

Newly added subsection:

5.1 Complex Sleep Behaviors

Complex sleep behaviors, including sleep-walking, sleep-driving, and engaging in other activities while not fully awake, may occur following the first or any subsequent use of AMBIEN. Patients can be seriously injured or injure others during complex sleep behaviors. Such injuries may result in a fatal outcome. Other complex sleep behaviors (e.g., preparing and eating food, making phone calls, or having sex) have also been reported. Patients usually do not remember these events. Postmarketing reports have shown that complex sleep behaviors may occur with AMBIEN alone at recommended doses, with or without the concomitant use of alcohol or other Central Nervous System (CNS) depressants. Discontinue AMBIEN immediately if a patient experiences a complex sleep behavior.

6 Adverse Reactions

Newly added to bulleted line listing:

Complex Sleep Behaviors

7 Drug Interactions

7.1 CNS-Active Drugs

Addition underlined of following heading:

CNS Depressants

Coadministration of zolpidem with other CNS depressants …

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

MEDICATION GUIDE

Additions and/or revisions underlined:

AMBIEN may cause serious side effects, including:

complex sleep behaviors that have caused serious injury and death. After taking AMBIEN, you may get up out of bed while not being fully awake and do an activity that you do not know you are doing (complex sleep behaviors). The next morning, you may not remember that you did anything during the night. These activities may occur with AMBIEN whether or not you drink alcohol or take other medicines that make you sleepy …
Stop taking AMBIEN and call your healthcare provider right away if you find out that you have done any of the above activities after taking AMBIEN.
Do not take AMBIEN if you:

have ever experienced a complex sleep behavior (such as driving a car, making and eating food, talking on the phone, or having sex while not being fully awake) after taking AMBIEN.

PATIENT COUNSELING INFORMATION

Newly added information:

Complex Sleep Behaviors

Instruct patients and their families that AMBIEN may cause complex sleep behaviors, including sleep-walking, sleep-driving, preparing and eating food, making phone calls, or having sex while not being fully awake. Serious injuries and death have occurred during complex sleep behavior episodes. Tell patients to discontinue AMBIEN and notify their healthcare provider immediately if they develop any of these symptoms.

02/06/2019 (SUPPL-45)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 CNS-Depressant Effects and Next-Day Impairment

(additions underlined)

…

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

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

PATIENT COUNSELING INFORMATION

(additions underlined)

…

CNS-Depressant Effects and Next-Day Impairment

Tell patients that AMBIEN has the potential to cause next-day impairment, and that this risk is increased if dosing instructions are not carefully followed. Tell patients to wait for at least 8 hours after dosing before driving or engaging in other activities requiring full mental alertness. Inform patients that impairment can be present despite feeling fully awake. Advise patients that increased drowsiness and decreased consciousness may increase the risk of falls in some patients.

…

09/14/2018 (SUPPL-42)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion)

Risk Summary

Neonates born to mothers using zolpidem late in the third trimester of pregnancy have been reported to experience symptoms of respiratory depression and sedation [see Clinical Considerations and Data]. Published data on the use of zolpidem during pregnancy have not reported a clear association with zolpidem and major birth defects [see Data]. Oral administration of zolpidem to pregnant rats and rabbits did not indicate a risk for adverse effects on fetal development at clinically relevant doses [see Data].

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

Clinical Considerations Fetal/neonatal adverse reactions

Zolpidem crosses the placenta and may produce respiratory depression and sedation in neonates. Monitor neonates exposed to AMBIEN during pregnancy and labor for signs of excess sedation, hypotonia, and respiratory depression and manage accordingly.

Data Human data

Published data from observational studies, birth registries, and case reports on the use of zolpidem during pregnancy do not report a clear association with zolpidem and major birth defects.

There are limited postmarketing reports of severe to moderate cases of respiratory depression that occurred after birth in neonates whose mothers had taken zolpidem during pregnancy. These cases required artificial ventilation or intratracheal intubation. The majority of neonates recovered within hours to a few weeks after birth once treated.

Zolpidem has been shown to cross the placenta.

Animal data

Oral administration of zolpidem to pregnant rats during the period of organogenesis at 4, 20, and 100 mg base/kg/day, which are approximately 5, 25, and 120 times the maximum recommended human dose (MRHD) of 10 mg/day (8 mg zolpidem base) based on mg/m2 body surface area, caused delayed fetal development (incomplete fetal skeletal ossification) at maternally toxic (ataxia) doses 25 and 120 times the MRHD based on mg/m2 body surface area.

Oral administration of zolpidem to pregnant rabbits during the period of organogenesis at 1, 4, and 16 mg base/kg/day, which are approximately 2.5, 10, and 40 times the MRHD of 10 mg/day (8 mg zolpidem base) based on mg/m2 body surface area caused embryo-fetal death and delayed fetal development (incomplete fetal skeletal ossification) at a maternally toxic (decreased body weight gain) dose 40 times the MRHD based on mg/m2 body surface area.

Oral administration of zolpidem to pregnant rats from day 15 of gestation through lactation at 4, 20, and 100 mg base/kg/day, which are approximately 5, 25, and 120 times the MRHD of 10 mg/day (8 mg zolpidem base) based on mg/m2 body surface area, delayed offspring growth and decreased survival at doses 25 and 120 times, respectively, the MRHD based on mg/m2 body surface area.

8.2 Lactation

(PLLR conversion)

Risk Summary

Limited data from published literature report the presence of zolpidem in human milk. There are reports of excess sedation in infants exposed to zolpidem through breastmilk [see Clinical Considerations]. There is no information on the effects of zolpidem on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for AMBIEN and any potential adverse effects on the breastfed infant from AMBIEN or from the underlying maternal condition.

Clinical Considerations

Infants exposed to AMBIEN through breastmilk should be monitored for excess sedation, hypotonia, and respiratory depression. A lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk during treatment and for 23 hours (approximately 5 elimination half-lives) after AMBIEN administration in order to minimize drug exposure to a breast fed infant.

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

MEDICATION GUIDE

(additions underlined)

…

AMBIEN may not be right for you. Before starting AMBIEN, tell your healthcare provider about all of your health 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 kidney or liver disease
have a lung disease or breathing problems
are pregnant, planning to become pregnant. Talk to your healthcare provider about the risk to your unborn baby if you take AMBIEN
Using AMBIEN in the last trimester of pregnancy may cause breathing difficulties or excess sleepiness in your newborn. Monitor for signs of sleepiness (more than usual), trouble breathing, or limpness in the newborn if AMBIEN is taken late in pregnancy.
are breastfeeding or plan to breastfeed. AMBIEN passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby while you take AMBIEN.

...

PATIENT COUNSELING INFORMATION

(additions underlined)

…

Pregnancy

Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with AMBIEN. Advise patients that use of AMBIEN late in the third trimester may cause respiratory depression and sedation in neonates. Advise mothers who used AMBIEN during the late third trimester of pregnancy to monitor neonates for signs of sleepiness (more than usual), breathing difficulties, or limpness.

Lactation

Advise breastfeeding mothers using AMBIEN to monitor infants for increased sleepiness, breathing difficulties, or limpness. Instruct breastfeeding mothers to seek immediate medical care if they notice these signs. A lactating woman may consider pumping and discarding breastmilk during treatment and for 23 hours after AMBIEN administration to minimize drug exposure to a breastfed infant.

03/03/2017 (SUPPL-38)

Approved Drug Label (PDF)

7 Drug Interactions

7.2 Drugs that Affect Drug Metabolism via Cytochrome P450

Additions and/or revisions underlined:

CYP3A4 Inducers

Rifampin

Rifampin, a CYP3A4 inducer, significantly reduced the exposure to and the pharmacodynamic effects of zolpidem. Use of Rifampin in combination with zolpidem may decrease the efficacy of zolpidem and is not recommended.

St. John’s wort

Use of St. John’s wort, a CYP3A4 inducer, in combination with zolpidem may decrease blood levels of zolpidem and is not recommended.

CYP3A4 Inhibitors

Ketoconazole

Ketoconazole, a potent CYP3A4 inhibitor, increased the exposure …

12/02/2016 (SUPPL-37)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.7 Precipitation of Hepatic Encephalopathy

(newly added subsection)

GABA agonists such as zolpidem tartrate have been associated with precipitation of hepatic encephalopathy in patients with hepatic insufficiency. In addition, patients with hepatic insufficiency do not clear zolpidem tartrate as rapidly as patients with normal hepatic function. Avoid AMBIEN use in patients with severe hepatic impairment as it may contribute to encephalopathy.

6 Adverse Reactions

6.2 Postmarketing Experience

(newly added subsection)

The following adverse reactions have been identified during post-approval use of AMBIEN.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Liver and biliary system: acute hepatocellular, cholestatic or mixed liver injury with or without jaundice (i.e., bilirubin greater than 2x ULN, alkaline phosphatase greater than or equal to 2x ULN, transaminase greater than or equal to 5x ULN).

8 Use in Specific Populations

8.7 Hepatic Impairment

(newly added subsection)

The recommended dose of AMBIEN in patients with mild to moderate hepatic impairment is 5 mg once daily immediately before bedtime. Avoid AMBIEN use in patients with severe hepatic impairment as it may contribute to encephalopathy.

08/11/2016 (SUPPL-36)

Approved Drug Label (PDF)

5 Warnings and Precautions

CNS Depressant Effects and Next-Day Impairment (Paragraph added)

Vehicle drivers and machine operators should be warned that, as with other hypnotics, there may be a possible risk of adverse reactions including drowsiness, prolonged reaction time, dizziness, sleepiness, blurred/double vision, reduced alertness and impaired driving the morning after therapy. In order to minimize this risk a full night of sleep (7-8 hours) is recommended.

7 Drug Interactions

CNS-active Drugs

Addition of the following sentence: Concomitant use of zolpidem with these drugs may increase drowsiness and psychomotor impairment, including impaired driving ability.

Drugs that Affect Drug Metabolism via Cytochrome P450

CYP3A4 Inducers replaces Rifampin section

Rifampin, a CYP3A4 inducer, significantly reduced the exposure to and the pharmacodynamics effects of zolpidem. Use of CYP3A4 inducers in combination with zolpidem may decrease the efficacy of zolpidem.

CYP3A4 Inhibitors replaces Ketoconazole section

Ketoconazole, a potent CYP3A4 inhibitor, increased the exposure to and pharmacodynamics effects of zolpidem. Consideration should be given to using a lower dose of zolpidem when a potent CYP3A4 inhibitor and zolpidem are given together.