Drug Safety-related Labeling Changes (SrLC)

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HALCION (NDA-017892)

(TRIAZOLAM)

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

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10/27/2021 (SUPPL-56)

Approved Drug Label (PDF)

7 Drug Interactions

7.1 Drugs Having Clinically Important Interactions With Halcion

(Addition of drug interaction with strong inducers of CYP 3A to Table 2; please refer to label)

02/05/2021 (SUPPL-55)

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.

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 (5.1, 7.1).

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

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

death. Before prescribing Halcion and throughout treatment, assess

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

• Abrupt discontinuation or rapid dosage reduction of Halcion 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 Halcion or reduce the dosage (2.3,

5.3).

5 Warnings and Precautions

5.1 Abuse, Misuse, and Addiction

(Newly added information)

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

5.2 Dependence and Withdrawal Reactions

To reduce the risk of withdrawal reactions, use a gradual taper to discontinue Halcion 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 Halcion, may lead to clinically significant physical dependence. Abrupt discontinuation or rapid dosage reduction of Halcion 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)].

5.6 Central Nervous System Manifestations

(Newly added information)

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

6 Adverse Reactions

(Additions and/or revisions underlined)

The following serious adverse reactions are discussed in greater detail in other sections:

• 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)

Medication Guide

(Extensive changes; please refer to label)

Patient Counseling Information

(Newly added information)

Abuse, Misuse, and Addiction

Inform patients that the use of Halcion, 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), Drug Abuse and Dependence (9.2)].

Withdrawal Reactions

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

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

10/09/2019 (SUPPL-50)

Approved Drug Label (PDF)

4 Contraindications

PLR conversion; as below:

Halcion is contraindicated in:

• Patients with known hypersensitivity to triazolam, any of component of Halcion, or other benzodiazepines. Reactions consistent with angioedema (involving the tongue, glottis, or larynx), dyspnea, and throat closing have been reported and may be fatal.

Concomitant administration of strong cytochrome P450 (CYP 3A) enzyme inhibitors (e.g., ketoconazole, itraconazole, nefazodone, lopinavir, ritonavir).

5 Warnings and Precautions

PLR conversion. Subsections titles as below; please refer to label for complete information:

5.1 Risks from Concomitant Use with Opioids

5.2 Persistent or Worsening Insomnia

5.3 “Sleep-driving” and Other Complex Behavior

5.4 Central Nervous System Manifestations

5.5 Effects on Driving and Operating Heavy Machinery

5.6 Triazolam Interaction with Drugs that Inhibit Metabolism via Cytochrome P450 3A

5.7 Patients with Depression

5.8 Tolerance/Withdrawal Phenomena

5.9 Neonatal Sedations and Withdrawal Syndrome

5.10 Comprised Respiratory Function

6 Adverse Reactions

PLR conversion. Newly created bulleted line listing:

The following serious adverse reactions are discussed in greater detail in other sections:

• Risks from Concomitant Use with Opioids

• Persistent or Worsening Insomnia

• “Sleep-driving” and Other Complex Behaviors

• Central Nervous System Manifestations

• Effects on Driving and Operating Heavy Machinery

• Patients with Depression

• Tolerance/Withdrawal Phenomena

• Compromised Respiratory Function

6.1 Clinical Trials Experience

PLR conversion; additions and/or revisions underlined:

The incidences cited below are estimates of clinical reactions among 1003 subjects who participated in the short term (duration of 1 to 42 days) placebo-controlled clinical trials of Halcion.

Adverse reactions leading to discontinuation in two multi-dose placebo controlled clinical trials include coordination disorders, drowsiness, grogginess, somnolence, depression, restlessness, dizziness, lightheadedness, headache, nausea, visual disturbance, nervousness, abdominal distress, bladder trouble, aching limbs, backache, and blepharitis.

In addition to the common reactions enumerated above in Table 1, the following adverse reactions have been reported at an incidence of 0.9% to 0.5%: euphoria, tachycardia, tiredness, confusional states/memory impairment, cramps/pain, depression, and visual disturbances.

Adverse reactions reported at an incidence less than 0.5% include: constipation, taste alterations …

6.2 Postmarketing Experience

PLR conversion; additions and/or revisions underlined:

General disorders and administration site conditions: Paradoxical drug reaction, chest pain and fatigue

Gastrointestinal disorders: Tongue discomfort, glossitis, stomatitis

Hepatobiliary disorders: Jaundice

Injury, poisoning and procedural complications: Fall

Metabolism and nutrition disorders: Anorexia

Nervous system disorders: Anterograde amnesia, altered state of consciousness, dystonia, sedation, syncope, dysarthria and muscle spasticity

Psychiatric disorders: Confusional state (disorientation, derealisation, depersonalization), mania, agitation, restlessness, irritability, sleep disorder and libido disorder, hallucination, delusion, aggression, somnambulism, and abnormal behavior

Renal and urinary disorders: Urinary retention and urinary incontinence

Reproductive system and breast disorders: Menstruation irregular

Skin and subcutaneous tissue disorders: Pruritis

PLR conversion; as below:

Halcion is contraindicated in:

• Patients with known hypersensitivity to triazolam, any of component of Halcion, or other benzodiazepines. Reactions consistent with angioedema (involving the tongue, glottis, or larynx), dyspnea, and throat closing have been reported and may be fatal.

Concomitant administration of strong cytochrome P450 (CYP 3A) enzyme inhibitors (e.g., ketoconazole, itraconazole, nefazodone, lopinavir, ritonavir).

7 Drug Interactions

PLR conversion. Newly added information with table;

7.1 Drugs Having Clinically Important Interactions with Halcion

Table 2 includes clinically significant drug interactions with Halcion

Table 2: Clinically Important Drug Interactions with Halcion please refer to label for complete information.

8 Use in Specific Populations

8.1 Pregnancy

PLLR conversion; please refer to label for complete information.

8.2 Lactation

PLR conversion, as below:

Risk Summary

There are no data on the presence of triazolam in human milk or the effects on milk production. There are reports of central nervous system depression (sedation, respiratory depression), withdrawal symptoms, and feeding problems in infants who are breastfed by mothers taking benzodiazepines. Triazolam and its metabolites are present in the milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for HALCION and any potential adverse effects on the breastfed infant from HALCION or from the underlying maternal condition.

Clinical Considerations

Infants exposed to HALCION through breast milk should be monitored for sedation, respiratory depression, withdrawal symptoms, and feeding problems. A lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk during treatment and for 28 hours (approximately 5 elimination half-lives) after HALCION administration in order to minimize drug exposure to a breast fed infant.

Data

Both triazolam and triazolam metabolites were detected in milk of rats. Lactating rats were orally administered 0.3 mg/kg 14C-triazolam; drug and metabolite levels were determined in milk collected at 6 and 24 hours after administration.

8.4 Pediatric Use

PLR conversion; as below:

Safety and effectiveness of Halcion have not been established in pediatric patients.

8.5 Geriatric Use

PLR conversion; as below:

Elderly patients exhibit higher plasma triazolam concentrations due to reduced clearance as compared with younger subjects at the same dose. Because elderly patients are especially susceptible to dose related adverse reactions and to minimize over sedation, the smallest effective dose should be used.

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

MEDICATION GUIDE

Newly created section; please refer to label for complete information.

PATIENT COUNSELING INFORMATION

PLR conversion; newly created section. Additions as below:

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 Halcion 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.

“Sleep-driving” and Other Complex Behaviors

There have been reports of people getting out of bed after taking a sedative-hypnotic and driving their cars while not fully awake, often with no memory of the event. Advise patients to report similar experiences to their healthcare provider immediately, since “sleep-driving” can be dangerous. This behavior is more likely to occur when sedative-hypnotics are taken with alcohol or other CNS depressants. Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sedative hypnotic. As with sleep-driving, patients usually do not remember these events.

Effects on Driving and Operating Heavy Machinery

Caution patients against driving a motor vehicle or operating heavy machinery until the effects of taking Halcion are determined due to its CNS depressant effects. Also advise patients to avoid the use of alcohol or other CNS depressants while taking Halcion.

Patients with Depression

Advise patients, their families and caregivers to look out for any signs of suicidality or worsening depression, and to inform the patient’s prescriber or healthcare provider immediately.

Concomitant Medications

Advise patients to inform their healthcare provider of all medicines they take, including prescription and nonprescription medicines, vitamins and herbal supplements.

Grapefruit Juice

Advise patients to avoid eating grapefruit or drinking grapefruit juice while taking Halcion.

Pregnancy

Benzodiazepines cross the placenta and may produce respiratory depression and sedation in neonates. Advise mothers using Halcion to monitor neonates for signs of sedation, respiratory depression, withdrawal, and feeding problems.

Lactation

Advise mothers using benzodiazepines to monitor neonates for signs of sedation, respiratory depression, withdrawal symptoms, and feeding problems. A lactating woman may consider pumping and discarding breastmilk during treatment and for 28 hours after Halcion administration to minimize drug exposure to a breastfed infant.

For full prescribing information, please visit www.pfizer.com.

02/06/2019 (SUPPL-54)

Approved Drug Label (PDF)

5 Warnings and Precautions

WARNINGS

 

(additions underlined)

… Because HALCION 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-49)

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

PRECAUTIONS

(additions underlined)

 

Risks from Concomitant Use with Opioids: Advise both patients and caregivers about the risks of potentially fatal respiratory depression and sedation when Halcion is used with opioids and not to use such drugs concomitantly unless supervised by a health care provider. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined.

WARNINGS

Risks from Concomitant Use with Opioids

Concomitant use of benzodiazepines, including Halcion, 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 Halcion 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 Halcion

than indicated in the absence of an opioid and titrate based on clinical response. If an opioid is initiated in a patient already taking Halcion, 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 Halcion 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.

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 HALCION?

·       HALCION 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 HALCION, 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 HALCION. Reported activities include:

·       driving a car (“sleep-driving”)

·       making and eating food

·       talking on the phone

·       having sex

·       sleep-walking

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

·       Do not take HALCION 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 HALCION than prescribed.

·       What is HALCION?

                        HALCION is a prescription medicine used to treat certain types of insomnia including difficulty falling asleep, waking up often during the night, or waking up early in the morning.

 

How should I take HALCION?

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

·       Take HALCION exactly as your healthcare provider tells you to take it.

·       Take HALCION right before you get into bed. Or you can take HALCION after you have been in bed and have trouble falling asleep.

·       Do not take HALCION with or right after a meal.

·       Do not take HALCION unless you are able to get a full night’s sleep before you must be active again.

·       If you take too much HALCION, get emergency treatment right away

·        

What should I avoid while taking HALCION?

·       Do not drive, operate machinery, do other dangerous activities or do anything that needs you to be alert until you know how HALCION affects you.

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

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

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

·       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.

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

·       Withdrawal symptoms. You may have withdrawal symptoms for 1 to 2 days when you stop taking HALCION

suddenly. Withdrawal symptoms include trouble sleeping, unpleasant feelings, stomach and muscle cramps, vomiting, sweating, shakiness, and seizures. Talk to your healthcare provider about slowly stopping HALCION to avoid withdrawal symptoms.

·       Abuse and dependence. Taking HALCION 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.

·       Memory loss, including “traveler’s amnesia”

·       Anxiety

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