FDA Label for Halcion

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 (5.1), Drug Interactions (7.1)].
• The use of benzodiazepines, including Halcion, 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 Halcion and throughout treatment, assess each patient's risk for abuse, misuse, and addiction [see Warnings and Precautions (5.2)].
• The continued use of benzodiazepines, including Halcion, 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 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 [see Dosage and Administration (2.3), Warnings and Precautions (5.3)].

1 Indications And Usage

Halcion is indicated for the short-term treatment of insomnia (generally 7 to 10 days) in adults.

2.1 Dosing Information

The recommended dosage is 0.25 mg once daily before bedtime. A dosage of 0.125 mg once daily may be sufficient for some patients (e.g., patients with low body weight). A dosage of 0.5 mg should be used only for patients who do not respond adequately to a trial of a lower dose. The maximum recommended dosage is 0.5 mg once daily.

Use the lowest effective dose for the patient as there are significant dose related adverse reactions.

Use of Halcion for more than 3 weeks requires evaluation of the patient for a primary psychiatric or medical condition [see Warnings and Precautions (5.4, 5.6)].

Prescriptions for Halcion should be written for short-term use (7 to 10 days) and it should not be prescribed in quantities exceeding a 1-month supply.

2.2 Use In Geriatric Patients

In geriatric patients, the recommended dosage is 0.125 mg to 0.25 mg once daily. Initiate therapy at 0.125 mg once daily. The 0.25 mg dose should be used only for patients who do not respond to a trial of the lower dose. The maximum recommended dosage is 0.25 mg once daily. Elderly patients have an increased risk of dose related adverse reactions [see Use in Specific Populations (8.5)].

2.3 Discontinuation Or Dosage Reduction Of Halcion

To reduce the risk of withdrawal reactions, use a gradual taper to discontinue Halcion or reduce the dosage. If a patient develops withdrawal reactions, consider pausing the taper or increasing the dosage to the previous tapered dosage level. Subsequently decrease the dosage more slowly [see Warnings and Precautions (5.3), Drug Abuse and Dependence (9.3)].

3 Dosage Forms And Strengths

Halcion is available as 0.25 mg tablets. The tablets are powder blue, elliptical, scored, and imprinted with HALCION 0.25.

4 Contraindications

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) [see Warnings and Precautions (5.8), Drug Interactions (7.1)].

5.1 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 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 [see Drug Interactions (7.1)].

5.2 Abuse, Misuse, And Addiction

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.

5.3 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.

Other

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)].

Strong CYP 3A Inhibitors

Halcion is contraindicated in patients receiving strong inhibitors of CYP 3A such as ketoconazole, itraconazole, nefazodone, ritonavir, indinavir, nelfinavir, saquinavir, and lopinavir [see Contraindications (4), Drug Interactions (7.1)].

Moderate and Weak CYP 3A Inhibitors

Halcion should be used with caution in patients receiving moderate or weak inhibitors of CYP 3A. If coadministered, consider dose reduction of Halcion.

Macrolide Antibiotics

Coadministration of erythromycin increased the maximum plasma concentration, decreased clearance and increased half-life of triazolam [see Drug Interactions (7.1), Clinical Pharmacology (12.3)]; caution and consideration of appropriate triazolam dose reduction are recommended. Similar caution should be observed during coadministration with clarithromycin and other macrolide antibiotics.

Cimetidine

Coadministration of cimetidine increased the maximum plasma concentration, decreased clearance and increased half-life of triazolam [see Drug Interactions (7.1), Clinical Pharmacology (12.3)]; caution and consideration of appropriate triazolam dose reduction are recommended.

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Halcion during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Other Psychiatric Medications at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/othermedications/.

Risk Summary

Infants born to mothers using benzodiazepines during the later stages of pregnancy have been reported to experience symptoms of sedation and neonatal withdrawal (see Clinical Considerations) [see Warnings and Precautions (5.10)]. At this time, there is no clear evidence that triazolam exposure in early pregnancy can cause major birth defects (see Data).

The estimated 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 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

Benzodiazepines cross the placenta and may produce respiratory depression and sedation in neonates. Monitor neonates exposed to Halcion during pregnancy and labor for signs of sedation, respiratory depression, withdrawal, and feeding problems and manage accordingly [see Warnings and Precautions (5.10)].

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. At this time, there is no clear evidence that triazolam exposure in early pregnancy can cause major birth defects.

Infants exposed to benzodiazepines during the late third trimester of pregnancy or during labor have been reported to exhibit sedation and neonatal withdrawal symptoms.

Animal Data

Oral administration of triazolam to pregnant rats and rabbits during the period of organogenesis caused skeletal developmental changes (variations and malformations) at maternally toxic doses in rats and at doses in rats and rabbits which are approximately equal to or greater than 200 times the maximum recommended human dose (MRHD) of 0.5 mg/day based on mg/m² body surface area. Oral administration of triazolam to male and female rats before mating, and continuing during gestation and lactation did not result in embryotoxicity at doses up to approximately 100 times the MRHD based on mg/m² body surface area, but did cause an increase in the number of stillbirths and postnatal pup mortalities at doses greater than or equal to approximately 40 times the MRHD based mg/m² body surface area. ¹⁴C-triazolam was administered orally to pregnant mice. Drug-related material appeared uniformly distributed in the fetus with ¹⁴C concentrations approximately the same as in the brain of the mother.

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 (see Clinical Considerations).

Triazolam and its metabolites are present in the milk of lactating rats (see Data). 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.

Physical Dependence

Halcion may produce physical dependence from continued therapy. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Abrupt discontinuation or rapid dosage reduction of benzodiazepines or administration of flumazenil, a benzodiazepine antagonist, may precipitate acute withdrawal reactions, including seizures, which can be life-threatening. Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages (i.e., higher and/or more frequent doses) and those who have had longer durations of use [see Warnings and Precautions (5.3)].

To reduce the risk of withdrawal reactions, use a gradual taper to discontinue Halcion or reduce the dosage [see Dosage and Administration (2.3), Warnings and Precautions (5.3)].

Acute Withdrawal Signs and Symptoms

Acute withdrawal signs and symptoms associated with benzodiazepines have included abnormal involuntary movements, anxiety, blurred vision, depersonalization, depression, derealization, dizziness, fatigue, gastrointestinal adverse reactions (e.g., nausea, vomiting, diarrhea, weight loss, decreased appetite), headache, hyperacusis, hypertension, irritability, insomnia, memory impairment, muscle pain and stiffness, panic attacks, photophobia, restlessness, tachycardia, and tremor. More severe acute withdrawal signs and symptoms, including life-threatening reactions, have included catatonia, convulsions, delirium tremens, depression, hallucinations, mania, psychosis, seizures, and suicidality.

Protracted Withdrawal Syndrome

Protracted withdrawal syndrome associated with benzodiazepines is characterized by anxiety, cognitive impairment, depression, insomnia, formication, motor symptoms (e.g., weakness, tremor, muscle twitches), paresthesia, and tinnitus that persists beyond 4 to 6 weeks after initial benzodiazepine withdrawal. Protracted withdrawal symptoms may last weeks to more than 12 months. As a result, there may be difficulty in differentiating withdrawal symptoms from potential re-emergence or continuation of symptoms for which the benzodiazepine was being used.

Tolerance

Tolerance to Halcion may develop from continued therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Tolerance to the therapeutic effect of Halcion may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.

Absorption

Peak plasma levels of triazolam are reached within 2 hours following oral administration. Following recommended doses of Halcion, triazolam peak plasma levels in the range of 1 to 6 ng/mL are seen. The plasma levels achieved are proportional to the dose given. In normal subjects treated for 7 days with four times the recommended dosage, there was no evidence of altered systemic bioavailability, rate of elimination, or accumulation.

Distribution

Extremely high concentrations of triazolam do not displace bilirubin bound to human serum albumin in vitro.

Elimination

Triazolam has a mean plasma elimination half-life in the range of 1.5 to 5.5 hours.

Metabolism

The initial step in triazolam metabolism is cytochrome P450 3A (CYP 3A)-mediated hydroxylation to form 1-hydroxytriazolam and 4-hydroxytriazolam, which are subsequently conjugated to form glucuronides.

Excretion

Triazolam and its metabolites, principally as conjugated glucuronides which are presumably inactive, are excreted primarily in the urine. Only small amounts of unmetabolized triazolam appear in the urine. The two primary metabolites accounted for 79.9% of urinary excretion. Urinary excretion appeared to be biphasic in its time course.

Specific Populations

Geriatric Patients

In a study of elderly (62 to 83 years old) versus younger subjects (21 to 41 years old) who received triazolam at the same dose levels (0.125 mg and 0.25 mg), the elderly experienced both greater sedation and impairment of psychomotor performance. These effects resulted largely from higher plasma concentrations of triazolam in the elderly.

Drug Interaction Studies

The effect of other drugs on triazolam:

Macrolide Antibiotics

Coadministration of erythromycin increased the maximum plasma concentration of triazolam by 46%, decreased clearance by 53%, and increased half-life by 35%.

Cimetidine

Coadministration of cimetidine increased the maximum plasma concentration of triazolam by 51%, decreased clearance by 55%, and increased half-life by 68%.

Isoniazid

Coadministration of isoniazid increased the maximum plasma concentration of triazolam by 20%, decreased clearance by 42%, and increased half-life by 31%.

Oral Contraceptives

Coadministration of oral contraceptives increased maximum plasma concentration by 6%, decreased clearance by 32%, and increased half-life by 16%.

Grapefruit Juice

Coadministration of grapefruit juice increased the maximum plasma concentration of triazolam by 25%, increased the area under the concentration curve by 48%, and increased half-life by 18%.

Ranitidine

Coadministration of ranitidine increased the maximum plasma concentration of triazolam by 30%, increased the area under the concentration curve by 27%, and increased half-life by 3.3%. Caution is recommended during coadministration with triazolam. Available data from clinical studies of benzodiazepines other than triazolam suggest a possible drug interaction with triazolam for the following: fluvoxamine, diltiazem, and verapamil. Data from in vitro studies of triazolam suggest a possible drug interaction with triazolam for the following: sertraline and paroxetine. Data from in vitro studies of benzodiazepines other than triazolam suggest a possible drug interaction with triazolam for the following: ergotamine, cyclosporine, amiodarone, nicardipine, and nifedipine.

The effect of triazolam on other drugs:

Warfarin

Halcion Tablets 0.5 mg, in two separate studies, did not affect the prothrombin times or plasma warfarin levels in male volunteers administered sodium warfarin orally.

Carcinogenesis

No evidence of carcinogenic potential was observed in rats or mice administered triazolam in the diet for 24-months at doses greater than or equal to 900 times the MRHD of 0.5 mg, based on mg/m² body surface area.

Mutagenesis

Triazolam was not mutagenic in the in vitro Ames bacterial reverse mutation assay, and no DNA damage was observed in an in vitro alkaline elution assay in Chinese hamster lung fibroblast cells.

Impairment of Fertility

Female rats were administered triazolam in the diet for 14 days before cohabitation, during gestation, and until 21 days post parturition, and male rats for 60 days before cohabitation. No effects on mating or fertility were observed in rats up to 5 mg/kg/day which is approximately 100 times the MRHD of 0.5 mg/day, based on mg/m² body surface area.

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 [see Warnings and Precautions (5.1), Drug Interactions (7.1)].

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)].

"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 [see Warnings and Precautions (5.5)]. 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.

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

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 [see Warnings and Precautions (5.7)].

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 [see Warnings and Precautions (5.9)].

Concomitant Medications

Advise patients to inform their healthcare provider of all medicines they take, including prescription and nonprescription medicines, vitamins and herbal supplements [see Drug Interactions (7.1)].

Grapefruit Juice

Advise patients to avoid eating grapefruit or drinking grapefruit juice while taking Halcion [see Drug Interactions (7.1)].

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 [see Warnings and Precautions (5.10), Use in Specific Populations (8.1)].

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 [see Use in Specific Populations (8.2)].

This product's labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com.

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5.4 Persistent Or Worsening Insomnia

Since sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after a careful evaluation of the patient. The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. Worsening of insomnia or the emergence of new thinking or behavior abnormalities may be the consequence of an unrecognized psychiatric or physical disorder. Such findings have emerged during the course of treatment with sedative-hypnotic drugs.

5.5 "Sleep-Driving" And Other Complex Behaviors

Complex behaviors such as "sleep-driving" (i.e., driving while not fully awake after ingestion of a sedative-hypnotic, with amnesia for the event) have been reported with Halcion use. These events can occur in sedative-hypnotic-naïve as well as in sedative-hypnotic-experienced persons. Although behaviors such as sleep-driving may occur with sedative-hypnotics alone at recommended dosages, the use of alcohol and other central nervous system (CNS) depressants with sedative-hypnotics appears to increase the risk of such behaviors, as does the use of sedative-hypnotics at doses exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontinuation of sedative-hypnotics should be strongly considered for patients who report a "sleep-driving" episode.

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, including Halcion. As with sleep-driving, patients usually do not remember these events.

5.6 Central Nervous System Manifestations

An increase in daytime anxiety has been reported for Halcion after as few as 10 days of continuous use. In some patients this may be a manifestation of interdose withdrawal. If increased daytime anxiety is observed during treatment, discontinuation of treatment may be advisable.

A variety of abnormal thinking and behavior changes have been reported to occur in association with the use of benzodiazepine hypnotics including Halcion. Some of these changes may be characterized by decreased inhibition, e.g., aggressiveness and extroversion that seem excessive, similar to that seen with alcohol and other CNS depressants (e.g., sedative/hypnotics). Other kinds of behavioral changes have also been reported, for example, bizarre behavior, agitation, hallucinations, depersonalization. In primarily depressed patients, the worsening of depression, including suicidal thinking, has been reported in association with the use of benzodiazepines [see Warnings and Precautions (5.9)].

Some adverse reactions reported in association with the use of Halcion such as drowsiness, dizziness, light-headedness, and amnesia appear to be dose related. More serious behavioral phenomena such as confusion, bizarre or abnormal behavior, agitation, and hallucinations may also be dose related, but this evidence is inconclusive. Therapy should be initiated at the lowest effective dose [see Dosage and Administration (2.1)].

It can rarely be determined with certainty whether a particular instance of the abnormal behaviors listed above is drug induced, spontaneous in origin, or a result of an underlying psychiatric or physical disorder. Nonetheless, the emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation.

Anterograde amnesia of varying severity and paradoxical reactions have been reported following recommended dosages of Halcion. Data from several sources suggest that anterograde amnesia may occur at a higher rate with Halcion than with other benzodiazepine hypnotics. Because HALCION can cause drowsiness and a decreased level of consciousness, patients, particularly the elderly, are at higher risk of falls.

Cases of "traveler's amnesia" have been reported by individuals who have taken Halcion to induce sleep while traveling, such as during an airplane flight. In some of these cases, insufficient time was allowed for the sleep period prior to awakening and before beginning activity. Also, the concomitant use of alcohol may have been a factor in some cases.

5.7 Effects On Driving And Operating Heavy Machinery

Due to its depressant CNS effects, patients receiving Halcion should be cautioned against engaging in hazardous occupations requiring complete mental alertness such as operating machinery or driving a motor vehicle. For the same reason, patients should be cautioned about the concomitant use of alcohol and other CNS depressant drugs during treatment with Halcion.

5.8 Triazolam Interaction With Drugs That Inhibit Metabolism Via Cytochrome P450 3A

The initial step in triazolam metabolism is hydroxylation catalyzed by CYP 3A. Drugs that inhibit this metabolic pathway may have a profound effect on the clearance of triazolam.

5.9 Patients With Depression

Benzodiazepines may worsen depression. Consequently, appropriate precautions (e.g., limiting the total prescription size and increased monitoring for suicidal ideation) should be considered in patients with depression.

5.10 Neonatal Sedation And Withdrawal Syndrome

Use of Halcion during the later stages of pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate. Observe newborns for signs of sedation and neonatal withdrawal syndrome and manage accordingly [see Use in Specific Populations (8.1)].

5.11 Compromised Respiratory Function

In patients with compromised respiratory function, respiratory depression and apnea have been reported. Closely monitor patients with compromised respiratory function. If signs and symptoms of respiratory depression or apnea occur, consider discontinuation.

6 Adverse Reactions

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)]
• Persistent or Worsening Insomnia [see Warnings and Precautions (5.4)]
• "Sleep-driving" and Other Complex Behaviors [see Warnings and Precautions (5.5)]
• Central Nervous System Manifestations [see Warnings and Precautions (5.6)]
• Effects on Driving and Operating Heavy Machinery [see Warnings and Precautions (5.7)]
• Patients with Depression [see Warnings and Precautions (5.9)]
• Compromised Respiratory Function [see Warnings and Precautions (5.11)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

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 Table1, 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, diarrhea, dry mouth, dermatitis/allergy, dreaming/nightmares, insomnia, paresthesia, tinnitus, dysesthesia, weakness, congestion, and death from hepatic failure in a patient also receiving diuretic drugs.

6.2 Postmarketing Experience

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

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

7.1 Drugs Having Clinically Important Interactions With Halcion

Table 2 includes clinically significant drug interactions with Halcion [see Clinical Pharmacology (12.3)].

8.4 Pediatric Use

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

8.5 Geriatric Use

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 oversedation, the smallest effective dose should be used [see Dosage and Administration (2.2), Clinical Pharmacology (12.3)].

9.1 Controlled Substance

Halcion contains triazolam, a Schedule IV controlled substance.

9.2 Abuse

Halcion is a benzodiazepine and a CNS depressant with a potential for abuse and addiction. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Even taking benzodiazepines as prescribed may put patients at risk for abuse and misuse of their medication. Abuse and misuse of benzodiazepines may lead to addiction.

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. Benzodiazepines are often sought by individuals who abuse drugs and other substances, and by individuals with addictive disorders [see Warnings and Precautions (5.2)].

The following adverse reactions have occurred with benzodiazepine abuse and/or misuse: abdominal pain, amnesia, anorexia, anxiety, aggression, ataxia, blurred vision, confusion, depression, disinhibition, disorientation, dizziness, euphoria, impaired concentration and memory, indigestion, irritability, muscle pain, slurred speech, tremors, and vertigo.

The following severe adverse reactions have occurred with benzodiazepine abuse and/or misuse: delirium, paranoia, suicidal ideation and behavior, seizures, coma, breathing difficulty, and death. Death is more often associated with polysubstance use (especially benzodiazepines with other CNS depressants such as opioids and alcohol).

10 Overdosage

Manifestations of overdosage with Halcion include somnolence, confusion, impaired coordination, slurred speech, and ultimately, coma. Respiratory depression and apnea have been reported with overdosages of Halcion. Seizures have been reported after overdosages.

Death has been reported in association with overdoses of Halcion. In addition, fatalities have been reported in patients who have overdosed with a combination of a single benzodiazepine, including Halcion, and alcohol; benzodiazepine and alcohol levels seen in some of these cases have been lower than those usually associated with reports of fatality with either substance alone.

Respiration, pulse, and blood pressure should be monitored and supported by general measures when necessary. Immediate gastric lavage should be performed. An adequate airway should be maintained. Intravenous fluids may be administered.

Flumazenil may be useful in situations when an overdose with a benzodiazepine is known or suspected. Prior to the administration of flumazenil, necessary measures should be instituted to secure airway, ventilation and intravenous access. Flumazenil is intended as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. Patients treated with flumazenil should be monitored for resedation, respiratory depression, and other residual benzodiazepine effects for an appropriate period after treatment. The prescriber should be aware of a risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose. The complete flumazenil package insert including Contraindications and Warnings and Precautions should be consulted prior to use.

Hemodialysis and forced diuresis are probably of little value. As with the management of intentional overdosage with any drug, the physician should bear in mind that multiple agents may have been ingested by the patient.

In case of an overdosage, consult a Certified Poison Control Center at 1-800-222-1222 for latest recommendations.

11 Description

Halcion Tablets contains triazolam, a triazolobenzodiazepine.

Triazolam is a white crystalline powder, soluble in alcohol and poorly soluble in water. It has a molecular weight of 343.21.

The chemical name for triazolam is 8-chloro-6-(o-chlorophenyl)-1-methyl-4H-s-triazolo-[4,3-α] [1,4] benzodiazepine.

The structural formula is represented below:

Chemical Structure - halcion 01

Each Halcion tablet, for oral administration, contains 0.25 mg of triazolam.

Inactive ingredients: cellulose, corn starch, docusate sodium, FD&C Blue No. 2, lactose, magnesium stearate, silicon dioxide, sodium benzoate.

12.1 Mechanism Of Action

Triazolam is a benzodiazepine. Triazolam exerts its effect for the short-term treatment of insomnia through binding to the benzodiazepine site of the gamma-aminobutyric acid-A (GABA_A) receptors in the brain and enhances GABA-mediated synaptic inhibition.

16 How Supplied/Storage And Handling

Halcion is supplied as a powder blue, elliptical, scored tablet in the following strengths and package configurations:

Storage And Handling

Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

17 Patient Counseling Information

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

Spl Medguide

MEDICATION GUIDE HALCION (HAL-cee-on) (triazolam) tablets, CIV
This Medication Guide has been approved by the U.S. Food and Drug Administration.		Revised 2/2021
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 (CNS) depressants (including street drugs) can cause severe drowsiness, breathing problems (respiratory depression), coma and death. Get emergency help right away if any of the following happens: shallow or slowed breathing breathing stops (which may lead to the heart stopping) excessive sleepiness (sedation) Do not drive or operate heavy machinery until you know how taking HALCION with opioids affects you. Risk of abuse, misuse, and addiction. There is a risk of abuse, misuse, and addiction with benzodiazepines, including HALCION which can lead to overdose and serious side effects including coma and death. Serious side effects including coma and death have happened in people who have abused or misused benzodiazepines, including HALCION. These serious side effects may also include delirium, paranoia, suicidal thoughts or actions, seizures, and difficulty breathing. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these serious side effects. You can develop an addiction even if you take HALCION as prescribed by your healthcare provider. Take HALCION exactly as your healthcare provider prescribed. Do not share your HALCION with other people. Keep HALCION in a safe place and away from children. Physical dependence and withdrawal reactions. HALCION can cause physical dependence and withdrawal reactions. Do not suddenly stop taking HALCION. Stopping HALCION suddenly can cause serious and life-threatening side effects, including unusual movements, responses, or expressions, seizures, sudden and severe mental or nervous system changes, depression, seeing or hearing things that others do not see or hear, an extreme increase in activity or talking, losing touch with reality, and suicidal thoughts or actions. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these symptoms. Some people who suddenly stop benzodiazepines, have symptoms that can last for several weeks to more than 12 months, including, anxiety, trouble remembering, learning, or concentrating, depression, problems sleeping feeling like insects are crawling under your skin, weakness, shaking, muscle twitching, burning or prickling feeling in your hands, arms, legs or feet, and ringing in your ears. Physical dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical dependence and drug addiction. Do not take more HALCION than prescribed or take HALCION for longer than prescribed. 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
	Call your healthcare provider right away if you find out that you have done any of the above activities after taking HALCION.
What is HALCION?
HALCION is a prescription medicine used in adults for the short-term treatment of a sleep problem called insomnia. HALCION is usually taken for 7 to 10 days. HALCION is a federal controlled substance (CIV) because it contains triazolam that can be abused or lead to dependence. Keep HALCION in a safe place to prevent misuse and abuse. Selling or giving away HALCION may harm others, and is against the law. Tell your healthcare provider if you have abused or been dependent on alcohol, prescription medicines or street drugs. It is not known if HALCION is safe and effective in children. It is not known if HALCION is safe and effective for use longer than 2 to 3 weeks.
Do not take HALCION if you: are allergic to triazolam, other benzodiazepines, or any of the ingredients in HALCION. Severe allergic reactions including swelling of the tongue or throat, trouble breathing and throat closing have happened and may lead to death. Get medical help right away if you have an allergic reaction to HALCION. See the end of this Medication Guide for a complete list of ingredients in HALCION. take antifungal medicines including ketoconazole and itraconazole take a medicine to treat depression called nefazodone take medicines to treat human immunodeficiency virus (HIV)-1 infection called protease inhibitors.
Before you take HALCION, tell your healthcare provider about all of your medical conditions, including if you: have a history of depression, mood problems, mental illness, suicidal thoughts or behavior have a history of drug or alcohol abuse or addiction have lung problems, breathing problems, or sleep apnea are pregnant or plan to become pregnant. If you become pregnant while taking HALCION, talk to your healthcare provider about registering with the National Pregnancy Registry for psychiatric medicines during pregnancy. You can register by calling 1-866-961-2388 or visit https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/othermedications/. Babies born to mothers who take benzodiazepine medicines, including HALCION, late in pregnancy may have symptoms of sedation, such as breathing problems, sluggishness, and low muscle tone (floppy baby syndrome), feeding problems and withdrawal symptoms. are breastfeeding or plan to breastfeed. It is not known if HALCION can pass through your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take HALCION.
Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
Taking HALCION with certain other medicines can cause side effects or affect how well HALCION or the other medicines work. Do not start or stop other medicines without talking to your healthcare provider.
How should I take HALCION? Take HALCION exactly as your healthcare provider tells you to take it. Take HALCION right before you get into bed. Do not eat grapefruit or drink grapefruit juice during treatment with HALCION. Call your healthcare provider if your insomnia worsens or is not better within 7 to 10 days of treatment with HALCION. This may mean that there is another condition causing your sleep problem. If you take too much HALCION, call your healthcare provider or have somebody drive you to the nearest hospital emergency room right away.
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?" Increased daytime anxiety. Abnormal thoughts and behavior. Symptoms include more outgoing or aggressive behavior than normal, confusion, agitation, hallucinations, worsening of depression, and suicidal thoughts or actions. Memory loss HALCION can make you sleepy or dizzy and can slow your thinking and motor skills. Do not drive, operate heavy machinery, or do other dangerous activities until you know how HALCION affects you. Do not drink alcohol or take other drugs that may make you sleepy or dizzy while taking HALCION without first talking to your healthcare provider. When taken with alcohol or drugs that cause sleepiness or dizziness, HALCION may make your sleepiness or dizziness much worse. Worsening depression. Call your healthcare provider right away if you have any thoughts of suicide or dying or worsening depression.
The most common side effects of HALCION include:
drowsiness dizziness		light-headedness difficulty with coordination
Elderly people have an increased risk of dose related side effects during treatment with HALCION.
These are not all the possible side effects of HALCION.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store HALCION? Store HALCION at room temperature between 68°F to 77° F (20°C to 25°C). Keep HALCION and all medicines out of the reach of children
General information about the safe and effective use of HALCION.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use HALCION for a condition for which it was not prescribed. Do not give HALCION to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about HALCION that is written for healthcare professionals.
What are the ingredients in HALCION?
Active ingredient: triazolam
Inactive ingredients: cellulose, corn starch, docusate sodium, FD&C Blue No. 2, lactose, magnesium stearate, silicon dioxide, sodium benzoate.
Logo - halcion 03
If you would like more information, call 1-800-438-1985 or visit www.pfizer.com.
LAB-0259-17.0

Principal Display Panel - 0.25 Mg Tablet Blister Pack

Halcion^®
triazolam tablets, USP
CIV
0.25 mg
Distributed by
Pharmacia & Upjohn Co
Div of Pfizer Inc,
NY, NY 10017

EXP &
LOT AREA

PRINCIPAL DISPLAY PANEL - 0.25 mg Tablet Blister Pack - halcion 04

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ALWAYS DISPENSE WITH MEDICATION GUIDE

NDC 0009-0017-55

Pfizer

Halcion^®
triazolam tablets,
USP
CIV

0.25 mg

For in-institution use only

100 Tablets
Reverse Numbered
Rx only

PRINCIPAL DISPLAY PANEL - 0.25 mg Tablet Blister Pack Carton - halcion 05

Principal Display Panel - 0.25 Mg Tablet Bottle Label

ALWAYS DISPENSE WITH MEDICATION GUIDE

NDC 0009-0017-58

Pfizer

Halcion^®
triazolam
tablets, USP
CIV

0.25 mg

10 Tablets
Rx only

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