Halcion

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

2 DOSAGE AND ADMINISTRATION • Adults : Recommended dosage is 0.25 mg once daily before bedtime. Maximum recommended dosage is 0.5 mg once daily • Geriatric patients : Reduce starting dosage to 0.125 mg once daily. May increase to 0.25 mg if no response. Geriatric patients should not exceed 0.25 mg once daily ( 2.2 , 8.5 ) • Halcion should not be prescribed in quantities exceeding a 1-month supply

2.1Dosing 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 . 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.

2.2Use 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 .

2.3Discontinuation 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 .

5 WARNINGS AND PRECAUTIONS • 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. • "Sleep-driving" and Other Complex Behaviors : Complex behaviors such as "sleep-driving" have been reported. The use of alcohol and other central nervous system (CNS) depressants with sedative-hypnotics appears to increase the risk, as well as doses exceeding the maximum recommended dose. • CNS Manifestations : An increase in daytime anxiety, abnormal thinking, and behavioral changes have been reported. Emergence of any new behavioral changes require careful and immediate evaluation. • Effects on Driving and Operating Heavy Machinery : Patients receiving triazolam should be cautioned against driving or operating heavy machinery, as well as avoiding concomitant use with alcohol and other CNS depressant drugs. • Patients with Depression: Caution should be exercised in patients with signs or symptoms of depression that could be intensified by hypnotic drugs. Prescribe the least number of tablets feasible to avoid intentional overdose. • Neonatal Sedation and Withdrawal Syndrome : Halcion use during pregnancy can result in neonatal sedation and/or neonatal withdrawal. ( 5.10 , 8.1 )

5.1Risks 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 .

5.2Abuse, 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 . 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.

5.3Dependence 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) . 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) . Protracted Withdrawal Syndrome In some cases, benzodiazepine users have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months .

5.4Persistent 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.

5.6Central 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 . 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 . 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.

5.7Effects 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.

5.8Triazolam 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. 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 . 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 ; 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 ; caution and consideration of appropriate triazolam dose reduction are recommended.

5.9Patients 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 .

5.10Neonatal Sedation and Withdrawal Syndrome Use

of Halcion late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate . Monitor neonates exposed to HALCION during pregnancy or labor for signs of sedation and monitor neonates exposed to HALCION during pregnancy for signs of withdrawal; manage these neonates accordingly.

5.11Compromised 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.

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) . • Known hypersensitivity to Halcion or other benzodiazepines • Concomitant use with medications that significantly impair the oxidative metabolism mediated by cytochrome P450 3A (CYP 3A) including ketoconazole, itraconazole, nefazodone, and several human immunodeficiency virus (HIV) protease inhibitors ( 4 , 5.8 , 17 )

8.1Pregnancy Pregnancy Exposure Registry There

is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to psychiatric medications, including Halcion, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/pregnancyregistry/ Risk Summary Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal . Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects . The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia, and sedation in neonates. Monitor neonates exposed to Halcion during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems.

Monitor neonates exposed to HALCION during pregnancy for signs of withdrawal. Manage these neonates accordingly . 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. 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/m 2 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/m 2 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/m 2 body surface area. 14 C-triazolam was administered orally to pregnant mice.

Drug-related material appeared uniformly distributed in the fetus with 14 C concentrations approximately the same as in the brain of the mother.

The following serious adverse reactions are discussed in greater detail in other sections: • Risks from Concomitant Use with Opioids • Abuse, Misuse, and Addiction • Dependence and Withdrawal Reactions • Persistent or Worsening Insomnia • "Sleep-driving" and Other Complex Behaviors • Central Nervous System Manifestations • Effects on Driving and Operating Heavy Machinery • Patients with Depression • Neonatal Sedation and Withdrawal Syndrome • Compromised Respiratory Function Most common adverse reactions (incidence ≥4% and twice placebo) are drowsiness, dizziness, light-headedness, and coordination disorder/ataxia. To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1Clinical 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.

Table 1: Common Adverse Drug Reactions in 1% or More of Halcion-Treated Subjects (and Greater than Placebo) Reported in Placebo-Controlled Clinical Trials Event Halcion (N=1003) % Patients Reporting Placebo (N=997) % Patients Reporting Central Nervous System Drowsiness 14.0

6.4Headache

9.7

8.4Dizziness

7.8

3.1Nervousness

5.2

4.5Light-headedness

4.9

0.9Coordination

disorders/ataxia 4.6

0.8Gastrointestinal Nausea/vomiting

4.6

3.7In

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.

6.2Postmarketing 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