HALCION® (triazolam) tablets, for oral use, CIV

HALCION (triazolam)

HALCION® (triazolam) tablets, for oral use, CIV

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.

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.

INDICATIONS AND USAGE

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

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 (GABAA) receptors in the brain and enhances GABA-mediated synaptic inhibition.

DOSAGE AND ADMINISTRATION

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.

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

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

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)

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: Use of Halcion during pregnancy can result in neonatal sedation and neonatal withdrawal syndrome.

Adverse reactions

  • 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

DRUG INTERACTIONS

Opioids 
Clinical implicationThe 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.
Prevention or managementLimit dosage and duration of concomitant use of Halcion and opioids, and monitor patients closely for respiratory depression and sedation
CNS Depressants 
Clinical implicationTriazolam produces additive CNS depressant effects when co-administered with other CNS depressants. 
Prevention or managementLimit dosage and duration of Halcion during concomitant use with CNS depressants. 
Strong Inhibitors of CYP 3A 
Clinical implicationConcomitant use of Halcion with strong CYP3A inhibitors has a profound effect on the clearance of Halcion, resulting in increased concentrations of triazolam and increased risk of adverse reactions. 
Prevention or managementDo not administer Halcion with a strong CYP3A4 inhibitor. 
Moderate and Weak Inhibitors of CYP 3A 
Clinical implicationConcomitant use of Halcion with moderate or weak inhibitors of CYP3A inhibitors may increase the concentrations of Halcion, resulting in increased risk of adverse reactions. 
Prevention or managementUse with caution and consider appropriate dose reduction of HALCION when coadministered with moderate and weak CYP3A inhibitors. 
Strong Inducers of CYP 3A 
Clinical implicationCoadministration of triazolam with strong inducers of CYP3A4 can significantly decrease the plasma concentration of triazolam and may decrease effectiveness of triazolam. 
Prevention or managementCaution is recommended during coadministration of Halcion with strong inducers of CYP3A4. 
Interactions Based on Experience with Other Benzodiazepines or in vitro Studies with Triazolam 
Clinical implicationAvailable data from clinical studies of benzodiazepines other than triazolam, from in vitro studies with triazolam, or from in vitro studies with benzodiazepines other than triazolam suggest a possible drug interaction with triazolam. 
Prevention or managementCaution is recommended during coadministration of Halcion with any of these drugs. 

USE IN SPECIFIC POPULATIONS 

Pregnancy: Infants born to mothers using benzodiazepines during the later stages of pregnancy have been reported to experience symptoms of sedation and neonatal withdrawal. At this time, there is no clear evidence that triazolam exposure in early pregnancy can cause major birth defects.

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

Lactation: 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.

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.

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

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.

DRUG ABUSE AND DEPENDENCE

Controlled Substance: Halcion contains triazolam, a Schedule IV controlled substance.

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.

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.

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