HALCION- triazolam_tablet

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 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. 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. 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.

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.

Adults 2. 1 Geriatric patients 2. 1 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. , patients with low body weight). 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. 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. In geriatric patients, the recommended dosage is 0. 125 mg to 0. 25 mg once daily. Initiate therapy at 0. 125 mg once daily. 25 mg dose should be used only for patients who do not respond to a trial of the lower dose. Elderly patients have an increased risk of dose related adverse reactions [see Use in Specific Populations (8. 5) 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.

The following serious adverse reactions are discussed in greater detail in other sections: [see Warnings and Precautions (5. 1) [see Warnings and Precautions (5. 2) [see Warnings and Precautions (5. 3) [see Warnings and Precautions (5. 4) [see Warnings and Precautions (5. 5) [see Warnings and Precautions (5. 6) [see Warnings and Precautions (5. 7) [see Warnings and Precautions (5. 9) [see Warnings and Precautions (5. 10) [see Warnings and Precautions (5. 11) Most common adverse reactions (incidence >=4% and twice placebo) are drowsiness, dizziness, light-headedness, and coordination disorder/ataxia. 1 To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www. gov/medwatch 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. 4 Headache 9. 4 Dizziness 7. 1 Nervousness 5. 5 Light-headedness 4. 9 Coordination disorders/ataxia 4. 8 Gastrointestinal Nausea/vomiting 4. 7 In addition to the common reactions enumerated above in Table1, the following adverse reactions have been reported at an incidence of 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. 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: Gastrointestinal disorders: Hepatobiliary disorders: Injury, poisoning and procedural complications: Metabolism and nutrition disorders: Nervous system disorders Psychiatric disorders: Renal and urinary disorders: Reproductive system and breast disorders: Skin and subcutaneous tissue disorders:.

Halcion is contraindicated in: [see Warnings and Precautions (5. 8) Drug Interactions (7. 1) 4 4 5.

Lactation 8. 2 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 [see Warnings and Precautions (5. 10) Clinical Considerations (see Data 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. 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 [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. 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 2 2 14 14 Risk Summary There are reports of sedation, poor feeding and poor weight gain in infants exposed to benzodiazepines through breast milk. There are no data on the presence of triazolam in human milk or the effects on milk production. Triazolam and its metabolites are present in the milk of lactating rats ( see Data 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, poor feeding and poor weight gain. 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 14 Safety and effectiveness of Halcion have not been established in pediatric patients. 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.

Use with Opioids 7. 1 Use with Other CNS Depressants 7. 1 Use with CYP 3A4 Inhibitors 4 5. 1 Table 2 includes clinically significant drug interactions with Halcion [see Clinical Pharmacology (12. 3) Table 2: Clinically Important Drug Interactions with Halcion Opioids Clinical implication 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 GABA A Prevention or management Limit dosage and duration of concomitant use of Halcion and opioids, and monitor patients closely for respiratory depression and sedation [see Warnings and Precautions (5. 1) CNS Depressants Clinical implication Triazolam produces additive CNS depressant effects when co-administered with other CNS depressants. Prevention or management Limit dosage and duration of Halcion during concomitant use with CNS depressants. Strong Inhibitors of CYP 3A Clinical implication Concomitant 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 [see Clinical Pharmacology (12. 3) Prevention or management Do not administer Halcion with a strong CYP3A4 inhibitor [see Contraindications (4) Warnings and Precautions (5. 8) Moderate and Weak Inhibitors of CYP 3A Clinical implication Concomitant use of Halcion with moderate or weak inhibitors of CYP3A inhibitors may increase the concentrations of Halcion, resulting in increased risk of adverse reactions [see Clinical Pharmacology (12. 3) Prevention or management Use with caution and consider appropriate dose reduction of HALCION when coadministered with moderate and weak CYP3A inhibitors [see Warnings and Precautions (5. 8) Strong Inducers of CYP 3A Clinical implication Coadministration of triazolam with strong inducers of CYP3A4 can significantly decrease the plasma concentration of triazolam and may decrease effectiveness of triazolam. Prevention or management Caution 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 implication Available 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 [see Clinical Pharmacology (12. 3) Prevention or management Caution is recommended during coadministration of Halcion with any of these drugs. [see Warnings and Precautions (5.

OVERDOSAGE
Overdosage of benzodiazepines is characterized by central nervous system depression ranging from drowsiness to coma. In mild to moderate cases, symptoms can include drowsiness, confusion, dysarthria, lethargy, hypnotic state, diminished reflexes, ataxia, and hypotonia. Rarely, paradoxical or disinhibitory reactions (including agitation, irritability, impulsivity, violent behavior, confusion, restlessness, excitement, and talkativeness) may occur. In severe overdosage cases, patients may develop respiratory depression and coma. Overdosage of benzodiazepines in combination with other CNS depressants (including alcohol and opioids) may be fatal [see Warnings and Precautions (5.2) In managing benzodiazepine overdosage, employ general supportive measures, including intravenous fluids and airway management. Flumazenil, a specific benzodiazepine receptor antagonist indicated for the complete or partial reversal of the sedative effects of benzodiazepines in the management of benzodiazepine overdosage, can lead to withdrawal and adverse reactions, including seizures, particularly in the context of mixed overdosage with drugs that increase seizure risk (e.g., tricyclic and tetracyclic antidepressants) and in patients with long-term benzodiazepine use and physical dependency. The risk of withdrawal seizures with flumazenil use may be increased in patients with epilepsy. Flumazenil is contraindicated in patients who have received a benzodiazepine for control of a potentially life-threatening condition (e.g., status epilepticus). If the decision is made to use flumazenil, it should be used as an adjunct to, not as a substitute for, supportive management of benzodiazepine overdosage. See the flumazenil injection Prescribing Information. Consider contacting the Poison Help line at (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.
NONCLINICAL TOXICOLOGY
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/m 2 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/m 2.

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