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美国辉瑞三唑仑HALCION(triazolam tablets)全面到货！

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英文说明书:

Pharmacology

Hypnotic

Triazolam is a benzodiazepine with a very short elimination half-life (about 3 hours).

In sleep laboratory studies in man of 1 to 21 days duration, triazolam reduced sleep latency, increased duration of sleep and decreased the number of nocturnal awakenings. However, after 2 weeks of consecutive nightly administration, the drug's effect on total wake time is decreased, and the values recorded in the last third of the night approach baseline levels. On the first and/or second night after drug discontinuance (first or second post-drug night), total time asleep, and percentage of time spent sleeping frequently were significantly decreased, and sleep latency significantly increased when compared to baseline (predrug) nights. This effect is often called "rebound" insomnia.

The duration of hypnotic effect and the profile of unwanted effects may be influenced by the alpha (distribution) and beta (elimination) half-lives of the administered drug and any active metabolites formed. When half-lives are long, the drug or metabolites may accumulate during periods of nightly administration and be associated with impairments of cognitive and motor performance during waking hours. If half-lives are short, the drug and metabolites will be cleared before the next dose is ingested, and carry-over effects related to sedation or CNS depression should be minimal or absent. However, during nightly use and for an extended period, pharmacodynamic tolerance or adaptation to some effects of benzodiazepine hypnotics may develop. If the drug has a very short elimination half-life, it is possible that a relative deficiency (i.e., in relation to the receptor site) may occur at some point in the interval between each night's use. This sequence of events may account for two clinical findings reported to occur after several weeks of nightly use of rapidly eliminated benzodiazepine hypnotics: (1) increased wakefulness during the last third of the night and (2) the appearance of increased day-time anxiety (see Warnings).

When sedation and psychomotor performance were compared in healthy elderly and young subjects, in response to 0.125 and 0.25 mg doses of triazolam, the degree of sedation was greater and the impairment of psychomotor performance more pronounced in the elderly. The age dependent difference was closely associated with the correspondingly higher plasma triazolam concentrations measured in elderly subjects.

Patients with severe liver disease also demonstrated greater psychomotor impairment than control subjects or patients with minimal liver dysfunction.

Pharmacokinetics:
Triazolam is rapidly absorbed and peak plasma levels are reached within 2 hours following oral administration. Peak plasma concentration (C (max)) and area under the plasma-concentration curve (AUC) increase in proportion to the dose, while the time to peak plasma concentration (T(max)), elimination half-life (t 1/2beta), and clearance are independent of dose. Triazolam has a short half-life; the range is reported to be 1.5 to 5.5 hours.

Triazolam is metabolized via hepatic microsomal oxidation. The hydroxylated metabolites, which are inactive, are excreted primarily in the urine as conjugated glucuronides. The two primary metabolites account for approximately 80% of the urinary excretion.

Repeated administration of triazolam for 7 days does not lead to accumulation and does not alter the rate of elimination.

Pharmacokinetics in the elderly:
The kinetics of triazolam are significantly influenced by age (see Table I). Following single oral doses of 0.125 mg and 0.25 mg of triazolam, peak plasma concentrations and area under the curve were significantly higher and clearance significantly lower in elderly subjects (mean age: 69 years) than in younger one (mean age: 30 years). Age, however, did not influence the time to peak plasma levels and differences in elimination half-life were small.

--------------------------------------------------------------------------------Table I   Mean (+/- standard deviation) pharmacokinetic parameters following   single oral doses of triazolam in young and elderly volunteers                        Triazolam 0.125 mg        Triazolam 0.25 mg                        Young       Elderly       Young        Elderly  Parameter               (n=26)      (n=21)        (n=26)       (n=21)Cmax (ng/mL)           1.08+/-0.08  1.67+/-0.16*  2.02+/-0.15  3.06+/-0.22*Tmax (hr)              0.88+/-0.08  0.95+/-0.11   0.96+/-0.10  0.88+/-0.07AUC (ng/mL.hr)         3.85+/-0.45  6.24+/-0.82*  7.01+/-0.68  12.03+/-1.11*t 1/2beta (hr)         2.94+/-0.4   3.03+/-0.25   2.43+/-0.16   3.00+/-0.24*Clearance (mL/min/kg)  11.4+/-2.2   6.8+/-0.9*    10.5+/-1.0    5.8+/-0.4 * Statistically significant for young versus elderly at indicated dose.--------------------------------------------------------------------------------

Pharmacokinetics in patients with renal failure:
Following oral administration of triazolam, 0.5 mg, peak plasma triazolam concentrations were lower in 11 patients with renal failure undergoing dialysis (4.04+/-1.83 ng/mL) than in patients with normal renal function (6.54+/-1.70 ng/mL). Other pharmacokinetic parameters were not significantly different between patients with impaired and normal renal function.

Pharmacokinetics in patients with hepatic failure:
Following oral administration of triazolam, 0.25 mg, triazolam clearance was reduced in 8 subjects with biopsy-proven cirrhosis (4.99+/-3.14 mL/min/kg) as compared to 7 normal subjects (6.69+/-2.52 mL/min/kg). Peak plasma levels and time to peak concentration were not different between the groups. The reduction in triazolam clearance in subjects with cirrhosis correlated with the severity of liver dysfunction.

Indications

For the symptomatic relief of transient and short-term insomnia in patients who have difficulty falling asleep. Triazolam is not recommended for early morning awakenings.

Treatment with triazolam should usually not exceed 7 to 10 consecutive days. Use for more than 2 to 3 consecutive weeks requires complete re-evaluation of the patient.

The use of hypnotics should be restricted for insomnia where disturbed sleep results in impaired daytime functioning.

Contraindications

In patients with known hypersensitivity to this drug or other benzodiazepines.

Triazolam is contraindicated in patients who in the past manifested paradoxical reactions to alcohol and/or sedative medications, and in subjects with a history of substance or alcohol abuse.

Pregnancy:
Triazolam is contraindicated in pregnant women. Benzodiazepines may cause fetal damage when administered during pregnancy. During the first trimester of pregnancy, several studies have suggested an increased risk of congenital malformations associated with the use of benzodiazepines. During the last weeks of pregnancy, ingestion of therapeutic doses of a benzodiazepine hypnotic has resulted in neonatal CNS depression due to transplacental distribution. If triazolam is prescribed to women of child-bearing potential, the patient should be warned of the potential risk to a fetus and advised to consult her physician regarding the discontinuation of the drug if she intends to become pregnant.

Triazolam is contraindicated in patients who have myasthenia gravis or a history of uncorrected narrow-angle glaucoma.

Warnings

General:
Sleep disturbance may be the presenting manifestation of a physical and/or psychiatric disorder. Consequently, a decision to initiate symptomatic treatment of insomnia should only be made after the patient has been carefully evaluated.

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.

Worsening of insomnia or the emergence of new abnormalities of thinking or behavior may be the consequence of an unrecognized psychiatric or physical disorder. These have also been reported to occur in association with the use of triazolam.

Memory Disturbance:
Anterograde amnesia of varying severity has been reported following therapeutic doses of benzodiazepines including triazolam. Anterograde amnesia is a dose-related phenomenon and elderly subjects may be at a particular risk. Data from several sources suggest that anterograde amnesia and next day memory loss may occur at a higher rate with triazolam than with other benzodiazepines.

Cases of transient global amnesia and "traveler's amnesia" have also been reported in association with triazolam, the latter in individuals who have taken the drug to induce sleep while travelling. Transient global amnesia and traveler's amnesia are unpredictable and not necessarily dose-related phenomena. Patients should be warned not to take triazolam under circumstances in which a full night's sleep and clearance of the drug from the body are not possible before they need again to resume full activity (e.g., an overnight flight of less than 7 to 8 hours).

Abnormal thinking and psychotic behavioral changes have been reported to occur in association with the use of benzodiazepine hypnotics including triazolam. Some of the changes may be characterized by decreased inhibition, e.g., aggressiveness or extroversion that seem excessive, similar to that seen with alcohol and other CNS depressants (e.g., sedative/hypnotics). Particular caution is warranted in patients with a history of violent behavior. Psychotic behavioral changes that have been reported include bizarre behavior, hallucinations, and depersonalization. Abnormal behaviors associated with triazolam have been reported more with chronic use or high doses.

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. Nevertheless, the emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation.

Confusion:
The benzodiazepines affect mental efficiency e.g., concentration, attention and vigilance. The risk of confusion is greater in the elderly and in patients with cerebral impairment.

Anxiety, restlessness:
An increase in daytime anxiety (interdose rebound anxiety) and/or restlessness have been observed during treatment with triazolam. This may be a manifestation of interdose withdrawal, due to the very short elimination half-life of the drug.

Depression:
Caution should be exercised if triazolam is prescribed to patients with signs or symptoms of depression that could be intensified by hypnotic drugs. Suicidal tendencies e.g., intentional overdose, is more common in these patients thus, the least amount of drug that is feasible should be available to them at any one time.

Caution:
Drug Interactions:
Triazolam produces additive CNS depressant effects when co-administered with alcohol, antihistamines, anticonvulsants, or psychotropic medications which themselves can produce CNS depression.

Pharmacokinetic interactions can occur when triazolam is administered along with drugs that interfere with its metabolism. Examples include cimetidine or erythromycin which when co-administered with triazolam cause an approximate doubling of the plasma levels and elimination half-life of triazolam. Consequently, consideration of dose reduction may be appropriate when patients are treated concomitantly with triazolam and either cimetidine or erythromycin.

Drug abuse, dependence and withdrawal:
Withdrawal symptoms, similar in character to those noted with barbiturates and alcohol (convulsions, tremor, abdominal and muscle cramps, vomiting, sweating, dysphoria, perceptual disturbances and insomnia) have occurred following abrupt discontinuance of benzodiazepines, including triazolam. The more severe symptoms are usually associated with higher dosages and longer usage, although patients given therapeutic dosages for as few as 1 to 2 weeks can also have withdrawal symptoms, including daytime anxiety, between nightly doses (see Pharmacology and Warnings). Consequently, abrupt discontinuation should be avoided and a gradual dosage tapering schedule is recommended in any patient taking more than the lowest dose for more than a few weeks. The recommendation for tapering is particularly important in patients with a history of seizures.

The risk of dependence is increased in patients with a history of alcoholism, drug abuse, or in patients with marked personality disorders (see Contraindications). Interdose daytime anxiety and rebound anxiety may increase the risk of dependency in triazolam treated patients.

As with all hypnotics, repeat prescriptions should be limited to those who are under medical supervision.

Patients with specific conditions:
Triazolam should be given with caution to patients with impaired hepatic or renal function, severe pulmonary insufficiency, or sleep apnea. Respiratory depression and apnea have been reported in patients with compromised respiratory function.

Occupational Hazards:
Because of triazolam's CNS depressant effect, patients receiving the drug 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 warned against the concomitant ingestion of triazolam and alcohol or CNS depressant drugs.

Pregnancy:
For teratogenic effects see Contraindications. Non-teratogenic effects: A child born to a mother who is on benzodiazepines may be at some risk for withdrawal symptoms from the drug during the postnatal period. Also, neonatal flaccidity has been reported in an infant born to a mother who had been receiving benzodiazepines.

Lactation:
Human studies have not been performed but studies in rats have shown that triazolam and its metabolites are secreted in the milk. Therefore, administration of triazolam to nursing mothers is not recommended.

Children:
The safety and effectiveness of triazolam in children below the age of 18 have not been established.

Geriatrics:
Elderly patients are especially susceptible to dose-related adverse effects, such as drowsiness, dizziness, or impaired co-ordination. Therefore, the lowest possible dose should be used in these subjects.

Adverse Effects

The most frequent adverse reactions associated with the use of triazolam are extensions of the pharmacological effects of the drug, e.g., sedation (morning drowsiness, somnolence), dizziness, nervousness/irritability and impaired coordination.

The most serious adverse reactions which may occur include memory impairment, abnormal thinking/behavior, confusion, anxiety, and depression (see Warnings).

The incidence of adverse reactions among patients receiving triazolam or placebo is listed in Table II. The figures cannot be used to predict precisely the incidence of untoward events in the course of usual medical practice where patient characteristics and other factors often differ from those in clinical trials. Comparison of the cited figures, however, can provide the prescriber with some basis for estimating the relative contributions of drug and nondrug factors to the untoward event incidence rate in the population studied.

The adverse reaction profile of triazolam observed in controlled clinical trials illustrates the dose-dependency of most of the adverse reactions. At present, the higher dose range is not recommended (see Dosage).

------------------------------------------------------------------------------Table II Percent of Patients Reporting Adverse Reactions (>=0.5%)                                              Triazolam    Triazolam                                               0.1-0.3 mg   0.4-0.6 mg  PlaceboBody System           Adverse Reaction         N=1002       N=2370     N=2036CNS                   drowsiness/sedation        9.5         18.6       14.5                       headache                   5.9          8.1        6.2                      dizziness                  4.4          9.0        5.8                      nervousness/irritability   3.7          4.6        6.4                      impaired coordination      1.7          4.3        1.2                      insomnia                   1.0          1.2        2.8                      confusion                  0.7          1.0        0.5                      mood changes               0.7          0.8        0.7                      depression                 0.5          1.1        0.7                      memory impairment          0.2          1.0         0 Metabolic/Nutrition   appetite change             0           0.5        0.6 Special Senses        visual disturbance         0.4          0.7        0.2                      taste alteration           0.4          0.6        0.3 Cardiovascular        palpitations               0.5          0.4        0.4Respiratory           respiratory infection      1.1          1.7        0.9 Gastrointestinal      nausea/vomiting            2.9          3.8        3.5                      dry mouth                  0.5          0.9        1.4                      abdominal pain/discomfort  0.4          0.6        0.5                      diarrhea                   0.2          0.8        0.4 Musculoskeletal       musculoskeletal/                      joint pain                 0.8          0.9        0.7------------------------------------------------------------------------------

Rare (i.e., less than 0.5%) adverse reactions include dysesthesia/paresthesia, dream abnormalities, drug abuse/habituation, drug withdrawal symptoms, hallucinations, muscle tone disorder, tremor, tinnitus, hearing impairment, eye irritation/redness, edema, chest pain, hot/cold flashes, hypertension, syncope, dyspnea, constipation, flatulence, oral irritation, micturition difficulties, dermatitis, diaphoresis, muscular cramps, muscular weakness, malaise, sexual dysfunction. Elevated levels of AST (SGOT), bilirubin, and alkaline phosphatase have also been noted.

Overdose

Symptoms and Treatment:
Manifestations of triazolam overdosage include extensions of it's pharmacological effects, namely, somnolence, confusion, impaired coordination, slurred speech, and ultimately, coma. Respiratory depression and apnea have been reported with overdosages to triazolam.

Death has been reported in association with overdoses of triazolam by itself, as it has with other benzodiazepines. In addition, fatalities have been reported in patients who have overdosed with a combination of alcohol and a single benzodiazepine, including triazolam. In some of these cases, blood levels of the benzodiazepine and alcohol were lower than those usually associated with reports of fatalities with either substance alone.

As in all cases of drug overdosage, respiration, pulse and blood pressure should be monitored and supported by general measure when necessary. Immediate gastric lavage should be performed. An adequate airway should be maintained. I.V. fluids may be administered. 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.

The benzodiazepine antagonist, flumazenil, is a specific antidote in known or suspected benzodiazepine overdose (For conditions of use, see Anexate product monograph.).

Experiments in animals have indicated that cardiopulmonary collapse can occur with massive i.v. doses of triazolam. This could be reversed with positive mechanical respiration and i.v. infusion of norepinephrine bitartrate or metaraminol bitartrate. Hemodialysis and forced diuresis are probably of little value.

Dosage

The lowest effective dose should be used. Treatment with triazolam should usually not exceed 7 to 10 consecutive days. Use for more than 2 to 3 consecutive weeks requires complete re-evaluation of the patient.

The starting dose in all patients should be 0.125 mg; for many patients this dose immediately before retiring should be sufficient. In most adults, a dose of 0.25 mg should not be exceeded. A dose of 0.5 mg should be used only for exceptional patients who do not respond adequately to a trial of the lower dose since the risk of several adverse reactions increases with the size of the dose administered.

For elderly, or debilitated patients and patients with disturbed liver/kidney function, the dose should not exceed 0.125 mg before retiring. The 0.25 mg dose should be used only for exceptional patients who do not respond to a trial of the lower dose.

Supplied

0.125 mg:
Each violet, scored tablet branded "Upjohn 10" contains: Triazolam 0.125 mg. Nonmedicinal ingredients: Cellulose, cornstarch, docusate sodium, erythrosine sodium, FD&C Blue No. 2, lactose, magnesium stearate, silicon dioxide. Gluten-free. Bottles of 100 and 500. Store at controlled room temperature (15 to 30°C).

0.25 mg:
Each powder blue, scored tablet branded "Upjohn 17" contains: Triazolam 0.25 mg. Nonmedicinal ingredients: Cellulose, cornstarch, docusate sodium, FD&C Blue No. 2, lactose, magnesium stearate, silicon dioxide. Gluten-free. Bottles of 100 and 500. Store at controlled room temperature (15 to 30°C).