Triazolam dosage

Coadministration of triazolam and nefazodone causes a significant increase in the plasma level of triazolam a 75% reduction in the initial triazolam dosage is recommended. Avoid the coadministration of triazolam and nefazodone for most... 

Nefazodone is an inhibitor of the CYP3A4 isoenzyme, so it can raise the level and thus exacerbate adverse effects of many 3A4-dependent drugs. For example, triazolam levels are increased by concurrent administration of nefazodone such that a reduction in triazolam dosage by 75% is recommended. Likewise, administration of nefazodone with simvastatin has been associated with 20-fold increase in plasma levels of simvastatin. 

Tolerance to hypnotic effects develops after 2 weeks of continuous use of triazolam. Efficacy offlurazepam, quazepam, and temazepam lasts for at least 1 month of continuous nightly use. Estazolam reportedly maintains efficacy at maximum dosage (2 mg nightly) for up to 12 weeks. 

For most child psychiatrists, the drug interactions most frequently encountered are interactions with other psychotropics. Fluoxetine inhibits the CYP3A isozymes and thus increase the plasma concentration of the tria-zolobenzodiazepines (alprazolam, midazolam, and triazolam), causing increased psychomotor effects (Shader and Greenblatt, 1995). To avoid unwanted psychomotor effects, the dosage of alprazolam should be decreased when it is coadministered with fluoxetine (Chouinard et ah, 1999). Nefazadone has also been shown to increase the pharmacodynamic effects of triazolam and, to a lesser extent, alprazolam (Chouinard et ah, 1999). 

Like fluoxetine, erythromycin and other macrolides inhibit the CYP-3A isoenzyme and increase the levels and effects of the triazolobenzodiazepines (Shader and Greenblatt, 1995 Chouinard et ah, 1999). Midazolam should be avoided or the dosage dropped by 50% in patients receiving erythromycin (Olkkola et ah, 1993). Ketoconazole and itraconazole may also interact with triazolam and midazolam, and combinations of these drugs should be avoided (Varhe et ah, 1994 Chouinard et ah, 1999). 

Most of the minor tranquilizers in the BZD exhibit similar clinical effects they differ primarily in their duration of action and in the dosage required to achieve the same effect. The BZDs are classified as short- (triazolam [Halcion]), intermediate- (alprazolam [Xanax] and lorazepam [Ativan]), and long-acting (chlordiazepoxide [Librium] and diazepam [Valium]). Of the various BZDs available in the United States in 2002, those primarily prescribed as anxiolytics and hypnotics include the intermediate- and long-acting variety. 

Figure 2 Mean ( SE) plasma concentrations of triazolam (left) or alprazolam (right) in a series of healthy individuals who participated in a clinical pharmacokinetic study. In one phase of the study, they ingested a single 0.25-mg oral dose of triazolam with ketoco-nazole, 200 mg twice daily, or with placebo to match ketoconazole (control). In the second phase of the study, they took 1.0 mg of alprazolam orally, either with the same dosage of ketoconazole or with placebo to match ketoconazole (control). Note that ketoconazole increases AUC and reduces clearance of both triazolam and alprazolam. For triazolam (a high-extraction compound), the effect is evident as reduced presystemic extraction, increased Cmax, and prolonged half-life. However, for alprazolam (a low-extraction compound), the effect of ketoconazole is evident only as a prolongation of half-life. Abbreviation AUC, the plasma concentration-time curve. Source Adapted, in part, from Ref. 74.

Macrolides cause increases in the serum concentrations, AUCs, and half-lives and reductions in the clearance of triazolam and midazolam (138-140). These changes can result in clinical effects, such as prolonged psychomotor impairment, amnesia, or loss of consciousness (141). Erythromycin can increase concentrations of midazolam and triazolam by inhibition of CYP3A4, and dosage reductions of 50% have been proposed if concomitant therapy is unavoidable (142). 

Erythromycin can increase concentrations of triazolam by inhibition of CYP3A4, and dosage reductions of 50% have been proposed if concomitant therapy is unavoidable (24). 

Via CYP450 3A4 inhibition, fluvoxamine may reduce clearance of carbamazepine and benzodiazepines such as alprazolam and triazolam, and thus require dosage reduction... 

Absorption. The rate of absorption from the gastrointestinal tract after oral dosage determines the speed of the onset of action of a benzodiazepine. For a quick onset of action, the benzodiazepine must dissolve completely in the stomach and cross the stomach mucosa into the systemic circulation. The different dissolution and absorption kinetics of benzodiazepines will affect their onset of action. Once the benzodiazepine is in the systemic circulation, it must also cross the blood-brain barrier to enter the CNS. Therefore, the lipophilidty of the benzodiazepine is important in determining the entry into the CNS and the onset of clinical action. Most benzodiazepines are highly lipophilic with the 3-hydroxy-substi-tuted benzodiazepines (lormetazepam, loraz-epam, temazepam, and doxefazepam) triazolam is the least lipophilic. 

Tolerance to benzodiazepine hypnotic effects develops sooner with triazolam (after 2 weeks of continuous use) than with other benzodiazepine hypnotics." The hypnotic efficacy of flurazepam, quazepam, and temazepam is maintained for 1 month of continuous nightly use." Estazolam reportedly maintains the duration and quality of sleep at the maximum dosage (2 mg nightly) for up to 12 weeks." Long-term use (greater than 6 months) of benzodiazepines was associated with a low risk of abuse, side effects, and tolerance in patients with severe, chronic sleep disorders however, efficacy has not been established."... 

It is very difficult to assess and compare the results of the very many studies of this interaction because of the differences between the tests, their duration, the dosages of the benzodiazepines and alcohol, whether given chronically or acutely, and a number of other variables. However, the overall picture seems to be that benzodiazepines and related drugs including diazepam, " alprazolam,bromazepam, brotizolam, chlo-rdiazepoxide, " clobazam, dipotassium clorazepate, flunitrazepam, flurazepam, loprazolam, " lorazepam, lormetazepam, medazepam, midazolam, nitrazepam, " " oxazepam, temazepam, " triazolam, and zopiclone enhance the effects of alcohol i.e. cause increased drowsiness, impaired performance and driving skills. 

The effects of alprazolam and brotizolam are increased and prolonged by ketoconazole and itraconazole, but the extent of this is less than that seen with midazolam or triazolam. However, some dosage reductions may still be necessary. 

Information is limited but the interactions appear to be established. Their clinical importance is uncertain but be alert for the need to decrease the dosages of diazepam and triazolam if isoniazid is started. There seems to be no direct information about other benzodiazepines, but those undergoing high first-pass extraction and/or liver microsomal metabolism may interact similarly. Oxazepam and clotiazepam appear not to interact. 

The interactions of midazolam with erythromycin and triazolam with clarithromycin, erythromycin or troleandomycin appear to be established, and of clinical importance. The dosages of the midazolam and triazolam should be reduced 50 to 75% when these antibacterials are used if excessive effects (marked drowsiness, memory loss) are to be avoided. Remember too that the hypnotic effects are also prolonged so that patients should be warned about hangover effects the following morning if they intend to drive. Much less is known about the use of midazolam with clarithromycin but similar precautions may be necessary. The manufacturers of zaleplon say that patients should be advised that increased sedation is possible with erythromycin, although a dose adjustment is usually not required. ... 

The interactions of nefazodone with alprazolam, midazolam, triazolam and zopiclone are established and clinically important. The practical consequences are that the effects of alprazolam, midazolam and triazolam are expected to be increased but the extent is uncertain. Be alert for any evidence of any psychomotor impairment, drowsiness etc. and reduce the benzodiazepine dosage if necessary. More study is needed. Lorazepam does not interact with nefazodone. There seems to be no direct information about other benzodiazepines and related drugs. 

This interaction is of clinical importance be alert for the need to reduce the midazolam dosage in the presence of saquinavir. The authors of the study suggest that continuous intravenous midazolam doses should be reduced by 50%, but do not consider dose adjustments to single intravenous doses necessary. The same precautions would seem appropriate with triazolam. However, the manufacturer of saquinavir contraindicates the concurrent use of oral midazolam and triazolam. They note that no studies have been conducted with ritonavir-boosted saquinavir but that a 3 to 4-fold increase in intravenous midazolam levels would be expected. Use of intravenous midazolam with saquinavir is not contraindicated but they... 

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