Drug Criteria & Outcomes
Formulary evaluation of sedative/hypnotic agents
By Robin Thrower
PharmD candidate
Auburn University and Huntsville (AL) Hospital
Objective
Several different sedative/hypnotic agents currently are on the market. They are divided into two broad categories: benzodiazepines and nonbenzodiazepines. Although some nonbenzodiazepine sedative/hypnotic agents, such as chloral hydrate or antihistamines, possess pharmacologic properties that do not allow direct drug class formulary comparison with the benzodiazepines, the nonbenzodiazepine agents zolpidem and zaleplon are similar pharmacologically to benzodiazepines, making comparison between these agents rational.
According to the current formulary policy at Huntsville Hospital, PRN zolpidem is interchanged with the benzodiazepine temazepam in certain situations. With the recent marketing of zaleplon, this formulary review was performed to evaluate the appropriateness of its use and the potential for drug interchange.
Drugs
Nonbenzodiazepine
Zolpidem (Ambien)
Zaleplon (Sonata)
Benzodiazepine
Triazolam (Halcion)
Temazepam (Restoril)
Pharmacology 1,2,3
Zaleplon, zolpidem, and benzodiazepine hypnotic agents share generally similar pharmacologic profiles. Benzodiazepine agents bind to the GABA-benzodiazepine receptor complex non-selectively to all three omega receptor subtypes. Zaleplon and zolpidem also bind to the GABA-benzodiazepine receptor complex, but bind more selectively to the omega-1 receptor subunit. Selectivity at the type-1 receptor theoretically could produce less muscle relaxation, cause less psychomotor impairment, lead to fewer effects on mental performance, and more effectively preserve deep sleep (Stage 3 and 4) when compared to nonselective drugs. This selectivity is a theoretical mechanism, and the clinical relevance of the drugs’ proposed benefits must be considered.
Indications 1,2
All of the agents are approved for short-term treatment of insomnia. "Short-term" typically means a treatment duration of seven to 10 days. If treatment is required for more than two to three weeks, the patient should be re-evaluated.
Contraindications 1,2
• Zaleplon: prior hypersensitivity or severe hepatic impairment;
• Zolpidem: prior hypersensitivity;
• Triazolam: hypersensitivity to benzodiazepines; pregnancy (Category X);
• Temazepam: hypersensitivity to benzodiazepines; pregnancy (Category X).
Precautions 1,2
• Zaleplon: elderly or debilitated patients, history of depression, mild/moderate hepatic impairment, severe renal impairment, compromised respiratory condition, pregnancy (category C), lactation, concurrent alcohol use;
• Zolpidem: elderly or debilitated patients, respiratory impairment, hepatic or renal impairment, depressed patients, pregnancy (category B), lactation, concurrent alcohol use;
• Triazolam: lactation, concomitant use of alcohol and other CNS depressant agents, elderly patients, depression, history of drug abuse, compromised respiratory function. Avoid abrupt discontinuation in patients with convulsive disorders;
• Temazepam: lactation, concomitant use of alcohol and other CNS depressant agents, elderly patients, depression, history of drug abuse, compromised respiratory function.
Pharmacokinetics
Zolpidem, triazolam, and temazepam have some differences in pharmacokinetic profiles. (See Table 1.) The pharmacokinetic profile of zaleplon shows it to have a rapid elimination half-life. The duration of effect of this drug therefore is shorter than the duration seen with other agents. Based on this, it has been proposed that the drug can be used for insomnia in patients who suffer from early-morning awakenings, and that patients will recover from doses given even just a few hours before awakening. The manufacturer, however, recommends that patients remain in bed at least four hours following drug administration.
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The half-life of temazepam is longer and its absorption tends to be somewhat slower and more variable; however, the time of maximum drug concentration does not greatly differ from the other agents. All four of these agents have generally similar times to onset of action, usually within one hour. All of the drugs are metabolized hepatically, but only temazepam is not metabolized by the CYP3A4 isoenzyme. This results in fewer potential drug interactions with this agent.
Dosing
A dosing schedule is presented in Table 2.
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Safety 1,2,3
Adverse effects. All of the drugs produce a low incidence of daytime residual effects when given at normal doses as the patient first goes to bed. Prolonged use and higher doses are associated with a greater incidence of adverse effects, such as increased potential for rebound insomnia or more pronounced daytime residual effects. Anterograde amnesia, which can be seen following administration of any of these agents, generally is not problematic unless the patient does not fall asleep following dose administration. Most patients already have fallen asleep at the time this adverse effect would present. Table 3 summarizes the side effect profiles of these drugs.
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Abuse potential. Abuse potential is present with all of these agents, and they are considered controlled substances (Class IV) by the U.S. Drug Enforcement Agency. Tolerance may occur with any of these agents, and it usually is seen when the drug is used for a prolonged period. Withdrawal symptoms that can be seen include anxiety, tremor, sweating, tachycardia, tachypnea, nausea, and gastric and abdominal pain.
Drug interactions:
• Zaleplon:
— Cimetidine (potential inhibition of metabolism of zaleplon);
— Rifampin (potential increased zaleplon metabolism);
— Imipramine, thioridazine (additive CNS effects).
• Zolpidem:
— Cimetidine (potential inhibition of metabolism of zolpidem);
— Rifampin (potential increased zolpidem metabolism);
— Ritonavir (may increase zolpidem concentrations).
• Triazolam:
— Amprenavir, delviradine, efavirenz, indinavir, nelfinavir, ritonavir, saquinavir (prolonged and excessive sedation due to impaired triazolam metabolism);
— Cimetidine (potential inhibition of metabolism of triazolam);
— Diltiazem (increased triazolam levels, increased sedative effects);
— Azole antifungals (increased and prolonged effects of triazolam);
— Nefazodone (impaired metabolism of triazolam);
— Rifampin (potential increased triazolam metabolism);
— Theophylline (decreased sedative effects).
• Temazepam:
— Theophylline (decreased sedative effects).
Review of clinical trials
Few studies directly compare these agents. Zaleplon has been studied most frequently in conjunction with zolpidem. There are a few studies that evaluated zaleplon and triazolam, but these studies used high, inappropriate doses, and their primary objective was to study abuse potential. No available trials have been conducted to compare zaleplon or zolpidem with temazepam. Vast experience with temazepam has been established at Huntsville Hospital, providing evidence of its safety and efficacy profile. The following trials were selected because their content and results contribute most to this evaluation and help to identify the role of zaleplon and other sedative/hypnotic agents in this institution.
Zaleplon vs. zolpidem vs. placebo 4
The primary objective of this study was to compare the safety and efficacy of three doses of zaleplon with a standard dose of zolpidem and placebo. Enrolled patients met DSM-III-R criteria for primary insomnia or insomnia associated with nonpsychotic psychiatric disorders. Patients were between the ages of 18 and 65 years. Exclusion criteria included presence of transient or situational insomnia, insomnia associated with shift-work, sleep apnea, restless leg syndrome, anxiety, and depression. A total of 615 patients were randomized to double-blind treatment with zaleplon 5 mg, zaleplon 10 mg, zaleplon 20 mg, zolpidem 10 mg, or placebo. A seven-night placebo (baseline) period was followed by 28 nights of study treatment. A three-night placebo period followed the treatment period.
Sleep maintenance, sleep latency, and sleep quality were evaluated using questionnaires, which the patients completed each morning. For comparisons of each dose of zaleplon and placebo, the authors used the Dunnett-test distribution, which adjusts for the number of comparisons. For other pair-wise comparisons (such as zolpidem vs. placebo), the F-test was used, which does not adjust for the number of comparisons. All of the drug-treatment regimens showed a statistically significant improvement in median sleep latency compared to placebo during the first week. The median sleep latencies for all treatment groups fell in a range of 30-50 minutes. As the study progressed, these values became even more similar. Zaleplon 20 mg significantly increased sleep duration compared to placebo for weeks 1, 2, and 4. Zolpidem 10 mg significantly increased sleep duration in all weeks of randomized treatment. None of the treatments showed an improvement in the number of awakenings per night when compared to placebo. Sleep quality was measured on a scale of 1-5, with 1 being excellent and 5 being poor. Statistically significant improvements were seen in sleep quality for zaleplon 10 and 20 mg and zolpidem 10 mg in week 1. Only zolpidem 10 mg showed statistically significant improvements for weeks 2-4. Table 4 summarizes the results of this study.
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On the first night of the placebo wash-out period, the zolpidem 10 mg patients showed a statistically significant, higher sleep latency period compared to placebo patients on the same night (30 minutes with placebo vs. 55 minutes with zolpidem). Zaleplon did not show a statistically significant difference compared to placebo on this night. All treatment groups were comparable on this night in sleep duration and number of awakenings.
Neither zaleplon nor zolpidem resulted in serious adverse effects. The most frequently reported adverse events were abdominal pain (1-9%), amnesia (1-5%), parasthesia (1-8%), somnolence (2-5%), pharyngitis (2-7%), and taste alterations (1-6%). Of the drug treatment groups, zaleplon 5 mg had the overall lowest frequency of adverse effects.
In this study, the two agents showed similar treatment effects, especially early in the treatment period. They also demonstrated similar safety profiles. When examining study results, it becomes obvious that even statistically significant improvements (compared to placebo) are small improvements. Patients also experienced adverse events that are associated with the benzodiazepine sedative/hypnotic agents, such as amnesia and somnolence.
This study did have weaknesses for the purpose of this formulary evaluation. The study population may not reflect the population of patients being treated with sedative/hypnotic agents in Huntsville Hospital. Patients in this institution requiring a sedative/hypnotic agent are often older than age 65; this study excluded those patients. Also excluded from this study were patients with "situational insomnia." Patients in this hospital with insomnia often are experiencing a situational sleep disturbance. The examination of the different treatment groups with two different statistical analyses could cause the results of the study to be questionable.
Zaleplon vs. zolpidem vs. placebo 5
The objective of this study was to evaluate the pharmacokinetic and pharmacodynamic effects of each of these agents. Ten male volunteers between the ages of 21 and 44 with no health complications received one dose each of placebo, zaleplon 10 mg, zaleplon 20 mg, zolpidem 10 mg, and zolpidem 20 mg with a 48-hour wash-out period between the administration of each agent. Plasma drug concentrations and pharmacodynamic parameters were measured for 8-24 hours following the administration of each agent.
The kinetics of zolpidem and zaleplon were not related to dose; however, pharmacodynamic effects were significantly related to dose. Only zolpidem 20 mg was significantly different from placebo in mean change from baseline for the self-rating and observer rating scales of sedative effects. At the usual clinically effective dose, 10 mg of either drug, there was a trend for greater benzodiazepine receptor agonist effects with zolpidem. This could be related to the shorter half-life of zaleplon.
Major weaknesses of this trial were its small sample size, brief period of drug administration, and use of a young, healthy study population. The omission of important clinical efficacy parameters, such as reduction in sleep latency, residual effects, or early-morning awakenings, limits the contributions that this study can make to drug evaluation.
Zaleplon vs. zolpidem vs. placebo 6
Thirty-six healthy patients were enrolled to evaluate the residual effects of zaleplon and zolpidem following administration two to five hours before awakening. The rationale of this study was to evaluate the utility of zaleplon compared with zolpidem and placebo for early-morning awakenings. Patients lived in standardized conditions during the study period. Zaleplon 10 mg, zolpidem 10 mg, or placebo was administered in a double-blind manner at predetermined times five, four, three, or two hours before awakening, which occurred eight hours after bedtime. Patients were awakened at their designated times to receive medication. The following morning, subjective (memory and functional exams) and objective (drug levels) results were obtained. Zaleplon did not show residual effects when administered as short as two hours before awakening. Zolpidem showed impairment on memory exams when administered as long as four to five hours before awakening. This study shows that late-night administration of zaleplon will have little to no effect on next-day functioning.
The administration of zaleplon and zolpidem in this study does not reflect the intended use of these drugs. The study also does not evaluate how efficacious these agents will be in patients actually experiencing early-morning awakenings because these patients were awakened to receive study drug. Although zaleplon had little effect on the subjective memory examinations used in this study, it is not recommended to use the drug in this manner. Patients are advised to remain in bed at least four hours following drug administration. The study did not evaluate efficacy parameters such as reduction in sleep latency, improvement in sleep quality, or increased total time slept. This study does provide data that the drug could have a role in early-morning awakenings for patients who must be awake four to five hours following drug administration. This situation would be a rare occurrence in the Huntsville Hospital patient population. The study does not evaluate the effects of taking the drug at bedtime and with early-morning awakening because only one dose was administered each night. Most patients requiring a sedative/hypnotic in this institution require the drug to induce sleep when they initially go to bed. Zaleplon was not shown to provide advantages over other sedative/hypnotics in this scenario.
Costs/usage at Huntsville Hospital
Table 5 indicates average monthly use over a recent 12-month period. With the initiation of a formulary interchange program for PRN zolpidem doses with temazepam, it can be expected that these numbers would change in the near future. Temazepam 15 mg and zolpidem 10 mg currently account for approximately 80% of the usage of these four drugs at Huntsville Hospital.
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Table 6 depicts cost savings at different rates of interchange. These figures are based on interchange of zaleplon 5 mg and zolpidem 5 mg with temazepam 15 mg, and zaleplon 10 mg and zolpidem 10 mg with temazepam 30 mg at the usage rates indicated in Table 5. The percentage of doses interchanged is based on total use of the drug, and not only on PRN doses, as these numbers were not readily available.
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Summary and recommendations
Zaleplon, zolpidem, triazolam, and temazepam have demonstrated efficacy as sedative/hypnotic agents. As a result of safety concerns with higher-dose triazolam, physicians have not used the drug in Huntsville Hospital during the last year. The majority of the safety concerns with sedative/hypnotic agents pertain to next-day residual effects. These effects are seen more frequently with prolonged use and higher doses. In this institution, the drugs typically are used for a very short period of time (one to two nights out of admit). Temazepam, which is considered to have increased residual effects with doses exceeding 40 mg/d, is most frequently dispensed in the lower-dose formulation of 15 mg, indicating low doses are used to avoid potential adverse effects when possible.
The nonbenzodiazepine agents evaluated here do have a place in therapy. Zolpidem has been assigned a pregnancy category B, whereas the benzodiazepine agents are contraindicated in pregnancy. Other sedative/hypnotic agents, such as the antihistamine agent diphenhydramine, also can be used in this population. If other nonbenzodiazepine agents do not produce satisfactory results, zaleplon or zolpidem may be considered for pregnant patients. In addition, if patients cannot tolerate standard doses of temazepam during short-term use, and drug use results in unusual daytime residual effects, zolpidem, with its shorter half-life, could be an alternative. A trial of the drug is warranted in this situation.
Given the potential for cost savings and the minimal threat of adverse events, it is recommended that Huntsville Hospital interchange zaleplon with temazepam in the same manner as temazepam is interchanged for zolpidem. Before the interchange takes place, it should be clarified that the patient is not pregnant and has no history of temazepam intolerance.
PRN dose exchange
| Zolpidem or Zaleplon 5 mg |  |
Temazepam 15 mg |
| Zolpidem or Zaleplon 10 mg | |
Temazepam 30 mg |
Because some patients may gain potential benefit from either zolpidem or zaleplon, an agent from this class also should be available for use. Given that these two drugs have very similar safety and efficacy profiles, only one agent should be made available on the formulary to reduce unnecessary inventory in the pharmacy. Given the larger amount of experience with zolpidem at Huntsville Hospital, it is recommended that zaleplon doses be interchanged with zolpidem when temazepam cannot be used. Doses of zolpidem should be given at bedtime.
When temazepam cannot be used, follow the scheduled dose interchange below:
| Zaleplon 5 mg | |
Zolpidem 5 mg |
| Zaleplon 10 mg | |
Zolpidem 10 mg |
The interchange program will result in patients receiving a safe and effective sedative/hypnotic agent and result in cost savings for Huntsville Hospital. Practitioners may order a nonformulary drug for a specific patient by writing "no substitution" with the original drug order.
References
1. McEvoy GK, ed. AHFS Drug Information: 1999. Bethesda, MD: American Society of Health-System Pharmacists; 1999.
2. Gelman CR, Rumack BH, Hess AJ, eds. Drugdex System. Englewood, CO: MicroMedex; 2000.
3. Anonymous. Zaleplon for insomnia. Medical Lett 1999; 41:93-94.
4. Elie R, Ruther E, Ibrahim F, et al. Sleep latency is shortened during four weeks of treatment with zaleplon, a novel non-benzodiazepine hypnotic. J Clin Psychiatry 1999; 60:536-544.
5. Greenblatt DJ, Harmatz JS, Von Moltke LL, et al. Comparative kinetics and dynamics of zaleplon, zolpidem and placebo. Clin Pharmacol Ther 1998; 64:553-561.
6. Danjou P, Paty I, Fruncillo R, et al. A comparison of the residual effects of zaleplon and zolpidem following administration 5 to 2 hours before awakening. Br J Clin Pharmacol 1999; 48:36-374.
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