B
Summary Tables of Literature Reviewed for Safety of Halcion
B-1 |
Evaluation of Comparability, Pharmacokinetics, and Pharmacodynamic Interactions of Halcion, |
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B-2 |
Results of In Vitro Binding Studies: Displacement of Flunitrazepam in the Human Cortex, |
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B-3 |
Displacement of [3H]Flumazenil in Rats as Determined by In Vivo Autoradiography, |
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B-4 |
Relative Lipophilicity of Benzodiazepines, |
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B-5 |
IOM Summary of Studies Investigating Possible Unique Amnestic Effects of Halcion, |
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B-6 |
IOM Summary of Studies Investigating Possible Unique Anxiogenic Effects During Administration of Halcion, and Anxiogenic or Insomnia-Promoting Effects with Withdrawal, |
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B-7 |
IOM Summary of Studies Investigating Possible Unique Ataxic or Dyscoordination Effects of Halcion, |
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B-8 |
IOM Summary of Studies Investigating Possible Unique Disinhibiting Effects of Halcion, |
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B-9 |
IOM Summary of Studies Investigating Possible Unique Psychotigenic, Confusion, or Dissociation-Generating Effects of Halcion, |
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B-10 |
IOM Summary of Studies Investigating Other Possible Adverse Events related to Halcion, |
TABLE B-1 Evaluation of Comparability, Pharmacokinetics, and Pharmacodynamic Interactions of Halcion
Source |
Type |
Population |
Number of Subjects |
Drug and Dose |
Duration |
Outcome/Comments |
Greenblatt et al. (1989) |
Placebo-control |
Healthy |
16 |
Placebo |
Single dose |
Time to peak: flurazepam, 1-1.2 ha; temazepam, 1.5 h; Halcion, 0.95 h. Time to elimination: flurazepam, >24 hb; temazepam, 8.7 h; Halcion, 2.0 h. |
12 |
flurazepam 15 mg |
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13 |
Temazepam 15 mg |
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12 |
Halcion 0.25 mg |
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Mouret et al. (1990) |
? |
? |
? |
Zopliclone |
Single dose |
Time to peak: 75 min; time to elimination: 5-6.5 h |
Mauri et al. (1993) |
? |
? |
? |
Quazepam Desalkylflurazepam Oxoquazepam OH-Triazolam |
Single dose, Very low concn. |
Time to elimination: quazepam, 30-40 h; Desalkylflurazepam Oxoquazepam, 40-70 h; OH-Triazolam, 30-40 h. |
Monti et al. (1994) |
? |
? |
? |
Zolpidem |
Single dose |
Time to peak: 0.33-0.67 h. Time to elimination: 2-3 h |
Adam and Oswald (1988) |
? |
? |
? |
Lormetazepam |
Single dose |
Time to elimination: 10-20 h. Humpel et al. (1980) |
Eberts et al. (1981) |
NA |
Bedtime |
6 |
71.1 mCi of Halcion Free alpha-OH triazolam Free 4-OH triazolam |
Single dose |
Time to peak: Halcion, 1.3 h; Alpha-OH triazolam gluconate, 1.3 h; 4-HTT-gluconate, 2.5 h; others, levels low for kinetics. Time to elimination: Halcion, 2.3 h; Alpha-OH triazolam gluconate, 3.9 h; 4-HTT-gluconate, 3.8 h. |
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|
|
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Alpha-OH triazolam gluconate 4-HTT-gluconate |
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Free alpha-OH triazolam 69% of urine14C (free + conjugated); Free 4-OH triazolam 11% of urine14C (free + conjugated) |
Source |
Type |
Population |
Number of Subjects |
Drug and Dose |
Duration |
Outcome/Comments |
Greenblatt et al. (1991) |
Placebo Halcion at 0.125 and 0.25 mg |
Elderly |
26 young, 21 elderly |
|
Single dose |
Halcion levels doubled in elderly controls, with greater cognitive/behavioral effects. |
Oliveto et al. (1991) |
Placebo, diazepam |
Bedtime |
7 |
Halcion 0.25 mg Halcion 0.1-0.56 mg/70 kg Diazepam 10-32 mg/70 kg Hydromorphone 1-6 mg/70 kg |
Single dose |
Halcion and diazepam are indistinguishable |
Rukstalis and de Wit (1995) |
Placebo |
Female |
6 |
Halcion 0.25 mg |
Three doses over 1 month |
No significant change in behavior over menstrual cycle. |
Rush et al. (1994) |
Placebo, dose |
Male |
9 |
Halcion 0 mg, 0.375 mg/70 kg, 0.75 mg/70 kg in combination with caffeine 0 mg, 250 mg/70 kg |
Balanced design |
Caffeine reduced Halcion sedation and cognitive effects, but not sense of Halcion strength. |
Villikka et al. (1997) |
NA |
Bedtime |
10 |
500 mg/70 kg Halcion 0.5 mg |
One dose after 5 days of rifampin |
Rifampin induces CYP 3A4. It reduced peak Halcion levels to 12.4% of levels in subjects receiving placebo, proportionately reducing behavioral effects. |
Kosuge et al. (1997) |
|
Bedtime |
7 |
Halcion 0.25 mg |
One dose after 3 days of diltiazem 180 mg |
AUC of concentration by time doubled; elimination half-life increased from 4.1 to 7.6 h; intensity of behavioral effects increased. |
von Moltke et al. (1996) |
NA |
In vitro |
|
Liver microsome preparation |
|
SSRIs (norfluoxetine most potent, fluoxetine least potent) and ketoconazole inhibit Halcion metabolism via cytochrome P-450 CYP 3A4 system. |
TABLE B-2 Results of In Vitro Binding Studies: Displacement of Flunitrazepam in the Human Cortex
Drug |
Kd (37§C) nMa |
t1/2-off (min)b |
Ratio to Kd Halcionc |
Halcion |
0.5 ± 0.01 |
5.3 |
1 |
Alpha-hydroxytriazolam |
2.2 ± 0.06 |
|
4 |
Clonazepam |
2.2 ± 0.2 |
3.4 |
4 |
Lorazepam |
3.8 ± 0.2 |
|
8 |
Midazolam |
4.9 ± 0.07 |
|
10 |
Diazepam |
9.8 ± 0.7 |
|
20 |
Desmethyldiazepam |
48 ± 2 |
|
96 |
Alprazolam |
10.6 ± 0.4 |
3.4 |
21 |
Oxazepam |
39 ± 3 |
|
78 |
Flurazepam |
51 ± 2 |
4.6 |
102 |
Desalkylflurazepam |
8.2 ± 0.3 |
|
16 |
Quazepam |
58 ± 4 |
|
116 |
Desalkylflurazepam |
8.2 ± 0.3 |
|
16 |
Temazepam |
66 ± 1 |
|
132 |
Chlordiazepoxide |
694 ± 8 |
|
>103 |
a Ratio of Kd of drug to Kd of Halcion bt1/2-off, dissociation half-life. cKd dissociation constant. SOURCE: Richelson et al. (1991). |
TABLE B-3 Displacement of [3H]Flumazenil in Rats as Determined by In Vivo Autoradiography
TABLE B-4 Relative Lipophilicity of Benzodiazepines
Source and Drug |
HPLC Retention Indexa |
Concentration in Whole Brain/Unbound Concentration in Serum |
Inhibitory Constant Ki |
Arendt et al. (1987) |
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Halcion |
0.6 |
19.5 |
0.4b |
Diazeparn |
1.0 |
26.05 |
9.57b |
Desmethyldiazepam |
0.8 |
22.18 |
5.58b |
Alprazolam |
0.5 |
2.62 |
4.4b |
Lorazepam |
0.5 |
16.0 |
1.6b |
Midazolam |
1.5 |
33.91 |
0.4b |
Miller et al. (1988) |
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Flurazepam |
56.8c |
8.2 |
12.7b |
Desalkylflurazepam |
29.1c |
7.0 |
0.85b |
Sethy and Harris (1982) (flunitrazepam displacement, ''brain" pellet) |
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Halcion |
|
|
0.76d |
Alpha-hydroxytriazolam |
|
|
0.92d |
4-Hydroxytriazolm |
|
|
0.32d |
a Relative to diazepam. HPLC, high-pressure liquid chromatography. b Units of Ki (inhibitory constant) are IC50/1 + S/Kd where IC50 is the 50% inhibitory concentration and S is the flunitrazepam concentration. c In minutes. d In nanomolar. |
TABLE B-5 IOM Summary of Studies Investigating Possible Unique Amnestic Effects of Halcion
Source |
Type |
Population |
Number of Subjects |
Drug and Dose |
Duration |
Outcome/Comment |
Roth et al. (1980) |
Placebo/BZ |
Bedtime |
11 |
Placebo Flurazepam 30 mg Halcion 0.5 mg Lorazepam 4 mg |
2 nights/week over 4 weeks |
Lorazepam equivalent to Halcion impairing, immediate and delayed (tested following morning) recall (both amnestic) vs. placebo and flurazepam. Flurazepam impairs vs. placebo to typical dose, but appropriate for the comparison. More rapid return to sleep may be a factor contributing to sleep may be a factor contributing to interference with memory consolidation with Halcion (difference in minutes). |
Spinweber and Johnson (1982) |
Placebo |
Male, insomniac |
10 10 |
Halcion 0.5 mg Placebo |
6 treatment nights 2 withdrawal |
Reaction time, digit symbol, Williams Word Memory and Card Song Sorting Deficits Evident Immediate to 5 h after drug administration. Paired associate task administered prior to Halcion did not show a.m. memory, impairment. |
Roehrs et al. (1983) |
Placebo/flurazepam secobarbital |
Male, Bedtime |
12 |
Halcion 0.25 and 0.5 mg Placebo Flurazepam 30 mg Secobarbital 200 mg Lorazepam 4 mg |
6 days of administration for each agent, 1 day of withdrawal |
Halcion memory impairment was dose-dependent. Acute: lorazepam = Halcion, 25 = flurazepam < Halcion. 0.5 = Secobarbital. Over 6 days no change with Halcion or secobarbital. Effect from flurazepam worsened (accumulation?) to equal that of Halcion at 5 mg. Tolerance to lorazepam appeared to develop. |
Scharf et al. (1988) |
Three studies |
Bedtime Insomniac Insomniac |
22 22 30 |
Halcion 0.5 mg/placebo Halcion 0.5 mg/placebo Temazepam 30 mg |
Single dose |
Halcion, but not temazepam, showed. evidence of anterograde memory impairment. |
Greenblatt et al. (1989) |
Placebo/active |
Bedtime |
16 12 13 11 |
Placebo Flurazepam 15 mg Temazepam 15 mg Halcion 0.25 mg |
Single dose |
List learning at 24 h: Halcion < flurazepam = temazepam placebo. Possible bias against Halcion from a State Department learning perspective. |
Penetar et al. (1989) |
Placebo |
Bedtime, Aerial Deployment |
33 35 |
Halcion 0.5 mg Placebo |
Single dose |
Logical memory WMS impairment at 8 h by Halcion vs. placebo. Stimuli presented while receiving drug. |
Griffiths et al. (1986) |
Placebo/active |
Bedtime (within subject) |
10 |
Zopiclone 7.5 mg Flurazepam 15 mg Lormetazepam 1 mg Halcion 0.25 mg Placebo |
Single dose |
Stroop, memory span, logical reasoning, mood, and saccadic eye movement all were similarly drug sensitive. |
Source |
Type |
Population |
Number of Subjects |
Drug and Dose |
Duration |
Outcome/Comment |
Baughman et al. (1989) |
Placebo/diazepam |
Surgery, Premedical |
12 |
Placebo |
Single dose |
Percent picture recall by dose: Halcion, 95, 82 and 63%; Diazepam, 100, 100 and 82%. Only Halcion 0.5 mg decreased recall significantly. |
12 |
Halcion 0.125 mg |
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12 |
Halcion 0.25 mg |
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12 |
Halcion 0.5 |
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Fleming et al. 1990) |
Zopiclone |
Insomniacs |
24 |
Zopiclone 7.5 mg |
21 days |
4/24 subjects receiving zopiclone vs. 3/24 subjects receiving Halcion reported memory difficulties. |
24 |
Halcion 0.25 mg |
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Baiter and Uhlenhuth (1991) |
Survey |
Insomniac |
|
Untreated (U) Halcion (H) Flurazepam (F) Temazepam (T) |
|
U: 44% subjective report of memory impairment. H: 12% subjective report of memory impairment. F: 12% subjective report of memory impairment. T: 14% subjective report of memory impairment. |
Bixler et al. (1991) |
Placebo/temazepam |
Insomniac |
6 |
Halcion 0.5 mg |
5 nights on medication per subject by placebo then 1-2 nights, then placebo |
Five of six subjects in Halcion group report inability to recall (3/4 followed episodes of (amnesia). No report of inability to recall or memory impairment in other group. Frequency increased over 5 nights. Better performance in immediate recall (vs. placebo) and delayed word recall (vs. placebo and temazepam) in Halcion group following drug withdrawal in morning test after p.m. drag. Worse delayed task recall in a.m. during drug administration for Halcion (temazepam not significant) vs. placebo group. |
6 |
Temazepam 30 mg |
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6 |
Placebo |
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Hedenbro et al. (1991) |
Placebo |
Endoscopy |
177 |
Placebo |
Single dose |
No clear amnestic effects regarding surgery events. |
182 |
Halcion 0.125 mg |
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Rush et al. (1993) |
Placebo/temazepam |
Bedtime |
6 |
Halcion 0.125, 0.25, and 0.5 mg/70 kg; Placebo Temazepam 15 and 30 mg/70 kg |
Single dose |
Halcion more amnestic, intoxicating sedating than temazepam |
|
Placebo/temazepam |
Bedtime |
6 |
Halcion, Placebo, 0.5 mg/70 kg Temazepam, placebo, 60 mg/70 kg |
Single dose |
Halcion equally sedating, subjective drunkeness, less cognitive impairment than temazepam. |
McMarten et al. (1995) |
ABA |
Alzheimer's disease |
7 |
Halcion 0.125 mg |
8 days |
No effect on delayed matching to sample. Not a clearly efficacious hypnotic. |
TABLE B-6 IOM Summary of Studies Investigating Possible Unique Anxiogenic Effects During Administration of Halcion, and Anxiogenic or Insomnia-Promoting Effects with Withdrawal
Source |
Type |
Population |
Number of Subjects |
Drug and Dose |
Duration |
Outcome/Comments |
Greenblatt et al. (1989) |
Placebo, active drug |
Bedtime |
16 12 13 11 |
Placebo Flurazepam 15 mg Temazepam 15 mg Halcion 0.25 mg |
Single dose |
Halcion only hypnotic to initially slow thinking speed. Similar increase above baseline for all but flurazepam at 24 h. Increased thinking speed could be related |
Pinnock et al. (1985) |
Placebo, diazepam |
Medical |
28 30 29 |
Placebo Diazepam 10 mg Halcion 0.25 mg |
Single dose presurgery |
VAS anxiety diazepam, but not Halcion acutely anxiolytic; no difference 6 h postawakening. |
Kales et al. (1986) |
Placebo, quazepam; sleep laboratory |
Insomnia |
6 6 |
Placebo, Halcion 0.25 mg Placebo, Quazepam 15 mg |
2 days then 14 days; 3-day withdrawal |
Carryover sedation with quazepam. (SWS suppression) rebound insomnia with halcion. Rate of "excitatory" effects reported to be 0.5 for Halcion vs. 0.14 for quazepam. Withdrawal-related anxiety/panic for Halcion ("excitatory effects": anxiety, hyperarousal, inability to concentrate, paranoid ideation, nightmares). Not clear that quazepam group was followed long enough to adequately rule out rebound (loss of quazepam). |
Hegelbach-Feller et al. (1988) |
Placebo, midazepam; crossover |
Insomnia |
30 |
Placebo Halcion 0.5 mg Midazepam 15 mg |
11 days |
More rebound decline in sleep quantity and restlessness during night with Halcion. |
Lee and Lader (1988) |
Placebo, quazepam; crossover |
Bedtime |
12 |
Placebo Quazepam 15 mg |
14 days |
Mild rebound anxiety more clear with quazepam. Withdrawal-related onset of metallic taste with Halcion. |
Fleming et al. (1990) |
Zopiclone |
Insomniacs |
24 24 |
Zopiclone 7.5 mg Halcion 0.25 mg |
21 days |
In first week of withdrawal subjective agitation equivalent: 3 zopiclone, 2 Halcion. |
Mouret et al. (1990) |
Zopiclone |
Elderly insomniacs |
10 |
Halcion 0.25 mg Zopiclone 7.5 mg |
15 days. |
Withdrawal insomnia during treatment with zopiclone but not Halcion; 3 days for Halcion vs. 2 days for zopiclone. Did not see "extremely marked" withdrawal as described by Kales et al. (1976, 1983). |
Elie et al. (1990) |
Zopiclone |
Elderly insomniacs |
44 |
Halcion 0.125 mg Halcion 0.25 mg Zopiclone 5 mg Zopiclone 7.5 mg |
3 weeks |
After withdrawal from Halcion, increased sleep latency and decreased sleep soundness end quality for 3 days. No significant change with zopiclone. |
Source |
Type |
Population |
Number of Subjects |
Drug and Dose |
Duration |
Outcome/Comments |
Mamelak et al. (1990) |
Placebo, dose |
Bedtime |
10 |
Placebo |
1 dose |
Halcion at 0.5 mg was most effective, but rebound reduction in subjective sleep soundness and quality of sleep relative to those for baseline and other groups. First withdrawal night, 0.5 nag increased REM index and reduced stage 3/4 sleep relative to those at baseline. |
10 |
Halcion 0.25 mg |
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10 |
Halcion 0.5 mg |
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McClusky et al. (1991) |
Behavior therapy |
Insomniac |
15 |
Behavior therapy |
4 weeks, then 5-week follow-up |
Over the 4 weeks of treatment, Halcion is as good or better than behavior therapy. At follow-up, behavior therapy is superior for sleep onset latency (both groups better than baseline), restedness (Halcion back to baseline), difficulty falling asleep (Halcion at baseline). |
15 |
Halcion 0.5 mg |
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Stopperich et al. (1993) |
Placebo |
Preoperative dental patients |
11 |
Placebo |
1 dose |
Reduced anxiety. |
11 |
Halcion 0.25 mg |
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Scharf (1993) |
Placebo, quazepam |
Insomniac |
26 |
Placebo |
9 days nightly; 14 every other night |
Both equally effective. Quazepam, but not Halcion, reduced daytime anxiety. Rebound reduction in sleep satisfaction with Halcion in night schedule. |
19 |
Halcion 0.5 mg |
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20 |
Quazepam 15 mg |
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Roger et al. (1993) |
Zolpidem |
Elderly insomniac inpatients |
70 |
Zolpidem 5 mg |
3 weeks |
One patient receiving Halcion withdrew bemuse of nightmares, agitation, and sense of "imminent death." Nightmares: 2 patients receiving zolpidem at 5 mg, 2 patients receiving Halcion, and 3 patients receiving zolpidem at 10 rag. Agitation: 1 patient receiving zolpidem at 5 mg, 3 patients receiving zolpidem at 10 mg, and 2 patients receiving Halcion. |
74 |
Zolpidem 10 mg |
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77 |
Halcion 0.25 mg |
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Mauri et al. (1993) |
Quazepam |
Insomniac outpatients |
32 |
Quazepam 15 mg |
8 weeks |
After discontinuation, Halcion group only showed increased awakening duration, reduction in total sleep time, reduction in sleep quality (vs. active treatments, not vs. pretreatment). (Ham A) anxiety reduction at week I with quazepam and week 2 with Halcion. No significant rebound. |
33 |
Halcion 0.5 mg |
Source |
Type |
Population |
Number of Subjects |
Drug and Dose |
Duration |
Outcome/Comments |
Monti et al. (1994) |
Placeo, zolpidem |
Insomniac outpatients |
8 |
Zolpidem 10 mg |
27 nights |
Subjective change of unclear statistical significance. Daytime Ham A reduction with zolpidem (relative to that at baseline) only. During withdrawal, Halcion worse than and week time (EEG). One adverse event for nervousness event for anxiety with Halcion during withdrawal. Worsening in nervous, discomfort VAS with Halcion and improvement with zolpidem of unclear statistical significance. |
8 |
Halcion 0.5 mg |
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8 |
Placebo |
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Bliwise et al. (1988) |
Placebo |
Insomnia |
7 |
Halcion 0.5 mg |
3 nights baseline, 9 nights placebo, 35 nights drug/placebo |
No increase in morning or evening anxiety measured by POMS. Power of anxiogenic effect estimated to be 0.26. |
7 |
Placebo |
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Adam and Oswald (1988) |
Placebo |
Insomnia |
40 |
Halcion 0.5 mg |
15 nights placebo, 25 nights medication, 5 nights placebo |
VAS anxiety: 52% increase with Halcion; -25% with placebo, 0.2% with lormetazepam (treatment: p = 0.004; no treatment-by-block interaction). Raw anxiety data not shown. Presence of treatment effect, but absence of treatment by-block interaction suggests baseline group differences. In Halcion group, 38% reported bad dreams on the first withdrawal night. Seven subjects on halcion, but no others repelled panic attacks. Derealization with Halcion reported. |
40 |
Lormetazepam 2 mg |
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40 |
Placebo |
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Kales et al. (1991) |
Placebo, temazepam |
Insomniac |
6 |
Halcion 0.5 mg |
Baseline nights 2-4, drug nights 5-7, withdrawal 2 nights, drugs 2 nights, withdrawal 1 night |
Halcion associated with rebound decrease in total sleep time (50-60%) with each episode of administration. Ternnzepem decreased total sleep time with second episode (39%). Halcion, but not temazepam Increased percent REM. |
6 |
Temazepam 30 mg |
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6 |
Placebo |
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Merlotti et al. (1991) |
Duration |
Healthy subjects |
11 |
Halcion 0.5 mg |
1, 6, or 12 nights of Halcion with 1 week between |
Except for percent stage 1 and REM latency, no evidence of tolerance. Rebound insomnia (reduction in sleep efficiency time asleep/time in bed x100). Not associated with duration. Rebound evident in subjects with lower efficiency at baseline and great drug benefit. |
TABLE B-7 IOM Summary of Studies Investigating Possible Unique Ataxic or Dyscoordination Effects of Halcion
Source |
Type |
Population |
Number of Subjects |
Drug and Dose |
Duration |
Outcome/Comments |
Open Label |
||||||
Gales and Menard (1995) |
Matched group |
Hospitalized elderly ± falls |
100 with fails |
Mixed |
17 mo |
Benzodiazepines received by more falling patients (40% vs. 20%; odds ratio, 2.7). Falls more common in patients with three or more psychoactive medication. |
100 without falls |
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Cooper (1994) |
Case-control |
Elderly |
44 |
No drug or receiving psychotropic drugs |
6 mo |
Number of subjects was too small to draw inferences about specific drugs. |
38 |
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Double-Blind |
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Fleming et al. |
Zopiclone |
Insomniacs |
24 |
Zopiclone 7.5 mg |
21 days |
In first week of withdrawal, psychomotor behavior worse in Halcion group on the basis of subjective report. |
24 |
Halcion 0.25 mg |
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Chaudoir et al. |
Zopiclone |
Insomniacs |
19 |
Zopiclone 7.5 mg |
2 weeks |
Improved alertness in a.m. and improved sense of balance and coordination. |
19 |
Halcion 0.25 mg |
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Robin et al. (1996) |
Placebo |
Elderly Young |
9 |
Halcion 0.375 mg |
Single dose |
Increased body sway with Halcion in elderly subjects. No greater magnitude of change in the elderly. Rather, elderly start with greater baseline body sway. More loss of balance ("fall") in elderly subjects receiving Halcion, also predicted by baseline body sway. |
9 |
Placebo |
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SOURCES: Cooper (1994) and Robin et al. (1996). |
TABLE B-8 IOM Summary of Studies Investigating Possible Unique Disinhibiting Effects of Halcion
Source |
Type |
Population |
Number of Subjects |
Drug and Dose |
Duration |
Outcome and Comments |
Monti et al. (1994) |
Placebo, zolpidem |
Insomniac outpatient |
8 |
Zolpidem 10 mg |
27 nights |
One episode of aggressiveness only for a subject receiving Halcion |
8 |
Halcion 0.5 mg |
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8 |
Placebo |
|||||
Adam and Oswald (1988) |
Placebo |
Insomnia |
40 |
Halcion 0.5 mg |
15 nights of placebo, 25 nights medication, 5 nights placebo |
One subject irritable, bragging, sarcastic |
40 |
Lormetazepam 2 mg |
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40 |
Placebo |
TABLE B-9 IOM Summary of Studies Investigating Possible Unique Psychotigenic, Confusion, or Dissociation-Generating Effects of Halcion
Source |
Type |
Population |
Number of Subjects |
Drug and Dose |
Duration |
Outcome/Comments |
Greenblatt et al. (1989) |
Placebo, flurazepam, temazepam |
Bedtime |
16 |
Placebo |
Single dose |
''Spacey." Halcion temazepam > flurazepam = placebo. Halcion effects were at 6 h. Highly correlated with sedation. |
12 |
Flurazepam 15 mg |
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13 |
Temazepam 15 mg |
|||||
11 |
Halcion 0.25 mg |
|||||
Pinnock et al. (1985) |
Placebo, diazepam |
Medical |
28 |
Placebo |
Single dose |
Letter search. No significant difference at 6 h. |
30 |
Diazepam 10 mg |
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29 |
Halcion 0.25 mg |
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Elie et al. (1990) |
Zopiclone |
Elderly insomniacs |
44 |
Halcion 0.125 mg |
3 weeks |
Nightmares in 5 patients not associated with treatment. |
Halcion 0.25 mg |
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Zopiclone 5 mg |
||||||
Zopiclone 7.5 mg |
||||||
Bonnet and Arand |
Placebo, dose |
Elderly insomniac (within subject) |
12 |
Placebo |
4-day episodes |
Subjects receiving Halcion at 0.25 mg were initially worse on a.m. addition and vigilance. Better than placebocebo after 4 days. |
Halcion 0.125 mg |
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Halcion 0.25 mg |
||||||
Roger et al. (1993) |
Zolpidem |
Elderly insomniac inpatients |
70 |
Zolpidem 5 mg |
3 weeks |
|
74 |
Zolpidem 10 mg |
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77 |
Halcion 0.25 mg |
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Wehli et al. (1985) |
Placebo, midazolam |
Trainee pilots |
8 |
Placebo |
Single dose, tested 7 h later |
More pilot errors with Halcion relative to placebo and midazolam (flight simulator). |
8 |
Midazolam 15 mg |
|||||
8 |
Halcion 0.5 mg |
|||||
Adam and Oswald (1988) |
Placebo |
Insomnia |
40 |
Halcion 0.5 mg |
15 nights of placebo, |
Three patients developed paranoid psychoses with visual hallucinations. |
40 |
Lormetazepam 2 mg |
25 nights of medication, |
||||
40 |
Placebo |
5 nights placebo |
TABLE B-10 IOM Summary of Studies Investigating Other Possible Adverse Events Related to Halcion
Source |
Type |
Population |
Number of Subjects |
Drug and Dose |
Duration |
Outcome/Comments |
Fleming et al. (1990) |
Zopiclone |
Insomniacs |
24 |
Zopiclone 7.5 mg |
21 days |
Early termination: 10/24 (42%) Halcion, 2/24 >(8%) zopiclone, chi-square = 5.4, p < 0.02. Subjects receiving zopiclone had taste changes. Moderate to severe adverse effects: 18% zopiclone, 42% Halcion (p < 0.05). Combined dropouts from lack of efficacy and side effects. |
24 |
Halcion 0.25 mg |
|||||
Thorpy et al. (1991) |
Single blind |
Narcoleptics |
10 |
Halcion 0.25 mg |
|
No unexpected side effects. |
Roehrs et al. (1992) |
Taper rate |
Insomniacs with normal sleep; Insomniacs without normal sleep; Bedtime |
7 |
Halcion 0.5 mg |
|
Bedtime did not use pm to restore sleep during withdrawal. Insomniacs did use pm, Halcion, and placebo, although not differently. |
7 |
||||||
7 |
||||||
Roger et al. (1993) |
Zolpidem |
Elderly insomniac inpatient |
70 |
Zolpidem 5 mg |
3 weeks |
Rate of AE (CNS AEs): 16% (10%) zolpidem 5 mg, 11% (11%) zolpidem 10 mg, 21% (16%) Halcion. One patient withdrew for tremor and malaise. Total withdrawal: 1 zolpidem 5 mg, 1 zolpidem 10 mg, 5 Halcion (1 inefficacy, 2 for AEs, and 2 for "other reasons"). |
74 |
Zolpidem 10 mg |
|||||
77 |
Halcion 0.25 mg |
|||||
Mauri et al. (1993) |
Quazepam |
Insomniac outpatients |
32 |
Quazepam 15 mg |
8 weeks |
No unexpected effects. |
33 |
Halcion 0.5 mg |
|||||
Jacobson et al. (1994) |
Placebo |
Surgery for breast cancer |
49 |
Halcion 0.125 mg increased to 0.25 mg pm. |
3 nights |
Halcion effective, less likely increased to 0.25 mg (2 caps) then placebo (7/49 vs. 15/51). Halcion proscription associated with less opiate (acetaminophen + oxycodone) use. No adverse reaction significantly more frequent in Halcion group. |
51 |
Placebo to 2 caps pm. |
Source |
Type |
Population |
Number of Subjects |
Drug and Dose |
Duration |
Outcome/Comments |
Hajak et al. (1994) |
Flunitrazepam Zopiclone Placebo |
Insomnia outpatient |
307 |
Halcion 0.25 mg |
28 nights |
Premature termination: 12.6% zopiclone (15 AEs; 5 metal taste), 12.4% Halcion (2 AEs), 10.3% flunitrazepam (6 AEs), 12.8% placebo (3 AEs). Twelve to 14% of each group on other CNS dropped out prior to study. "Total response; zopiclone one better than total placebo and flunitrazepam. Halcion not better than placebo and all better than baseline. Response was not defined. "Total response" during withdrawal, zopiclone better than Halcion and placebo. No other differences. No clear rebound. Daytime well-being, zopiclone reported as only drug significantly better than placebo, statistic not reported. Of 9 checklist items: no significant differences in spontaneously reported items, metallic taste associated with zopiclone (6.7% zopiclone, 2.0% Halcion, 0.3% flunitrazepam, 0.7% placebo). |
612 |
Zopiclone 7.5 mg |
|||||
290 |
Flunitrazepam 1 mg |
|||||
298 |
Placebo |
|||||
Wehli et al. (1985) |
|
Swiss Air pilots |
36 |
Placebo |
1 night tested 7 h after dose |
Side effects: no difference for moderate or severe. Mild: halcion > midazolam = placebo (vertigo, mild confusion, drowsiness, fatigue). Total side effects: 72% Halcion, 21% midazolam, 19% placebo. |
34 |
Midazolam 15 mg |
|||||
32 |
Halcion 0.5 mg |
|||||
Adam and Oswald (1988) |
Placebo, active (drug) |
Insomnia |
40 |
Halcion 0.5 mg |
15 nights of placebo, |
Global ratings: very bad, 16 in Halcion group, 4 in lormetazepam group, 0 in placebo group; bad, 6 in halcion group, 2 in lormetazepam group, 4 in placebo group; neutral, 2 in Halcion group, 6 in lormetazepam group, 25 in placebo group; good, 13 in Halcion group, 14 in lormetazepam group, 9 in placebo group; very good, 3 in Halcion group, 14 in lormetazepam group, 2 in placebo group. Hypothesize accumulation of metabolite for toxic reactions. Only known metabolite is OH-triazolam. Distress-related ratings increased after 10 days of treatment. |
40 |
Lormetazepam 2 mg |
25 nights medication, |
||||
40 |
Placebo |
5 nights of placebo |
||||
Kamien et al. (1995) |
Placebo |
Bedtime |
50 |
Halcion 0.32 mg/70 kg |
Drug discrimination training plus test. |
Thirty-one subjects able to discriminate placebo from Halcion; 19 unable to do this due to high placebo response. |