B
Summary Tables of Literature Reviewed for Safety of Halcion

B-1

 

Evaluation of Comparability, Pharmacokinetics, and Pharmacodynamic Interactions of Halcion,

 

124

B-2

 

Results of In Vitro Binding Studies: Displacement of Flunitrazepam in the Human Cortex,

 

127

B-3

 

Displacement of [3H]Flumazenil in Rats as Determined by In Vivo Autoradiography,

 

128

B-4

 

Relative Lipophilicity of Benzodiazepines,

 

129

B-5

 

IOM Summary of Studies Investigating Possible Unique Amnestic Effects of Halcion,

 

130

B-6

 

IOM Summary of Studies Investigating Possible Unique Anxiogenic Effects During Administration of Halcion, and Anxiogenic or Insomnia-Promoting Effects with Withdrawal,

 

133

B-7

 

IOM Summary of Studies Investigating Possible Unique Ataxic or Dyscoordination Effects of Halcion,

 

137

B-8

 

IOM Summary of Studies Investigating Possible Unique Disinhibiting Effects of Halcion,

 

138

B-9

 

IOM Summary of Studies Investigating Possible Unique Psychotigenic, Confusion, or Dissociation-Generating Effects of Halcion,

 

139

B-10

 

IOM Summary of Studies Investigating Other Possible Adverse Events related to Halcion,

 

140



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Halcion: An Independent Assessment of Safety and Efficacy Data B Summary Tables of Literature Reviewed for Safety of Halcion B-1   Evaluation of Comparability, Pharmacokinetics, and Pharmacodynamic Interactions of Halcion,   124 B-2   Results of In Vitro Binding Studies: Displacement of Flunitrazepam in the Human Cortex,   127 B-3   Displacement of [3H]Flumazenil in Rats as Determined by In Vivo Autoradiography,   128 B-4   Relative Lipophilicity of Benzodiazepines,   129 B-5   IOM Summary of Studies Investigating Possible Unique Amnestic Effects of Halcion,   130 B-6   IOM Summary of Studies Investigating Possible Unique Anxiogenic Effects During Administration of Halcion, and Anxiogenic or Insomnia-Promoting Effects with Withdrawal,   133 B-7   IOM Summary of Studies Investigating Possible Unique Ataxic or Dyscoordination Effects of Halcion,   137 B-8   IOM Summary of Studies Investigating Possible Unique Disinhibiting Effects of Halcion,   138 B-9   IOM Summary of Studies Investigating Possible Unique Psychotigenic, Confusion, or Dissociation-Generating Effects of Halcion,   139 B-10   IOM Summary of Studies Investigating Other Possible Adverse Events related to Halcion,   140

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Halcion: An Independent Assessment of Safety and Efficacy Data 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 13 Temazepam 15 mg 12 Halcion 0.25 mg 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.         Alpha-OH triazolam gluconate 4-HTT-gluconate   Free alpha-OH triazolam 69% of urine14C (free + conjugated); Free 4-OH triazolam 11% of urine14C (free + conjugated)

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Halcion: An Independent Assessment of Safety and Efficacy Data 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.

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Halcion: An Independent Assessment of Safety and Efficacy Data Source Type Population Number of Subjects Drug and Dose Duration Outcome/Comments Hukkinen et al. (1995)   Bedtime 10 Halcion 0.25 mg with 250 ml of grapefruit juice   Mean AUC of plasma Halcion concentration increased 1.5 times and peak plasma Halcion concentration increased 1.3 times; peak Halcion level delayed from 1.6 to 2.5 h; potentiation of drowsiness was noted. Robin et al. (1993) Placebo Bedtime, cirrhosis 6 6 Halcion Single dose No potentiation of PK or behavioral effects. Wright et al. (1992) Placebo Bedtime 24 Halcion 0.25 mg Repeated before and after, 8 days of treatment with fluoxetine at 60 mg/day No potentiation of PK or behavioral effects. McAuley et al. (1995) Placebo Post menopause 16 Halcion 0.5 mg administered intravenously with oral progesterone at 300 mg, (eight groups each)   Potentiation of DSST, CPT, hand-eye parallel coordination; impairments produced by Halcion. Intravenous treatment terminated before maximum Halcion dose was admin. due to SE more frequent after progesterone (7/8 vs. 5/8 group). Kroboth et al. (1993)   Bedtime   Halcion Intravenous infusion Evidence of acute tolerance (review based on abstract only). NOTE: NA, not available; AUC, area under the concentration-time curve; PK, pharmacokinetic; DSST, Digit Symbol Substitution Test; CPT, current perception threshold; and SE, side effects. a Flurazepam and hyroxyethylflurazepam. b Desalkylflurazepam.

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Halcion: An Independent Assessment of Safety and Efficacy Data 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 b t1/2-off, dissociation half-life. c Kd dissociation constant. SOURCE: Richelson et al. (1991).

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Halcion: An Independent Assessment of Safety and Efficacy Data TABLE B-3 Displacement of [3H]Flumazenil in Rats as Determined by In Vivo Autoradiography   Cortex   Spinal Cord   Cerebellum   Drug IC50 (mg/kg) Ratio IC50 (mg/kg) Ratio IC50 (mg/kg) Ratio Halcion 0.7 ± 0.1 1 0.1 ± 0.8 1 0.5 ± 0.08 1.0 Clonazepam 0.3 ± 0.07 0.04 0.3 ± 0.08 3 0.3 ± 0.07 0.6 Lorazepam 0.8 ± 0.3 1.1 1.0 ± 0.3 10 0.4 ± 0.09 0.8 Alprazolam 3.9 ± 1.2 5.6 1.9 ± 0.4 19 3.4 ± 0.9 6.8 Zopiclone 6.6 ± 1.1 9.4 5.7 ± 0.5 57 4.7 ± 0.7 9.4 Zolpidem 7.0 ± 1.6 10.0 13.4 ± 2.8 134 6.8 ± 1.0 13.6 Diazepam 10.9 ± 0.5. 15.6 7.4 ± 0.6 74 10.6 ± 0.5 21.2 NOTE: IC50 is the 50% inhibitory concentration. Ratio indicates ratio of IC50 of drug to IC50 of Halcion. SOURCE: Sanger and Benavides (1993).

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Halcion: An Independent Assessment of Safety and Efficacy Data 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) 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) Flurazepam 56.8c 8.2 12.7b Desalkylflurazepam 29.1c 7.0 0.85b Sethy and Harris (1982) (flunitrazepam displacement, ''brain" pellet) 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.

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Halcion: An Independent Assessment of Safety and Efficacy Data 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.

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Halcion: An Independent Assessment of Safety and Efficacy Data 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 12 Halcion 0.25 mg 12 Halcion 0.5 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 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 6 Placebo Hedenbro et al. (1991) Placebo Endoscopy 177 Placebo Single dose No clear amnestic effects regarding surgery events. 182 Halcion 0.125 mg 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.

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Halcion: An Independent Assessment of Safety and Efficacy Data Source Type Population Number of Subjects Drug and Dose Duration Outcome/Comments Milgrom et al. (1994) Placebo/dose Anxious dental patients 31 Halcion 0.375 mg Halcion 0.50 mg Single dose Drug reduced anxiety and observed movement, 75% strong preference for drug, 25% prefer drug, 0% neutral or negative. Impairment in implicit and explicit memory on drawings and word association task both when testing occurred during drug administration and when testing occurred after drug was eliminated (24 h). Weingartner et al. (1995c) Placebo Bedtime alcoholics 9 8 Halcion 0.375 mg Single dose Halcion increased recall of past dissociative experiences in both groups as assessed by Dissociative Experiences Scale. Weingartner et al. (1995a) Placebo/dose Bedtime 15 Halcion 0, 0.25, 0.375, and 0.5 mg 4 days Halcion effects on subjective and objective measures of sedation differed. Authors hypothesize an effect of drug on reflective processes. Weingartner et al. (1995b) Placebo/dose Bedtime 9 15 Halcion 0, 4.5, and 61 mg/kg, and 0, 0.25, 0.375, and 0.5 mg Repeated measures Enhancement of learning of information presented before Halcion administration suggested to be reduction in interference from stimuli presented while receiving drug. Wesensten et al. (1996) Placebo/zolpidem Bedtime   Halcion 0.125, 0.25, and 0.5 mg Zolpidem, 5, 10, and 15 mg Placebo Single dose Equal impairment produced by halcion and Zolpidem on Walter Reed Performance Assessment Performance Battery. Hindmarch et al. (1993)           In relation to its sedative effects, the amnestic effects of Halcion arc proportionate. Berlin et al. (1993)       Zolpidem 10 mg Halcion 0.25 mg   Comparable amnestic effects. Kuribara and Asahi (1997) Several BZs Mice   Diazepam 10 mg/kg Alprazolan 1-10 mg/kg Halcion 1 and 3 mg/kg Single dose No evidence of increased amnestic potency relative to sedative potency. NOTE: BZ, benzodiazepine; WMS, working memory system.

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Halcion: An Independent Assessment of Safety and Efficacy Data 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.

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Halcion: An Independent Assessment of Safety and Efficacy Data 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 10 Halcion 0.5 mg 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 Stopperich et al. (1993) Placebo Preoperative dental patients 11 Placebo 1 dose Reduced anxiety. 11 Halcion 0.25 mg 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 20 Quazepam 15 mg 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 77 Halcion 0.25 mg 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

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Halcion: An Independent Assessment of Safety and Efficacy Data 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 8 Placebo 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 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 40 Placebo 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 6 Placebo 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.

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Halcion: An Independent Assessment of Safety and Efficacy Data Source Type Population Number of Subjects Drug and Dose Duration Outcome/Comments Roehrs et al. (1992) Taper rate Insomniac with normal sleep; insomnise without normal sleep. Bedtime 7 Halcion 0.5 mg Abrupt vs. taper Taper substantially reduces rebound insomnia. 7 7 Hajak et al. (1994) FNZ/Placebo See other adverse reactions         Saletu et al. (1994) Quazepam Insomniac 45 Halcion 0.25-0.5 mg Quazepam 15-30 mg Placebo 1 week, drug 4 weeks, placebo 2 weeks Anxiety improved with both drugs. Rebound insomnia in Halcion group only, and only on first night. NOTE: VAS, Visual Analog Scale; SWS, slow wave sleep; EEG = electroencephelogram; POMS = Profile of Mood States.

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Halcion: An Independent Assessment of Safety and Efficacy Data 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 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 Double-Blind 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 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 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   SOURCES: Cooper (1994) and Robin et al. (1996).

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Halcion: An Independent Assessment of Safety and Efficacy Data 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 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 40 Placebo

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Halcion: An Independent Assessment of Safety and Efficacy Data 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 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 29 Halcion 0.25 mg 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 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 Halcion 0.25 mg Roger et al. (1993) Zolpidem Elderly insomniac inpatients 70 Zolpidem 5 mg 3 weeks   74 Zolpidem 10 mg 77 Halcion 0.25 mg 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

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Halcion: An Independent Assessment of Safety and Efficacy Data 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.

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Halcion: An Independent Assessment of Safety and Efficacy Data 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.

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Halcion: An Independent Assessment of Safety and Efficacy Data Source Type Population Number of Subjects Drug and Dose Duration Outcome/Comments Kitunen (1994) Multiple Bedtime 12 Zopicione 7.5 mg   Alcohol comparably potentiates motor incoordination, vestibular impairment; subjective incbriation with zopiclone and Halcion. Halcion 0.25 mg Placebo Alcohol 0.8 g/kg Zopiclone + alcohol Halcion + alcohol Deny et al. (1995) Placebo Bedtime, obese subjects 12 Halcion 0.5 mg Two doses separated by 1 week. Small increase in half-life in obese subjects (31.6 vs. 3.83 h). Increases in sedative and amnestic effects with second Halcion exposure. 12 Halcion 0.5 mg Kroboth et al. (1995) Placebo Bedtime, Study 1: obese subjects 12 Halcion 0.5 mg Two doses separated by 6 days. In all three studies, there were incremental increases in observed sedation and impairment in performance on a continuous performance test of attention suggestive of potentiated effects (learning?) with repeated dosing.     Study 2: bedtime 11 Halcion 0.2, 0.25 mg Three doses of 0.25 mg followed by a test dose of 0.2 mg all separated by 6 days.       Study 3: Bedtime ? Halcion 0, 0.5, 4 mg Balanced crossover of placebo and 0.5 and 0.4 mg twice on test days all separated by 6 days.   Mendelson et al. (1996)           Review of AEs, highest rate with lorazepam most mild. Halcion not distinctive. Mendelson et al. (1996)           Same review of AEs. Halcion was the only BZ not associated with increased falls. Faure et al. (1996) Flunitrazepam, placebo     Flunitrazepam 0.5, 2 mg Single dose Flunitrazepam causes greater euphoria.     Halcion 0.25, 0.5 mg Martinez-Cane et al. (1996)           Halcion more commonly used than several other BZs by individuals dependent on doses at high end of clinical spectrum. NOTE: CNS, central nervous system; AE, adverse event; SE, side effect; BZ, benzodiazepine.