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Halcion: An Independent Assessment of Safety and Efficacy Data (1997)

Chapter: Appendix B: Summary Tables of Literature Reviewed for Safety of Halcion

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Suggested Citation:"Appendix B: Summary Tables of Literature Reviewed for Safety of Halcion." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
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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

Suggested Citation:"Appendix B: Summary Tables of Literature Reviewed for Safety of Halcion." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
×

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)

Suggested Citation:"Appendix B: Summary Tables of Literature Reviewed for Safety of Halcion." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
×

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.

Suggested Citation:"Appendix B: Summary Tables of Literature Reviewed for Safety of Halcion." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
×

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.

Suggested Citation:"Appendix B: Summary Tables of Literature Reviewed for Safety of Halcion." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
×

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).

Suggested Citation:"Appendix B: Summary Tables of Literature Reviewed for Safety of Halcion." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
×

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).

Suggested Citation:"Appendix B: Summary Tables of Literature Reviewed for Safety of Halcion." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
×

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.

Suggested Citation:"Appendix B: Summary Tables of Literature Reviewed for Safety of Halcion." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
×

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.

Suggested Citation:"Appendix B: Summary Tables of Literature Reviewed for Safety of Halcion." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
×

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.

Suggested Citation:"Appendix B: Summary Tables of Literature Reviewed for Safety of Halcion." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
×

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.

Suggested Citation:"Appendix B: Summary Tables of Literature Reviewed for Safety of Halcion." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
×

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.

Suggested Citation:"Appendix B: Summary Tables of Literature Reviewed for Safety of Halcion." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
×

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

Suggested Citation:"Appendix B: Summary Tables of Literature Reviewed for Safety of Halcion." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
×

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.

Suggested Citation:"Appendix B: Summary Tables of Literature Reviewed for Safety of Halcion." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
×

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.

Suggested Citation:"Appendix B: Summary Tables of Literature Reviewed for Safety of Halcion." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
×

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).

Suggested Citation:"Appendix B: Summary Tables of Literature Reviewed for Safety of Halcion." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
×

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

Suggested Citation:"Appendix B: Summary Tables of Literature Reviewed for Safety of Halcion." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
×

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

Suggested Citation:"Appendix B: Summary Tables of Literature Reviewed for Safety of Halcion." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
×

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.

Suggested Citation:"Appendix B: Summary Tables of Literature Reviewed for Safety of Halcion." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
×

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.

Suggested Citation:"Appendix B: Summary Tables of Literature Reviewed for Safety of Halcion." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
×

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.

Suggested Citation:"Appendix B: Summary Tables of Literature Reviewed for Safety of Halcion." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
×
Page 123
Suggested Citation:"Appendix B: Summary Tables of Literature Reviewed for Safety of Halcion." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
×
Page 124
Suggested Citation:"Appendix B: Summary Tables of Literature Reviewed for Safety of Halcion." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
×
Page 125
Suggested Citation:"Appendix B: Summary Tables of Literature Reviewed for Safety of Halcion." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
×
Page 126
Suggested Citation:"Appendix B: Summary Tables of Literature Reviewed for Safety of Halcion." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
×
Page 127
Suggested Citation:"Appendix B: Summary Tables of Literature Reviewed for Safety of Halcion." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
×
Page 128
Suggested Citation:"Appendix B: Summary Tables of Literature Reviewed for Safety of Halcion." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
×
Page 129
Suggested Citation:"Appendix B: Summary Tables of Literature Reviewed for Safety of Halcion." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
×
Page 130
Suggested Citation:"Appendix B: Summary Tables of Literature Reviewed for Safety of Halcion." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
×
Page 131
Suggested Citation:"Appendix B: Summary Tables of Literature Reviewed for Safety of Halcion." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
×
Page 132
Suggested Citation:"Appendix B: Summary Tables of Literature Reviewed for Safety of Halcion." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
×
Page 133
Suggested Citation:"Appendix B: Summary Tables of Literature Reviewed for Safety of Halcion." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
×
Page 134
Suggested Citation:"Appendix B: Summary Tables of Literature Reviewed for Safety of Halcion." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
×
Page 135
Suggested Citation:"Appendix B: Summary Tables of Literature Reviewed for Safety of Halcion." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
×
Page 136
Suggested Citation:"Appendix B: Summary Tables of Literature Reviewed for Safety of Halcion." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
×
Page 137
Suggested Citation:"Appendix B: Summary Tables of Literature Reviewed for Safety of Halcion." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
×
Page 138
Suggested Citation:"Appendix B: Summary Tables of Literature Reviewed for Safety of Halcion." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
×
Page 139
Suggested Citation:"Appendix B: Summary Tables of Literature Reviewed for Safety of Halcion." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
×
Page 140
Suggested Citation:"Appendix B: Summary Tables of Literature Reviewed for Safety of Halcion." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
×
Page 141
Suggested Citation:"Appendix B: Summary Tables of Literature Reviewed for Safety of Halcion." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
×
Page 142
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Regulatory agencies within the United States and the United Kingdom, among several other countries, have reviewed extensively the safety and efficacy of Halcion (triazolam)--a once commonly used hypnotic drug. Concerns began to emerge about the safety of Halcion when a Dutch physician reported a possible link between it and a syndrome that included such effects as depression, amnesia, hallucinations, and increased anxiety. In addition, in 1991 its manufacturer, Upjohn, noted that "errors had been identified in a report of one of the clinical studies included in the original" application for approval. Since then, the drug has been removed from the market in several countries, whereas in the United States and Canada, the drug's labeling has been modified to reduce the recommended dose and duration of treatment and to heighten awareness of possible side effects. Yet different data and analyses have resulted in conflicting messages that are difficult to reconcile and interpret. In response to a request from the Food and Drug Administration to resolve these controversial issues related to the safety and efficacy of Halcion, this IOM book assesses the adequacy of the drug's clinical trials; the quality and quantity of data on adverse reactions; overall confidence in the data on effectiveness, adverse events, and side effects at different doses; and whether additional studies are needed.

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