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

Chapter: Assessment of Safety Data

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Suggested Citation:"Assessment of Safety Data." 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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3
Assessment of Safety Data

Concerns about the safety of the hypnotic drug Halcion (triazolam) have existed since C. van der Kroef reported a syndrome of adverse reactions to the drug in 1979 (van der Kroef, 1979)1. Many changes in the labeling guidelines have been made since then, but concerns have persisted and are described most succinctly in the 1992 Public Citizen petition to remove Halcion from the U.S. market. In its investigation of these and other concerns, the Institute of Medicine (IOM) committee reviewed and assessed the relevant data from Upjohn's New Drug Application (NDA; NDA 17-892) and other sources, including the published literature, as they pertain to whether triazolam (1) produces a unique profile or syndrome of adverse events and (2) produces adverse effects that are qualitatively similar but quantitatively different from those associated with other benzodiazepine hypnotic agents.

More specifically, the committee reviewed and evaluated (1) protocols and data from well-controlled pre- and postmarketing clinical trials; (2) data from studies performed in countries other than the United States, including data from a cohort study; (3) spontaneous reports of adverse events; and (4) data from the published literature. This chapter is organized according to these sources of data and their analyses. The committee then presents its conclusions and recommendations at the end of the chapter.

WELL-CONTROLLED PREMARKETING CLINICAL TRIALS

In assessing the data from well-controlled premarketing clinical trials, the IOM committee reviewed and performed independent statistical reanalyses of two comprehensive summaries of the safety data: Upjohn's Integrated Summary of Safety (ISS) (The Upjohn Company, 1991) and the reconstructed tabular data of adverse events analyzed by the U.S.

1  

An English text description of the Dutch experience is available (Meyboom, 1992).

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

Food and Drug Administration (FDA) (Laughren and Lee, 1992); both had been presented at a May 1992 meeting of the FDA Psychopharmacologic Drugs Advisory Committee (PDAC). The committee first analyzed the frequency of adverse events and then examined the frequency and nature of adverse events that led to the withdrawal of subjects from the trials (i.e., dropouts).

Adverse Events

In 1992 Upjohn created a new database of safety information by reentering the data from the case-report forms for the 116 clinical trials in the NDA. FDA oversaw this effort and verified that ''there was a highly accurate transfer of pertinent data" from the case reports to the new database (Laughren and Lee, 1992, p. 9). Upjohn also developed an ISS using results from 79 studies (from among the 116 studies from the NDA, but without the Phase I studies and including the available postmarketing clinical trials) comparing approximately 4,000 subjects treated with Halcion (0.1 to 1.0 mg), 1,300 subjects treated with flurazepam (Dalmane; 15 to 30 mg), and 2,100 subjects treated with placebo.

A subset of the 116 studies was selected specifically to compare Halcion with placebo and another benzodiazepine hypnotic drug. That subset consisted of the 25 studies that (1) involved subjects with insomnia, (2) had a parallel-group design, (3) were at least 1 week in duration, and (4) involved placebo or flurazepam as the comparator drug. Upjohn used this subset of 25 studies in its comparative analysis in the ISS, and FDA used this subset in its analysis of dropouts. The IOM committee first examined Upjohn's comparative analysis of the frequency of adverse events as described in the ISS.

Integrated Summary of Safety

Table 3-1 indicates the frequency of adverse events involving the central nervous system (CNS) from the 79 clinical trials in the ISS. Tables 3-2 through 3-5 present tabular summaries of the data from the subset of 25 studies using the following classifications: adult and geriatric insomniac populations, low and high doses, and shorter and longer durations. In reviewing these data, the committee made the following three observations.

Observation 1: Comparable Safety Profile

Halcion at the currently recommended doses (0.125 and 0.25 mg) and for the shortest durations of use (1 to 7 days) has a safety profile comparable to those of both placebo and the lowest dose of flurazepam (15 mg), even for those undesirable events associated with the pharmacologic activity of benzodiazepines, namely, restlessness, nervousness, drowsiness, impaired coordination, light-headedness, and dizziness (Tables 3-2, 3-4, and 3-5). Rates of response for the most frequently occurring CNS-related adverse event (sedation or drowsiness) were 16.7, 23.5, and 11.3 percent for the three groups (Halcion, flurazepam, and placebo), respectively (see Table 3-1), Dizziness and headache were second and third most common adverse events. Other events of interest described in the tabulated summaries were impaired memory (at rates of 0.7, 0.5, and 0.2 percent, respectively) and impaired coordination (at rates of 3.4, 4.6, and 1.5 percent, respectively).

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

TABLE 3-1 Number (percent) of Subjects Reporting CNS-Related Adverse Events in Adequate and Well-Controlled Phase II/III Studies () with a Duration of Treatment of 1 to 92 days

Medical Event

Halcion

(n = 3,982)

Flurazepam

(n = 1,295)

Placebo

(n = 2,151)

Othera

(n = 1,098)

Drowsiness/sedation

664 (16.7)

304 (23.5)

244 (11.3)

178 (16.2)

Dizziness

350 (8.8)

68 (5.3)

132 (6.1)

80 (7.3)

Headache

307 (7.7)

110 (8.5)

175 (8.1)

41 (3.7)

Tiredness

183 (4.6)

77 (5.9)

171 (7.9)

122 (1.1)

Nervousness

164 (4.1)

61 (4.7)

117 (5.4)

19 (1.7)

Impaired coordination

136 (3.4)

60 (4.6)

33 (1.5)

3 (0.3)

Depression

100 (2.5)

47 (3.6)

81 (3.8)

1 (0.1)

Insomnia

73 (1.8)

28 (2.2)

98 (4.6)

9 (0.8)

Confusion

53 (1.3)

14 (1.1)

50 (2.3)

1 (0.1)

Excitement

49 (1.2)

1 (0.1)

52 (2.4)

0

Euphoria

38 (1.0)

25 (1.9)

26 (1.2)

2 (0.2)

Memory impairment

27 (0.7)

7 (0.5)

5 (0.2)

0

Tremor

22 (0.6)

5 (0.4)

24 (1.1)

1 (0.1)

Concentration difficulty

21 (0.5)

15 (1.2)

16 (0.7)

5 (0.5)

Vasomotor disturbances

21 (0.5)

5 (0.4)

8 (0.4)

0

a Pentobarbital, secobarbital, chloral hydrate, methaqualone, diazepam, and oxazepam.

SOURCE: The Upjohn Company (1992).

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

TABLE 3-2 CNS-Related Medical Events for Adult Insomniac Subjects, 1 to 2 Weeks of Treatment

 

Triazolam 0.25 mg (n = 35) vs. Placebo (n = 35)a

Triazolam 0.25-0.5 mg (n = 121) vs. Flurazepam 15-30 mg (n = 52) and Placebo (n = 77)b

Triazolam 0.5 mg (n = 418) vs. Flurazepam 30 mg (n = 216) Flurazepam 30 mg (n = 216)c

Medical Event

TZ

PBO

TZ

FLU

PBO

TZ

FLU

PBO

Drowsiness/ sedation

3 (8.6)

4 (11.4)

55 (45.5)

11 (21.2)

47 (61.0)

107 (25.6)

68 (31.5)

29 (13.7)

Headache

9 (25.7)

6 (17.1)

12 (9.9)

4 (7.7)

2 (2.6)

65 (15.6)

24 (11.1)

36 (17.0)

Dizziness

5 (14.3)

0

25 (20.7)

1 (1.9)

21 (27.3)

39 (9.3)

15 (6.9)

10 (4.7)

Nervousness

1 (2.9)

1 (2.9)

6 (5.0)

2 (3.8)

1 (1.3)

27 (6.5)

11 (5.1)

9 (4.2)

Tiredness

0

0

46 (38.0)

1 (1.9)

59 (76.6)

13 (3.1)

6 (2.8)

2 (0.9)

Paresthesia

3 (8.6)

0

0

0

0

2 (0.5)

0

0

Dysesthesia

1 (2.9)

0

0

0

1 (1.3)

1(0.2)

0

0

Insomnia

1 (2.9)

0

0

0

0

2 (0.5)

3(1.4)

3 (1.4)

Impaired coordination

0

0

2 (1.7)

2 (3.8)

0

22 (5.3)

7 (3.2)

6 (2.8)

Memory impairment

0

0

0

0

0

2 (0.5)

1 (0.5)

0

Confusion

0

0

0

0

0

2 (0.5)

0

1 (0.5)

Disorientation

0

0

0

0

0

1 (0.2)

0

0

Vasomotor disturbances

0

0

3 (2.5)

1 (1.9)

0

3 (0.7)

0

0

Derealization

0

0

1 (0.8)

0

0

0

1 (0.5)

0

Dream abnormalities

0

0

1 (0.8)

0

0

1 (0.2)

2 (0.9)

1 (0.5)

Euphoria

0

0

I (0.8)

0

0

1 (0.2)

0

0

Fear

0

0

1 (0.8)

0

0

1 (0.2)

0

0

Intellectual impairment

0

0

1 (0.8)

0

0

1 (0.2)

0

0

Irritability

0

0

1 (0.8)

0

2 (2.6)

2 (0.5)

3 (1.4)

3 (1.4)

Shakiness

0

0

1 (0.8)

0

0

0

0

0

Depression

0

0

0

0

0

7 (1.7)

4 (1.9)

3 (1.4)

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

 

Triazolam 0.25 mg (n = 35) vs. Placebo (n = 35)a

Triazolam 0.25-0.5 mg (n = 121) vs. Flurazepam 15-30 mg (n = 52) and Placebo (n = 77)b

Triazolam 0.5 mg (n = 418) vs. Flurazepam 30 mg (n = 216) Flurazepam 30 mg (n = 216)c

Medical Event

TZ

PBO

TZ

FLU

PBO

TZ

FLU

PBO

Intoxicated/ inebrious state

0

0

0

0

0

2 (0.5)

0

0

Concentration difficulty

0

0

0

0

0

1 (0.2)

2 (0.9)

0

Muscle tone disorders

0

0

0

0

0

1 (0.2)

1 (0.5)

1 (0.5)

Syncope

0

0

0

0

0

1 (0.2)

0

0

NOTE: Abbreviations: n, number of subjects in the treatment group; TZ, triazolam; FLU, flurazepam; PBO, placebo.

a Includes Protocol 6401.

b Includes flexible-dose Protocols 6400 and 2401.

c Includes Protocols 6004, 6016, 6042, 6043, and 6044.

SOURCE: The Upjohn Company (1992).

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

TABLE 3-3 CNS-related Medical Events for Adult Insomniac Subjects, 4 to 6 and 12 to 13 Weeks of Treatment

 

4-6 Weeks' Duration

 

 

 

12-13 Weeks' Duration

 

Triazolam 0.25 mg (n = 54) vs Flurazepam 30 mg (n = 27)a

Triazolam 0.5 mg (n = 220) vs Flurazepam 30 mg (n = 121) and Placebo (n = 96)b

Triazolam 0.5 or 0.6 mg (n = 119) vs Flurazepam 30 mg (n = 97)c

Medical Event

TZ

FLU

TZ

FLU

PBO

TZ

FLU

Drowsiness/

sedation

14 (25.9)

15 (55.6)

62 (28.2)

33 (27.3)

10 (10.4)

38 (31.9)

40 (41.2)

Headache

5 (9.3)

4 (14.8)

38 (17.3)

10 (8.3)

12 (12.5)

31 (26.1)

20 (20.6)

Dizziness

7 (13.0)

7 (25.9)

49 (21.8)

10 (3.3)

3 (3.1)

9 (7.6)

5 (5.2)

Impaired coordination

6 (11.1)

8 (29.6)

17 (7.7)

8 (6.6)

0

9 (7.6)

7 (7.2)

Tiredness

4 (7.4)

1 (3.7)

4 (1.8)

5 (4.1)

2 (2.1)

2 (1.7)

7 (7.2)

Insomnia

3 (5.6)

1 (3.7)

2 (0.9)

0

2 (2.1)

2 (1.7)

1 (l.0)

Depression

2 (3.7)

0

3 (1.4)

3 (2.5)

0

6 (5.0)

5 (5.2)

Memory impairment

0

0

2 (0.9)

0

0

11 (9.2)

1 (1.0)

Confusion

1 (1.9)

0

0

0

0

3 (2.5)

0

Disorientation

0

0

2 (0.9)

0

0

1 (0.8)

1 (1.0)

Paresthesia

0

0

1 (0.5)

0

0

0

1 (1.0)

Dysesthesia

0

0

1 (0.5)

0

1 (1.0)

1 (0.8)

0

Vasomotor disturbances

1 (1.9)

0

2 (0.9)

0

0

3 (2.5)

2 (2.1)

Derealization

0

0

1 (0.5)

0

0

0

0

Dream abnormalities

0

0

1 (0.5)

0

1 (1.0)

2 (1.7)

2 (2.1)

Increased motor activity

0

0

0

0

0

1 (0.8)

0

Intellectual impairment

5 (9.3)

0

0

0

0

2 (1.7)

0

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

 

4-6 Weeks' Duration

 

 

 

12-13 Weeks' Duration

 

Triazolam 0.25 mg (n = 54) vs Flurazepam 30 mg (n = 27)a

Triazolam 0.5 mg (n = 220) vs Flurazepam 30 mg (n = 121) and Placebo (n = 96)b

Triazolam 0.5 or 0.6 mg (n = 119) vs Flurazepam 30 mg (n = 97)c

Medical Event

TZ

FLU

TZ

FLU

PBO

TZ

FLU

Irritability

0

1 (3.7)

1 (0.5)

0

0

1 (0.8)

0

Shakiness

1 (1.9)

0

0

0

1 (1.0)

1 (0.8)

0

Excitement

0

0

0

0

0

1 (0.8)

0

Mood changes

0

0

2 (0.9)

0

0

1 (0.8)

0

Apathy

1 (1.9)

0

1 (0.5)

0

0

0

0

Drug withdrawal symptoms

1 (1.9)

0

0

0

0

0

0

Personality changes

0

0

1 (0.5)

0

0

0

0

Hallucinations

0

0

0

0

0

2 (1.7)

0

Concentration difficulty

0

0

0

0

0

1 (0.8)

0

Drug abuse

0

0

0

0

0

1 (0.8)

0

Agitation

0

0

0

0

0

1 (0.8)

0

NOTE: Abbreviations: n, number of subjects in the treatment group; TZ, triazolam; FLU, flurazepam; PBO, placebo.

a Includes Protocol 6401.

b Includes flexible-dose Protocols 6400 and 2401.

c Includes Protocols 6004, 6016, 6042, 6043, and 6044.

SOURCE: The Upjohn Company (1992).

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

TABLE 3-4 CNS-Related Medical Events for Geriatric Subjects, 1 Week of Treatment

 

Triazolam 0.25 mg (n = 46) vs Placebo (n = 44)a

Triazolam 0.125-0.25 mg (n = 18) vs Placebo (n = 19)b

Medical Event

TZ

PBO

TZ

PBO

Drowsiness/sedation

5 (10.9)

4 (9.1)

2 (11.1)

1 (5.3)

Headache

4 (8.7)

3 (6.8)

0

1 (5.3)

Dizziness

2 (4.3)

2 (4.5)

0

1 (5.3)

Tiredness

1 (2.2)

0

0

1 (5.3)

Nervousness

1 (2.2)

4 (9.1)

0

3 (15.8)

Memory impairment

1 (2.2)

0

0

0

NOTE: Abbreviations: n, number of subjects in the treatment group; TZ, triazolam; PBO, placebo.

a Includes Protocol 6401.

b Includes flexible-dose Protocols 6400 and 2401.

SOURCE: The Upjohn Company (1992).

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

TABLE 3-5 CNS-Related Medical Events for Geriatric Subjects, 1 to 2 and 4 Weeks of Treatment

 

1-2 Weeks' Duration

4 Weeks' Duration

 

 

 

 

Triazolam 0.25 mg (n = 35) vs Flurazepam 15 mg (n = 58) and Placebo (n = 48)a

Triazolam 0.25 mg (n = 14) vs Flurazepam 15 mg (n = 13) and Placebo (n = 14)b

Triazolam 0.25-0.5 mg (n = 40) vs Flurazepam 15-30 mg (n = 40) and Placebo (n = 41)c

Medical Event

TZ

FLU

PBO

TZ

FLU

PBO

TZ

FLU

PBO

Drowsiness/

sedation

19 (18.1)

17 (29.33)

3~ (6.3)

4 (25.6)

3 (23.1)

2 (14.3)

24 (60.0)

31 (77.5)

19 (46.33)

Dizziness

1 (1.0)

0

0

0

0

0

22 (55.0)

28 (70.0)

15 (43.9)

Headache

15 (14.3)

S (13.8)

4 (8.3)

1 (7.1)

1 (7.7)

0

5 (12.5)

3 (7.5)

4 (9.8)

Impaired coordination

2 (1.9)

1 (1.7)

0

1 (7.1)

1 (7.1)

0

5 (12.5)

7 (17.5)

4 (9.8)

Nervousness

3 (2.9)

0

2 (4.2)

1 (7.1)

0

0

12 (30.0)

8 (20.0)

6 (14.6)

Memory impairment

0

0

0

0

0

0

1 (2.5)

0

0

Confusion

1 (1.0)

1 (1.7)

0

0

0

0

0

1 (2.5)

1 (2.4)

Disorientation

0

0

0

0

0

0

2 (5.0)

0

 

Paresthesia coordination

0

0

0

0

0

0

1 (2.5)

1 (2.5)

 

Dysesthesia impairment

0

0

0

0

0

0

2 (5.0)

1 (2.5)

 

Insomnia

1 (1.0)

0

0

0

0

0

5 (12.5)

3 (7.5)

1 (2.4)

Vasomotor disturbances

0

1 (1.7)

0

0

0

0

4 (10.0)

0

1 (2.4)

Dream abnormalities

0

0

0

0

0

0

1 (2.5)

1 (2.5)

2 (4.9)

Tremor

0

0

0

0

0

0

1 (2.5)

0

0

Fear

0

0

0

1 (7.1)

0

0

0

0

0

Intellectual impairment

0

0

0

0

0

0

1 (2.5)

0

0

Irritability

0

0

0

1 (7.1)

0

0

2 (5.0)

0

1 (2.4)

Shakiness

0

0

0

0

0

0

1 (2.5)

0

0

Excitement impairment

0

0

0

0

0

0

1 (2.5)

0

1 (2.4)

Mood changes

1 (1.0)

0

0

0

0

0

0

0

0

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

 

1-2 Weeks' Duration

4 Weeks' Duration

 

 

 

 

Triazolam 0.25 mg (n = 35) vs Flurazepam 15 mg (n = 58) and Placebo (n = 48)a

Triazolam 0.25 mg (n = 14) vs Flurazepam 15 mg (n = 13) and Placebo (n = 14)b

Triazolam 0.25-0.5 mg (n = 40) vs Flurazepam 15-30 mg (n = 40) and Placebo (n = 41)c

Medical Event

TZ

FLU

PBO

TZ

FLU

PBO

TZ

FLU

PBO

Depression

3 (2.9)

0

0

0

0

0

1 (2.5)

3 (7.5)

2 (4.9)

Concentration difficulty

0

0

0

0

0

0

1 (2.5)

2.(5.0)

0

Drug withdrawal symptoms

1 (1.0)

0

0

0

0

0

0

0

0

Drug habituation

0

0

0

1 (7.1)

0

0

0

0

0

Agitation

0

0

1 (2.1)

0

0

0

1 (2.5)

0

0

Sexual dysfunction

0

0

0

0

0

0

1 (2.5)

1 (2.5)

1 (2.4)

Apathy

0

0

0

0

0

0

2 (5.0)

1 (2.5)

1 (2.4)

NOTE: Abbreviations: n, number of subjects in the treatment group; TZ, triazolam; FLU, flurazepam; PBO, placebo.

a Includes Protocol 6401.

b Includes flexible-dose Protocols 6400 and 2401.

c Includes Protocols 6004, 6016, 6042, 6043, and 6044.

SOURCE: The Upjohn Company (1992).

Suggested Citation:"Assessment of Safety Data." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
×
Observation 2: Comparable Rates of CNS-Related Events

In studying the data in Tables 3-2 through 3-5 the committee concluded that for studies comparing Halcion, flurazepam, and placebo in non-geriatric adults, and geriatric subjects in studies of comparable length, the rates of CNS-related adverse events for the two drugs and placebo do not differ remarkably. There were, however, a very few instances in which the rate of CNS-related adverse events was at least threefold greater for Halcion relative to that for placebo. In comparing Halcion with flurazepam, the committee found a few comparisons in which the rate of adverse events for flurazepam is lower by twofold and a few instances in which the rate is lower by as much as threefold. For example, a significant difference in memory impairment was noted for the 0.5-mg Halcion dose.

As seen in the last two columns of Table 3-3, the occurrence of memory impairment in 9.2 percent of subjects treated with Halcion (0.5 or 0.6 mg) stands out in comparison with a rate of memory impairment of only 1 percent among subjects treated with flurazepam (30 mg). It is important to note that the data in these two columns are from studies in which relatively high doses (higher than the current Halcion labeling recommends as an initial or starting dose) of the two drags (0.5 or 0.6 mg of Halcion or 30 mg of flurazepam) were used, and in which there was a long duration of treatment (12 to 13 weeks). These differences were not observed at 4 to 6 Weeks of treatment.

Observation 3: Increased Sensitivity in Geriatric Subjects

Consistent differences can be seen for geriatric subjects, suggesting an increased risk of adverse CNS-related events with the highest Halcion dose and the longer duration of treatment compared with the risk with the lowest dose and shorter durations (Tables 3-4 and 3-5), and the same is true for flurazepam. Comparing the results for adults (younger and middle-aged adults) in Tables 3-2 and 3-3, there is little evidence of increases in the rate of any of the more than two dozen types of CNS-related adverse events listed for those receiving Halcion, and the same is true for flurazepam. However, the rates (in Tables 3-2 to 3-5) come from different studies and it is difficult to evaluate the significance of the comparisons in terms of possible dose and duration effects. No statistical analyses were presented as an aid in differentiating among the many possible comparisons to focus on those possibly occurring on a more than random basis.

Summary

Based on a visual inspection of the tabular data, the committee concludes that the currently recommended doses of Halcion (0.125 and 0.25 mg) and the shortest durations of use (1 to 7 days) have a safety profile comparable to those of both placebo and the lowest dose of flurazepam (15 mg), including comparable rates of CNS-related adverse events. The data also suggest that geriatric subjects may be at an increased risk of adverse CNS-related events with the highest Halcion dose and the longest duration of treatment compared with the risk with the lowest dose and shorter durations.

IOM Analysis of Upjohn's Integrated Summary of Safety

To provide a broader view of the dose-response relation, particularly for the lower doses that are relevant to current labeling (i.e., 0.25 mg for non-geriatric subjects and 0.125 mg for

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

geriatric subjects), the committee performed an additional statistical analysis of the tabulated data provided in the Integrated Summary of Safety (see Tables 3-2 through 3-5). Became the data were summarized by pooling data from studies with similar populations, durations, and doses, protocol-specific data were unavailable. Nevertheless, the fixed effects of duration, dose, and age and their interactions on the incidence of various adverse events can be examined by using a fixed-effects probit regression model applied to the frequencies listed in Tables 3-2 through 3-5. For this analysis the committee selected the adverse events nervousness, memory impairment, impaired coordination, and confusion. (The category ''all psychiatric" adverse events was created by FDA and was not available in these tables for analysis.) Analyses were performed separately for Halcion and flurazepam, and placebo was used as the zero dose in both analyses. The overall observed proportions of adverse events for each drag and dose are presented in Table 3-6, as are the expected proportions of adverse events for geriatric and non-geriatric subjects for each drug and dose. Results of the analysis are as follows.

Nervousness

In the committee's analysis, significant dose, duration, and age effects were found for both Halcion (p < 0.00001 for dose, p < 0.00004 for duration, and p < 0.005 for age) and flurazepam (p < 0.0002 for dose, p < 0.0015 for duration, and p < 0.04 for age), indicating increased incidence of nervousness with increased dose, duration, or age. For Halcion (see Table 3-6), observed incidence rates were 4 percent (placebo), 2 percent (0.125-mg dose), 7 percent (0.25-mg dose), and 10 percent (0.5-mg dose), with expected rates ranging from 1.7 to 9.7 percent for non-geriatric subjects and 5.9 to 14.3 percent for geriatric subjects. For flurazepam (see Table 3-6), the observed incidence rates were 3 percent (placebo), 0 percent (15-mg dose), and 7 percent (30-mg dose), with expected rates ranging from 1.2 to 6.5 percent for non-geriatric subjects and 3.7 to 12.3 percent for geriatric subjects. These results indicate similar incidences of nervousness for Halcion at 0.25 mg and flurazepam at 30 mg.

Memory Impairment

A significant duration effect was found for Halcion (p < 0.018), indicating an increased incidence of memory impairment with increased duration of use. No statistically significant dose-related effects were observed for either drug. For Halcion, the overall observed incidence rates were between 0 and 2 percent (the highest rate was observed at a dose of 0.125 mg) and were all less than 1 percent for flurazepam (see Table 3-6). These results indicate similar incidences of memory impairment for placebo and all active doses for both drugs.

Impaired Coordination

A significant dose effect was noted for Halcion (p < 0.0002), indicating an increased incidence of impaired coordination with increased dose. For Halcion, observed incidence rates were 2 percent (placebo), 0 percent (0.125-mg dose), 4 percent (0.25-mg dose), and 8 percent (0.5-mg dose), with expected rates ranging from 1.3 to 6.4 percent for non-geriatric subjects and 1.2 to 9.5 percent for geriatric subjects. For. flurazepam, the observed incidence rates were 2 percent (placebo), 3 percent (15-mg dose), and 6 percent (30-mg dose), with expected rates ranging from 1.4 to 5.0 percent for non-geriatric subjects and 3.6 to 12.7 percent for geriatric subjects. These results indicate a similar incidence of impaired coordination for Halcion between doses of 0.25 and 0.5 mg and flurazepam at a dose of 30 mg.

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

TABLE 3-6 Comparisons of Observed and Expected Incidence of Four Adverse Events in Subjects in Controlled Clinical Trials Receiving Low Doses of Halcion and Flurazepama

 

Halcion

 

 

Flurazepam

 

 

 

 

 

Expected Incidenceb

 

 

Expected Incidence

Adverse Event

Dose (mg)

Observed Incidence

Adult

Geriatric

Dose (mg)

Observed Incidence

Adult

Geriatric

Nervousness

0

0.04

0.017

0.059

0

0.03

0.012

0.037

 

0.125

0.02

0.028

0.075

15

0.00

0.029

0.070

 

0.25

0.07

0.044

0.094

30

0.07

0.065

0.123

 

0.5

0.10

0.097

0.143

 

 

 

 

Memory impairment

0

0.00

0.000

0.001

0

0.00

0.000

0.000

 

0.125

0.02

0.001

0.003

15

0.00

0.000

0.000

 

0.25

0.00

0.001

0.007

30

0.00

0.000

0.000

 

0.5

0.01

0.006

0.026

 

 

 

 

Impaired coordination

0

0.02

0.013

0.012

0

0.02

0.014

0.036

 

0. 125

0.00

0.020

0.022

15

0.03

0.028

0.071

 

0.25

0.04

0.030

0.038

30

0.06

0.050

0.127

 

0.5

0.08

0.064

0.095

 

 

 

 

Confusion

0

0.00

0.003

0.006

0

0.00

0.002

0.017

 

0.125

0.00

0.003

0.005

15

0.01

0.001

0.013

 

0.25

0.01

0.003

0.004

30

0.00

0.001

0.010

 

0.5

0.00

0.003

0.003

 

 

 

 

a The data used in these analyses were extracted from tabular data from the Upjohn Company, 1992; pp. 30-40

b Duration of 2 weeks.

SOURCE: The Upjohn Company (1992).

Suggested Citation:"Assessment of Safety Data." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
×
Confusion

No significant effects of dose, duration, or age were found for either drug. The overall observed incidence rates for both drags were between 0 and 1 percent (see Table 3-6).

Summary

In summary (as shown in Table 3-6), the committee's analysis of the data presented in the ISS tables (Tables 3-1 to 3-5; which present data for a wider range of doses and durations than the FDA analysis of adverse event data, i.e., particularly the lower doses that represent the current labeling) does show evidence of dose-response relations for nervousness and impaired coordination that are similar for patients treated with Halcion and flurazepam. In general, the 0.25-mg dose of Halcion seems similar to the 30-mg dose of flurazepam in terms of the incidence rates for these two adverse events. However, no statistically significant dose-related increases in the rates of memory impairment or confusion were noted for these two drugs over those for placebo.

Analysis of Dropouts

To examine the significance of adverse event occurrences further, the committee reviewed and analyzed the data for subjects who withdrew (i.e., dropouts) from the 25 studies2 that had been selected by FDA for analysis of adverse events in 1992. The committee examined and assessed the FDA analysis of these data and then reanalyzed the data by its own methods.

FDA Analysis

In 1992, FDA reexamined adverse event data for Halcion derived from clinical trials sponsored by Upjohn and conducted before and after approval of the drug. FDA reviewed data from 116 clinical trials, and from among those studies selected the 25 parallel-group studies of 1 week or more in duration for analysis. Upjohn created a new database containing data from these 25 studies, and the FDA validated the data by checking data listings with case reports.

In their analysis of the data from these 25 studies, FDA focused on adverse events that led to the withdrawal of subjects from the trials (i.e., dropouts). However, "no attempt was made to pool data across different studies because of variability of study designs (dose, duration, population) and also variability in results, even for studies of the same design" (Laughren and Lee, 1992, p. 14). Instead, FDA provided a tabular display of the adverse event incidence data for each study protocol separately and grouped the data from each study by non-geriatric and geriatric subjects and ordered them by duration and dose (Laughren and Lee, 1992; see Appendix A, Tables A-1 through A-13).

2  

This is the same set of 25 studies that is described previously in this chapter (see the section on Adverse Events).

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

In addition, FDA pooled data for dropouts across studies to conduct statistical comparisons of risk ratios between Halcion and placebo and Halcion and flurazepam for various subgroups: study population (e.g., geriatric versus non-geriatric), dose (low dose [Halcion, <0.25 mg; flurazepam, 15 mg] versus high dose [Halcion, >0.25 and <0.6 mg; flurazepam, 15 to 30 mg]), and duration (short [<14 days] versus long [>28 days]) (see Table 3-7).

For the category "all psychiatric" adverse events (which includes anxiety, confusion, depression, psychosis, impaired concentration, insomnia, irritability, mood change, psychiatric miscellaneous, and unusual dreams, FDA found risk ratios of approximately 2.5 to 1 for Halcion versus flurazepam and placebo in clinical trials of longer duration that study the higher doses of Halcion in non-geriatric populations (see Table 3-7). A notable exception was a risk ratio of approximately 7 to 1 for Halcion versus placebo in long-term studies (Halcion, 10.6 percent; flurazepam, 4.1 percent; and placebo, 1.5 percent).

For any adverse events leading to dropping out of a study (Table 3-8), the rate for the placebo group was 6.9 percent, that for the Halcion group was 12.4 percent, and that for the flurazepam group was 9.6 percent. Note, for example, that the low-dose Halcion group has a rate of adverse events approximating that for the placebo group (7.0 and 6.9 percent, respectively), whereas the higher-dose Halcion group has a rate of adverse events of 14.1 percent. The rates for the low- and high-dose flurazepam groups were 4.2 and 10.3 percent, respectively. For short- and long-term durations of treatment with Halcion, the overall dropout rates were 7.6 and 20.6 percent, respectively, compared with rates of 7.0 and 6.6 percent, respectively, for the placebo group; the rates for the flurazepam groups were 6.6 and 12.7 percent, respectively. The committee notes, however, that these simple post-hoe marginal risk comparisons are somewhat confounded by the study designs that were selected for reanalysis. For example, the comparison of low-dose and high-dose studies is confounded by age, in that almost all of the low-dose studies were with geriatric populations. This does not bias the relative risk estimates between Halcion and flurazepam or placebo, but it does leave in question the source of the difference (i.e., one cannot attribute the difference in risk to dose or age, since the low dose was given almost exclusively to the geriatric subjects in these 25 studies).

Table 3-9 shows that for the 17 different adverse event groups, the rates for the placebo group range from 0.0 to 3.9 percent (with. miscellaneous reasons being the highest), the rates for the flurazepam group range from 0.0 to 7.6 percent (with sedation/hypnosis being the highest), and the rates for the Halcion group range from 0.0 to 7.5 percent (with sedation/hypnosis being the highest). Note that for 6 of the 17 categories of adverse events there was a sufficiently large frequency of events for which statistical significance could be assessed, and the increased rate for Halcion was high enough compared with that for placebo to judge the difference to be statistically: significant (denoted in the table). The categories were impaired coordination, light-headedness, dizziness, anxiety, memory impairment; and sedation/hypnotic. The rates for flurazepam also tended to be higher than those for placebo but lower than those for Halcion, with a few exceptions. No subjects receiving placebo or flurazepam reported memory impairment, but 8 of the 1,168 subjects assigned to the Halcion group reported memory impairment.

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

TABLE 3-7 FDA Analysis of Dropouts for "All Psychiatric" in the 25 Studies for 1992 Advisory Committee Meeting

 

No. of Subjects with Adverse Event/Total No. of Subjects (%)

Risk Ratios for Dropouts

Subject Group

Triazolam

Flurazepam

Placebo

Triazolam/ Flurazepam

Triazolam/ Placebo

All subjects

63/1,168

15/607

16/566

2.2a

1.9a

 

(5.4)

(2.5)

(2.8)

 

 

Sorted by age:b

 

 

 

 

 

Geriatric

11/215

4/104

6/152

1.3

1.3

 

(5.1)

(3.8)

(3.9)

 

 

Non-geriatric

52/953

11/503

10/414

2.5a

2.3a

 

(5.5)

(2.2)

(2.4)

 

 

Sorted by dose:c

 

 

 

 

 

Low

9/272

0/71

16/566

d

1.2

 

(3.3)

(0.0)

(2.8)

 

 

High

54/896

15/536

16/566

2.1a

2.1a

 

(6.0)

(2.8)

(2.8)

 

 

Sorted by duration:e

 

 

 

 

 

Short term

17/735

3/316

14/430

2.4

0.7

 

(2.3)

(0.9)

(3.3)

 

 

Long term

46/433

12/291

2/136

2.6a

7.2a

 

(10.6)

(4.1)

(1.5)

 

 

ap < 0.05, one-sided p value, Fisher's exact test.

b For sorted by age, the age groups are defined by nominal study designation, i.e., geriatric or non-geriatric, and not by actual age.

c For sorted by dose, the all patients placebo group is used for comparison. Dose groups are defined by assigned dose, as follows: for triazolam, low is 0.125, 0.125 to 0.25, and 0.25 mg and high is 0.25 to 0.5, 0.5, and 0.6 mg; for flurazepam, low is 15 mg and high is 15 to 30 and 30 mg.

d Risk ratio cannot be calculated because of zero denominator.

e For sorted by duration, groups are defined by assigned duration, as follows, Short term is days and long term is days.

SOURCE: Laughren and Lee (1992).

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

TABLE 3-8 FDA Analysis of Dropouts in the 25 Studies for 1992 Advisory Committee Meeting

 

No. of Subjects with Adverse Event/Total No. of Subjects (%)

Risk Ratios for Dropouts

 

Subject Group

Triazolam

Flurazepam

Placebo

Triazolam/ Flurazepam

Triazolam/ Placebo

All subjects

145/1,168

58/607

39/566

1.3a

1.8a

 

(12.4)

(9.6)

(6.9)

 

 

Sorted by age:b

 

 

 

 

 

Geriatric

23/215

14/104

10/152

0.8

1.6

 

(10.7)

(13.5)

(6.6)

 

 

Non-geriatric

122/953

44/503

29/414

1.5a

1.8a

 

(12.8)

(8.7)

(7.0)

 

 

Sorted by dose:c

 

 

 

 

 

Low

19/272

3/71

39/566

1.7

1.0

 

(7.0)

(4.2)

(6.9)

 

 

High

126/896

55/536

39/566

1.4a

2.0a

 

(14.1)

(10.3)

(6.9)

 

 

Sorted by duration:d

 

 

 

 

 

Short term

56/735

21/316

30/430

1.2

1.1

 

(7.6)

(6.6)

(7.0)

 

 

Long term

89/433

37/291

9/136

1.6a

3.1a

 

(20.6)

(12.7)

(6.6)

 

 

ap < 0.05, one-sided p value, Fisher's exact test.

b For sorted by age, the age groups are defined by nominal study designation i.e., (geriatric or non-geriatric), and not by actual age.

c For sorted by dose, the all patients placebo group is used for comparison. Dose groups are defined by assigned dose, as follows: for triazolam, low is 0.125, 0.125 to 0.25, and 0.25 mg and high is 0.25 to 0.5, 0.5, and 0.6 mg; for flurazepam, low is 15 mg and high is 15 to 30 and 30 mg.

d For sorted by duration, groups are defined by assigned duration, as follows: Short term is days and long term is days.

SOURCE: Laughren and Lee (1992).

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

TABLE 3-9 IOM Summary of FDA Analysis of Dropout Rates by Category of Events

 

Dropout Rates (%)

 

 

Event Category

Halcion

(n = 1,168)

Flurazepam

(n = 607)

Placebo

(n = 566)

All dropouts

12.4

9.6a

6.9a

Drowsiness

5.0

6.3

2.7a

Impaired coordination

2.7

2.0

0.4a

Light-headed

1.6

0.8

0.2a

Dizziness

2.7

1.3a

0.9a

Medical miscellaneous

5.8

4.0

3.9a

Anxiety

5.8

1.5a

2.1a

Memory impairment

0.7

0.0a

0.0a

Depression

0.8

0.5

0.4

Irritability

0.3

0.2

0.4

Confusion

0.5

0.0

0.2

Fatigue

1.3

0.8

0.5

Sedation/hypnotic

7.5

7.6

3.2a

Impaired concentration

0.0

0.2

0.0

Hallucination

0.2

0.0

0.0

Dreams

0.3

0.0

0.0

Mood change

0.2

0.0

0.0

Insomnia

0.1

0.0

0.2

a Statistically significant when compared to Halcion by chi-square analysis or the Fisher exact test, p < 0.05.

SOURCE: Laughren and Lee (1992) Tables 6.5 to 6.25.

For the other five categories of adverse events whose rates of occurrence were statistically significant, the rate for the Halcion group ranged from 2 to 8 times the rate for the placebo group, with the latter being the 1.6 percent versus 0.2 percent rates for light-headedness. The ratios for the 11 nonstatistically significant categories followed a similar pattern, with ratios (rate for the Halcion group to rate for the placebo group) being in the two-

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

to threefold range for categories in which the rates of adverse events were above 0.3 percent for those receiving placebo.

IOM Analysis

To shed further light on these issues and to provide a more rigorous review of the adverse events in general (i.e., not only those leading to dropping out of the study), the data from Tables A-1 through A-13 were used by the committee to reconstruct the actual adverse event frequencies and are reported in Tables 3-10 through 3-12 for Halcion, flurazepam, and placebo, respectively.3 Tables 3-10 through 3-12 describe the research design (age, duration, dose) of each of the 25 studies, the sample size (number of subjects), and the frequency of the adverse events anxiety, depression, memory impairment, and the "all psychiatric" summary measure. A visual inspection of Tables 3-10 through 3-12 reveals that the primary adverse event reported was anxiety, and the inclusion of anxiety in the all psychiatric summary measure largely accounts for its high incidence. Note the low incidence of memory impairment under all conditions.

Statistical Analysis

To provide a further evaluation of these data that is sensitive to FDA's earlier concerns regarding their variability and different experimental designs, the committee analyzed the data in Tables 3-10 to 3-12 using a random-effect probit model (see Gibbons et al. [1994] for a similar example). Analyses were restricted to the all psychiatric summary category because it examines the possibility of a "Halcion syndrome" and because the frequency of adverse events for this measure was large enough for a meaningful analysis.

Using the data in Tables 3-10 to 3-12, the committee compared data for Halcion versus flurazepam and Halcion versus placebo separately from those studies in which they were both tested. Because the majority of studies with non-geriatric subjects were performed with doses of Halcion of 0.5 and 0.6 mg and doses of flurazepam of 30 mg, this comparison was restricted to these doses (lower-dose comparisons are presented elsewhere in this chapter). Similarly, because studies with geriatric and non-geriatric subjects were conducted with different doses, separate analyses were performed for geriatric and non-geriatric subjects. Use of the random-effect probit model allowed the committee to compare Halcion versus placebo and Halcion versus flurazepam adjusted for study duration and variability among studies (i.e., study is a random effect in the design, and standard errors and hypothesis tests of the main effects of duration and drug; and the duration-by-drug interaction are adjusted for the heterogeneity of those effects across the 25 studies).

3  

In a few instances, the reconstructed frequencies in Table 3-10 through 3-12 were fractional and were therefore rounded to an integer value. The fractional frequencies may be due to rounding errors made in the incidence rates in Tables A-1 through A-13 or small discrepancies in sample sizes given in Tables A-14 and A-15. These small differences should not change the results of the analyses in any substantial way.

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

TABLE 3-10 Adverse Event Frequencies for Halcion-Treated Groups in 25 Parallel-Group Studies

 

Design

 

 

 

Frequency of Adverse Events

 

Protocol

Geriatric Subjects

Weeks

Dose (mg)

Sample Size

Anxiety

Depression

Memory Impairment

All Psychiatric

6401

No

1

0.25

35

1

0

0

2

2401

No

1

0.375

66

3

0

0

4

6400

No

1

0.375

53

4

0

0

6

6041

No

1

0.5

70

3

I

0

4

6042

No

1

0.6

62

3

0

1

5

6004

No

1

0.5

16

1

0

1

4

6043

No

2

0.5

138

11

3

0

15

6016

No

2

0.5

14

I

0

0

1

6044

No

2

0.5

112

8

3

0

11

6042

No

4

0.25

54

11

2

0

14

6045

No

4

0.5

31

5

0

0

9

6046

No

4

0.5

55

6

I

0

7

6047

No

6

0.5

59

9

0

I

9

6048

No

6

0.5

72

3

3

1

7

6023B

No

12

0.5

9

1

0

1

1

6023

No

12

0.6

33

3

I

5

7

6049

No

13

0.5

74

10

5

5

17

6417

Yes

I

0.125

46

1

0

0

1

6417A

Yes

I

0.175

18

0

0

0

0

6061

Yes

1

0.025

31

0

0

0

0

6062

Yes

I

0.25

36

0

0

0

0

6063

Yes

2

0.25

18

1

I

0

2

6064

Yes

2

0.25

20

2

2

0

3

6065

Yes

4

0.25

14

2

0

0

2

2601

Yes

4

0.375

32

10

3

1

15

NOTE: FDA used these studies in an integrated evaluation of safety (Laughren and Lee, 1992). See Appendix A, Tables A-1 through A-13, for more specific information concerning dropout rates.

SOURCE: Laughren and Lee (1992).

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

TABLE 3-11 Adverse Event Frequencies for the Flurazepam-Treated Groups in the 15 of the 25 Parallel-Group Studies That Used Flurazepam as a Comparator Drug

 

Design

 

 

 

Frequency of Adverse Events

 

Protocol

Geriatric Subjects

Weeks

Dose (mg)

Sample Size

Anxiety

Depression

Memory Impairment

All Psychiatric

6400

No

1

22.5

52

2

0

0

2

6042

No

1

30

59

0

0

1

2

6004

No

1

30

21

5

0

0

9

6016

No

2

30

16

0

0

0

0

6044

No

2

30

110

6

4

0

11

6042

No

4

30

27

6

0

0

8

6046

No

4

30

50

1

0

0

0

6048

No

6

30

71

4

3

0

0

6023B

No

12

30

6

0

0

0

1

6023

No

12

30

18

0

0

0

4

6049

No

13

30

73

6

5

0

11

6062

Yes

I

15

35

0

0

0

0

6064

Yes

2

15

23

0

0

0

1

6065

Yes

4

15

13

0

0

0

0

2601

Yes

4

22.5

33

6

2

0

11

NOTE: FDA used these studies in an integrated evaluation of safety (Laughren and Lee, 1992). See Appendix A, Tables A-1 through A-13, for more specific information concerning dropout rates.

SOURCE: Laughren and Lee (1992).

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

TABLE 3-12 Adverse Event Frequencies for Placebo-Control Groups in the 12 of the 25 Parallel-Group Studies That Included a Placebo Control

 

Design

 

 

Frequency of Adverse Events

 

Protocol

Geriatric Subjects

Weeks

Sample Size

Anxiety

Depression

Memory Impairment

All Psychiatric

6401

No

1

35

1

0

0

1

2401

No

1

77

1

0

0

3

6041

No

1

72

2

2

0

4

6043

No

2

135

7

1

0

14

6045

No

4

31

4

0

0

4

6047

No

6

64

2

0

0

5

6417

Yes

1

44

4

0

0

6

417A

Yes

1

19

3

0

0

3

6061

Yes

1

28

0

0

0

0

6063

Yes

2

20

2

0

0

8

6065

Yes

4

14

0

0

0

0

2601

Yes

4

27

4

2

0

7

NOTE: FDA used these studies in an integrated evaluation of safety (Laughren and Lee, 1992). See Appendix A, Tables A-1 through A-13, for more specific information concerning dropout rates.

SOURCE: Laughren and Lee (1992).

Results of the analyses for all psychiatric adverse events revealed the following.

Halcion (0.5 mg) Versus Placebo in Non-geriatric Subjects

There were no statistically significant effects of duration or dose. The overall incidence of the event in those studies that tested both Halcion and placebo was 9 percent in the placebo group and 12 percent in the group treated with Halcion.

Halcion (0.5 mg) Versus Flurazepam (30 mg) in Non-geriatric Subjects

There were no statistically significant effects of duration or dose. The overall incidence of the event in those studies that tested both Halcion and flurazepam was 10 percent in the group receiving flurazepam and 15 percent in the group receiving Halcion. Note that the difference in the incidence for the Halcion group is due to the fact that different studies compared Halcion versus placebo and Halcion versus flurazepam. As such, the overall incidence of psychiatric events among those receiving Halcion will vary on the basis of the specific comparison. Within these two-group comparisons, however, variability between studies is directly

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

incorporated into the statistical comparisons.

Halcion (0.25 mg) Versus Placebo in Geriatric Subjects

There were no statistically significant effects of duration or dose. The overall incidence of the event in those studies that tested both Halcion and placebo was 12 percent in the placebo group and 13 percent in the group treated with Halcion.

Halcion (0.25 mg) Versus Flurazepam (15 mg) in Geriatric Subjects

There were no statistically significant effects of dose; however, a significant main effect of duration was noted (i.e., an increased study duration was associated with an increased frequency of psychiatric adverse events). The overall incidence of the event in those studies that tested both Halcion and flurazepam was 12 percent in the group treated with flurazepam and 20 percent in the group treated with Halcion. Note that the higher incidences for both Halcion and flurazepam are due to the smaller number of available studies (i.e., four studies in which both Halcion and flurazepam were tested in geriatric subjects) and the high incidence observed in Protocol 2601 (see Tables 3-10 and 3-11). The restriction of this effect to a single study increases the committee's uncertainty in the between-group comparison and yields nonsignificant statistical test results. It is important to note, however, that of all studies, Protocol 2601 had the longest duration and used the highest doses in geriatric subjects, and the results of the study might be confirmed if data from more studies of this length and with this dose were available. The question of whether such studies are relevant, given the package insert suggesting a dose of only 0.125 mg for elderly subjects for 7-10 nights, remains an open issue of concern since it is likely that many patients exceed the recommended dose and duration.

Summary

In summary, the committee's reanalysis of FDA's recompiled database for adverse psychiatric events reveals no significant difference in the incidence of adverse events between subjects receiving Halcion and placebo, or between subjects receiving Halcion and flurazepam, in protocols with geriatric and non-geriatric subjects when duration, dose, and interstudy variability are accounted for. Similarly, there was no evidence of a specific syndrome or clustering of psychiatric adverse events at the 0.25- or 0.125-rag doses. Although the rates of psychiatric adverse events in general are somewhat higher than the rates associated with study dropout, the relative risks remain statistically nonsignificant when heterogeneity between studies is incorporated. Although FDA found that significant adverse psychiatric events were associated with increased dropout rates by Halcion-treated subjects, the severity of these symptoms may have been greater in the Halcion-treated subjects, leading to somewhat increased rates of dropout due to adverse events. Inspection of the tabulated data suggests that differences may exist at doses in excess of 0.5 mg in non-geriatric subjects and at doses in excess of 0.25 mg in geriatric subjects; however, the data available in the recompiled database are too sparse for a meaningful analysis at these levels. Note that the studies evaluated by FDA were predominantly conducted with doses of 0.5 mg with non-geriatric subjects and 0.25 mg with geriatric subjects, when the currently recommended doses are 0.25 and 0.125 mg, respectively.

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

DATA SETS FOR POSTMARKETING STUDIES

Even though thousands of patients and study subjects may be exposed to a new molecular entity during the development of a product, given the difficulties of evaluating risks of low-frequency toxicities in randomized controlled studies done primarily for the assessment of efficacy, questions related to the toxicity of an entity can be resolved only with larger studies targeted to resolving such specific questions. The questions arising from the data summarized above have to do with the apparent increased risk of a number of toxicities that are associated with Halcion, especially for older subjects and at higher doses and for longer durations of use. It is important to note that this is true of most drugs, and in fact, among the 25 studies that FDA analyzed the percentage of geriatric subjects receiving Halcion who withdrew from the studies (10.7 percent) was lower than the percentage of geriatric subjects receiving flurazepam who withdrew (13.5 percent; see Table 3-8). For this drug, the use of higher doses and longer durations is likely.

The committee examined data from several postmarketing studies that investigated these safety issues. The following is a discussion of one large questionnaire study (Protocol M/2100/0235), 2 polysomnographic studies (Protocols M/2100/0366 and M/2100/0373) and a nonrandomized, controlled study (the Evaluation of Medications for Insomnia in Canada [EMIC]).

Randomized Study: Protocol M/2100/0235

One of the studies (Protocol M/2100/0235) recently completed under the sponsorship of Upjohn was a study of approximately 8,000 subjects randomly assigned to receive either Halcion (at a starting dose of 0.125 mg for older subjects and a starting dose of 0.125 or 0.25 mg for other subjects, with an option of increasing the dose as needed, with physician consultation) or temazepam (Restoril) (at a lower dose of 15 mg and a higher dose of 30 rag, with the instructions for dose escalation being the same as those for Halcion). The doses were chosen so that the two medications had equivalent efficacies estimated on the basis of prior information. The study was designed so that it was masked (i.e., blinded) with respect to study assignment for the subjects, the medical team, and the evaluators of efficacy and toxicity. There were 4,104 subjects in the Halcion group and 4,101 subjects in the temazepam group treated by a total of 946 investigators.

The IOM committee reviewed the protocol for the study, a detailed report of the methods, tables summarizing the data, the statistical analyses and results, and the conclusions drawn by Upjohn.

Subjects were admitted to the study by a physician. Medical information and informed consent were obtained, and the subject was then registered by telephone with a central contractor for the study. The center randomly assigned each subject a numbered bottle containing unidentified capsules. The center scheduled each subject for a telephone interview that was conducted within a day of entry into the study. The interview was carded out before the subject took the first capsule. Two more interviews were conducted, at 2 and at 4 weeks after entry into the study. The three telephone interviews were conducted by centrally located,

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

trained interviewers, under a contract to a private firm, who used set protocols for eliciting and recording the information. No visits to the physician were scheduled after the first visit, although contact by telephone or a visit could be initiated, and systematic capture and use of any resulting information was part of the protocol.

With regard to adverse events, this study provides valuable data on rates of toxicity categorized by type or category. However, the study was not placebo controlled, so there is no way of knowing the background, drag-flee rates of toxicity that would have been experienced. The rates of toxicity for the comparator drag, temazepam, at the doses studied do provide valuable information concerning the possible increases in the rates of toxicity that might characterize Halcion as a drug with peculiar toxicities or increased levels of toxicity relative to those for temazepam.

In examining the data, the committee saw no evidence of either special toxicities peculiar to Halcion compared with those for temazepam and no increases in the rates of putative CNS-related adverse events thought to be of possible concern. Some results of interest are as follows:

  1. Overall dropout rates were essentially the same for subjects receiving the two drugs (16.2 percent for the Halcion group and 14.6 percent for the temazepam group), with the difference largely being due to the personal decision of the subjects among those receiving Halcion. The small difference was statistically significant because Of the large samples involved.

  2. Examination of the Upjohn report on the study leads the IOM committee to confirm the conclusion of the FDA reviewer: ''In summary, it appears that the effects of the two hypnotics are similar in terms of the kinds of medical events reported. There has been some concern about psychiatric events. There was no difference between triazolam (Halcion) and temazepam (Restoril) in the incidence of depression, anxiety, hostility, memory problems and nervousness. Among the reasons for dropout, there were 'possible' hallucinations, amnesia, unspecified dysphoria, CNS stimulation and suicide attempts. The incidence of these events was small and did not differ between treatments" (Lee, 1996, p. 17). Among the more than 4,000 patients in each of the groups, the latter events numbered 12 for the Halcion group and 11 for the temazepam group. The FDA reviewer concludes that "there was essentially no difference between the efficacy and safety for adults treated With insomnia" (Lee, 1996, p. 17).

Randomized Polysomnographic Studies

Protocol M/2100/0366 was a placebo-controlled, double-blind, five-site study with a single drug (Halcion) given as a single bedtime dose of 0.0625, 0.125, or 0.25 mg. A total of 240 participants were evaluated by inducing transient insomnia in a sleep-laboratory setting. Twelve medically related events, none serious, were reported; they included drowsiness, grogginess, heaviness, nausea, stomach cramps, headaches, restlessness, and sweating. This study showed a significant linear dose-response effect for polysomnographic sleep latency to stage 2 and total sleep time. Medical events possibly related to the study medication were infrequent, and none was serious.

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

Protocol M/2100/0373 was a placebo-controlled, double-blind, two-site study with a single drug (Halcion) administered at bedtime at a dose of 0.0625, 0.125, 0.25, or 0.5 mg in a sleep-laboratory setting for two nights. The 102 participants ranged in age from 21 to 54 years. Eleven medical events were reported. The events were categorized as mild, moderate, and severe, with no severe events being reported. The events reported were headaches, gastrointestinal symptoms, light-headedness, depression, lethargy, and irregular heartbeats. Sleep latency to stage 2 decreased, and total sleep time increased with increased doses. The medical events were infrequent, and none was serious.

In conclusion, both of the postmarketing sleep-laboratory studies (Protocols M/2100/0366 and M/2100/0373) showed minimal adverse events within 30 minutes to hours following the use of Halcion at the doses used in subjects who had not previously been exposed to Halcion or any other hypnotic agent within the previous 30 days.

A Nonrandomized Controlled Study: EMIC

Another earlier (mid-1980s) postmarketing study sponsored by Upjohn was the unpublished study entitled Evaluation of Medications for Insomnia in Canada, referred to as the EMIC study. The report on the EMIC study from Upjohn to FDA is dated December 2, 1988 (Mariano and Gardner, 1988). The IOM committee reviewed the protocol description, the final report, and summary tables. The committee believes that the method used and the data from this study provide useful information concerning the toxicity and use of Halcion.

The study serves to capture subjects in routine practice as they are prescribed one of three medications: Halcion, flurazepam, or oxazepam. The study follows the subjects from the time that they bring their prescription to a pharmacy and are enrolled in the study. Information was collected from these volunteers at the pharmacy and then from a 3-day diary that each subject filled out and mailed in and from a telephone call 2 weeks later. Over a period of 2.5 years, 7,554 subjects were recruited into the study by 264 cooperating pharmacies.

Because the labeling of Halcion recommends caution in the use of higher doses of the drug and for an extended duration, it is interesting that 64 percent of the subjects reported that they were continuing users, and most continued to use it during the period of study as needed, from the time of entry to the telephone interview at the end of their 2-week terminal-phase interview. Of the 488 subjects (6.5 percent) who did discontinue use of the drug during the study, the majority were first-time users. The most frequent reason given for discontinuation was that it was no longer needed. Among those continuing to use the drug, half reported using it at least once daily during this 2-week period.

This study, although not a randomized and blind experiment, provides a useful snapshot of a group large enough to provide statistically stable rates of toxicities for each of the drugs studied among groups of people prescribed specific doses. However, results depend on variations in prescription practices and the characteristics of patients who come for prescriptions, their continuation habits, and how they use the drugs that they are given. Nonetheless, the rates of adverse events after use of the three drugs at different doses complement those in the randomized studies described above. Table 3-13 presents some of the main results of the EMIC study. The toxicity profiles and the overall rates of toxicity are

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

strikingly similar for those receiving various doses of each drug and for the three drugs. The rate of toxicity for a small group of patients receiving the lowest dose of Halcion is a bit higher than those for the other groups, although the profile of toxicities is not remarkable. A noteworthy event is the rates of "memory problems," in which 0.4 and 1.1 percent of the subjects receiving Halcion at 0.25 and 0.50 mg, respectively, reported this adverse event, whereas 0.2 to 0.3 percent of the subjects receiving flurazepam and oxazepam, respectively, reported this adverse event.

VAMP: A COHORT STUDY

VAMP (Value Added Medicinal Products) Research Ltd. conducted but did not publish a study of Halcion and adverse events in the United Kingdom based on data from 2,000 general practices and an estimated 4 million patients. The computerized database for this study is part of a large system of linked databases in the British National Health Service that gathers information from practicing physicians.4 The physicians enter their patients into a cohort and provide data for each patient at the time of entry along with the information accumulated for each patient during the course of his or her continuing care by the physician. The information includes diagnoses and medical interventions such as prescriptions, hospitalizations, and other outcomes.

The IOM committee reviewed copies of a past presentation to a professional meeting, but little more was available in the way of the protocol for the study, protocols or procedures for enlisting collaborating physicians, procedures for entering patient data into the database, the quality of the data in the database, or the quantitative information and statistical analysis used for the Halcion study presentation. Some general information on the database and how it operates is available in the paper by Mann et al. (1992a), but details on procedures and quality were not provided. One useful note in that paper was that protocols and analyses conducted with the data in the database are all reviewed by the United Kingdom Medical Advisory Board.

Despite difficulty in obtaining further information on the quality of the database and the VAMP Halcion study itself, the IOM committee believes that this approach to studies of adverse events can be a most useful strategy for detecting toxicities that are rare, unexpected, or due to off-label use and is especially valuable for testing hypotheses generated by spontaneous reports. Of course, there are barriers that preclude satisfactory study through the usual means of experimental evaluation and even the kinds of studies described in preceding sections. On the basis of the data provided and the information, albeit incomplete, on methods and quality, the committee believes that the VAMP study data provide a body of additional data that may be valid and informative.

4  

The database is now called the General Practice Research Database (GPRD).

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

TABLE 3-13 People Reporting Neurological, Medical, Psychological, and Emotional Medical Events in EMIC

 

No. (%) of Subjects

 

Halcion

 

 

Flurazepam

 

Oxazepam

 

Event Category and

Adverse Event

0.125 mg

(n = 92)

<0.25 mg

(n = 2,265)

0.5 mg

(n = 2,375)

15 mg

(n= 416)

30 mg

(n = 999)

(n = 462)

30 mg

(n = 327)

Neurologic system

 

 

 

 

 

 

 

Drowsiness or sleeping

4 (4.3)

99 (4.4)

94 (4.0)

21 (5.0)

46 (4.6)

19 (4.1)

21 (6.4)

Tired

11 (12.0)

228 (10.1)

227(9.6)

54 (13.0)

119 (11.9)

42 (9.1)

36 (11.0)

Dizziness

1 (1.1)

42 (1.9)

43 (1.8)

5 (1.2)

16 (1.6)

8 (1.7)

6 (1.8)

Balance disorders

 

11 (0.5)

3 (0.1)

1 (0.2)

5 (0.5)

1 (0.2)

3 (0.9)

Weakness

2 (2.2)

32 (1.4)

41 (1.7)

11 (2.6)

31 (3.1)

10 (2.2)

8 (2.4)

Hangover

 

7 (0.3)

16 (0.7)

2 (0.5)

4 (0.4)

2 (0.4)

 

Medication too strong ·

 

1 (0.0)

2 (0.1)

1 (0.2)

1 (0.1)

 

1 (0.3)

Migraine

 

3 (0.1)

4 (0.2)

 

3 (0.3)

1 (0.2)

 

Headache

4 (4.3)

74 (3.3)

77 (3.2)

10 (2.4)

21 (2.1)

11 (2.4)

6 (1.8)

CVA

 

1 (0.0)

1 (0.0)

1 (0.2)

 

 

1 (0.3)

Paresthesia

 

5 (0.2)

9 (0.4)

 

2 (0.2)

1 (0.2)

 

Syncope

1 (1.1)

4 (0.2)

6 (0.3)

 

1 (0.1)

 

1 (0.3)

Seizure disorder

 

1 (0.0)

1 (0.0)

 

 

 

 

Sleep difficulty and insomnia

2 (2.2)

24 (1.1)

24 (1.0)

3 (0.7)

12 (1.2)

8 (1.7)

2 (0.6)

Dream disorder/nightmare

2 (2.2)

13 (0.6)

7 (0.3)

2 (0.5)

12 (1.2)

5 (1.1)

2 (0.6)

Sleep walking

 

1 (0.0)

3 (0.1)

 

 

 

 

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

 

No. (%) of Subjects

 

Halcion

 

 

Flurazepam

 

Oxazepam

 

Event Category and Adverse Event

0.125 mg

(n = 92)

<0.25 mg

(n = 2,265)

0.5 mg

(n = 2,375)

15 mg

(n= 416)

30 mg

(n = 999)

(n = 462)

30 mg

(n = 327)

Speech disorders

 

2 (0.1)

 

 

 

1 (0.2)

 

Tinnitus

 

2 (0.1)

3 (0.1)

1 (0.2)

 

 

 

Shaky or tremors

 

6 (0.3)

14 (0.6)

1 (0.2)

5 (0.5)

 

 

Other

 

5 (0.2)

7 (0.3)

2 (0.5)

3 (0.3)

1 (0.2)

1 (0.3)

Total neurologic system

20 (21.7)

406 (17.9)

419 (17.6)

79 (19.0)

196 (19.6)

80 (17.3)

67 (18.4)

Mental, psychological, and emotional

Addiction

 

8 (0.4)

5 (0.2)

1 (0.2)

 

1 (0.2)

 

Alcohol abuse

 

1 (0.0)

2 (0. 1)

 

 

 

 

Phobia

 

 

 

2 (0.5)

1 (0.1)

 

 

Hallucinations

 

 

1 (0.0)

 

 

 

 

Memory problems

 

9 (0.4)

25 (1.1)

1 (0.2)

2 (0.2)

1 (0.2)

1 (0.3)

Confusion

 

13 (0.6)

23 (1.0)

1 (0.5)

9 (0.9)

3 (0.6)

1 (0.3)

Nervous stomach

 

1 (0.0)

2 (0.1)

 

 

 

 

Nervousness

6 (6.5)

65 (2.9)

82 (3.5)

10 (2.4)

20 (2.0)

12 (2.6)

12 (3.7)

Depression

3 (3.3)

52 (2.3)

66 (2.8)

7 (1.7)

23 (2.3)

10 (2.2)

9 (2.8)

Manic depression

 

 

 

 

2 (0.2)

 

 

Emotional lability

1 (1.1)

27 (1.2)

35 (1.5)

2 (0.5)

14 (1.4)

5 (1.1)

4 (1.2)

Communication disorder

 

1 (0.0)

1 (0.0)

 

 

 

 

Nervousness improved

 

 

3 (0.1)

 

2 (0.2)

 

1 (0.3)

Drag tolerance

 

3 (0.1)

1 (0.0)

 

 

 

 

Paranoia

 

 

2 (0.1)

 

 

 

 

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

 

No. (%) of Subjects

 

Halcion

 

 

Flurazepam

 

Oxazepam

 

Event Category and Adverse Event

0.125 mg

(n = 92)

<0.25 mg

(n = 2,265)

0.5 mg

(n = 2,375)

15 mg

(n= 416)

30 mg

(n = 999)

(n = 462)

30 mg

(n = 327)

Could not concentrate

 

2 (0.1)

2 (0.1)

2 (0.5)

2 (0.2)

4 (0.9)

2 (0.6)

Other

 

1 (0.0)

2 (0.1)

 

 

 

 

Total mental, psychological, and emotional

9 (9.8)

156 (6.9)

203 (8.5)

22 (5.3)

62 (6.2)

34 (7.4)

25 (7.6)

Total combined

24 (26.1)

478 (2.1)

522 (22.0)

88 (21.2)

221 (22.1)

96 (20.8)

78 (23.9)

NOTE: The table includes data for participants for whom the dosage of the study medication was available. The numbers and percents do not sum because respondents may report in more than one category.

SOURCE: Mariano and Gardner (1988).

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

The VAMP study of Halcion was done over a 2-year period ending on October 2, 1991. The data are based on patients who were prescribed Halcion (n = 3,727), temazepam (n = 26,714), nitrazepam (n = 4,532), or a combination of more than one benzodiazepine, plus a control group of 41,127 subjects. The control subjects were chosen to match the subjects receiving a study drug by age at the time of the index prescriptions, gender, medical practice, period of follow-up for the study subject, and consultation date within half a year of the index prescription for the matching study patient.

The VAMP study investigators searched the database for the following adverse events of a drug in the treatment groups and over comparable times in matching control subjects: suicide and attempted suicide, amnesia, depression, psychosis, aggression, bizarre behavior, and anxiety. The percentage of patients with any target event for each of the treatments groups were as follows: Halcion group, 16.3 percent; temazepam group, 18.8 percent; nitrazepam group, 13.1 percent; and control group, 3.5 percent (Mann et al., 1992b). The times of follow-up and the rates of adverse events for subgroups by dose, age, and duration of use before and after taking the index prescription were not given. Although rates were not given by subgroups according to these variables, the percentages of adverse events for the seven subcategories of targeted adverse events had the following breakdown for the overall rate of 16.3 percent for patients receiving Halcion: depression, 49.3 percent; anxiety, 27.4 percent; psychosis, 19.0 percent; suicide and attempted suicide, 3.1 percent; amnesia, 0.5 percent; aggression, 0.4 percent; and bizarre behavior, 0.3 percent. The profiles for the other two drugs were similar.

SPONTANEOUS REPORTING OF ADVERSE EVENTS: THE FDA SYSTEM

The socialized medicine system in the United Kingdom allows for the ongoing surveillance of the population of patients under care, their experiences with health interventions for prevention and treatment, and the outcomes associated with those interventions. Few health care delivery systems in the United States have computerized patient records linked to prescription drag use, and the systems in general do not afford similar opportunities for uniform data collection on a defined-cohort basis. However, FDA requires the manufacturer to report all adverse events possibly associated with a drug product. In addition, FDA receives reports directly from health care providers and patients. FDA enters these events into a database, reports regularly on the data assembled, and interprets these data with a view to estimating rates and relationships that might signal toxicity problems with marketed drugs. This system is called the Spontaneous Reporting System (SRS).5 In interpreting the numbers of reported adverse events and trends and in comparing a drug with other, similar drugs used for similar indications, it is necessary to take into account the relative rates of use of the drugs, the sizes of the populations taking the drugs, and the occurrences of other factors that might be changing or differentially affecting the rates of adverse events reported over time. To this end, for example, FDA uses other databases in conjunction with the data collected in SRS.

5  

The current system for monitoring and reporting adverse events is called Med Watch, the FDA Medical Products Reporting Program.

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

Two of these are the commercial National Prescription. Audit and the commercial National Disease and Therapeutic Index. The first provides national estimates of prescription drug use based on information from pharmacies; the second estimates drug use on the basis of prescription information obtained from physicians in various types of practice and from various geographic areas. Either of these databases can be used to estimate proportions of patients exposed to drugs with similar prescription patterns and indications for use.

Statistical Evaluation of the SRS Data

In contrast to the controlled clinical trials, from which little evidence of an increased incidence of adverse events associated with Halcion use was noted, the frequency of adverse events recorded for Halcion in SRS was reported by Wysowski and Barash (1991) to be high relative to the frequency recorded for temazepam. They noted risk ratios as high as 56 to 1 for amnesia (see Table 3-14). The results of these analyses led to considerable debate and criticism within FDA. As a result, these data were reanalyzed by Yi Tsong of the Division of Biometrics at FDA. Tsong's analysis is the most statistically rigorous analysis of these data to date. Tsong made attempts to adjust statistically for (1) time of entry into the market, (2) secular trends in overall reporting rates, (3) publicity through the popular literature and media, (4) variability in rate ratios, and (5) differences in manufacturer reporting patterns. Despite these statistical adjustments the rate ratio for amnesia was 28 to 1 for the period from 1983 to 1991 and 23 to 1 for the period before 1988 (i.e., when major media coverage began). For example, before 1988, there were 174 spontaneous reports of amnesia by people taking Halcion (155 of these were reported by the manufacturer), whereas there were only 3 reports for temazepam (all were reported by the manufacturer). During this period, however, there were 32,933,000 prescriptions for Halcion and 19,122,000 for temazepam. Over the entire 9-year period that Halcion was marketed (i.e., before 1992), there were 356 spontaneous reports of amnesia by people taking Halcion (324 were reported by the manufacturer),. whereas there were only 6 reports for temazepam (all were reported by the manufacturer). These signal an increase in the numbers of adverse events that cannot be accounted for by any of the previously mentioned methodological caveats. Note, however, that during the same periods (i.e., before 1988 and before 1992) the adjusted rate ratios for seizures were 17 to 1 and 26 to l, respectively. It would seem unlikely that Halcion would be responsible for this type of adverse event at relative rates that parallel those for amnesia. Even spontaneous reports of mortality exhibited rate ratios of 3 to 1 in both time periods.

In summary, careful statistical analysis of the SRS data did not eliminate the high relative rate of adverse events for Halcion. Note, however, that the rate ratios were comparable for amnesia and seizures, which seems inconsistent with the pharmacology of Halcion. The memory impairment effects of Halcion were not observed in the randomized controlled clinical trial data compiled by either Upjohn or FDA. This may be due to (1) remaining artifacts in the SRS, (2) the difference between controlled studies in which dose and duration are monitored and the natural environment, in which much higher doses at much longer durations may be used, or (3) the huge difference in the number of at-risk individuals whose data are included in the SRS database relative to the much smaller number of at-risk individuals whose

Suggested Citation:"Assessment of Safety Data." 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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data are available in the clinical research database. On the basis of the available data there is no clear answer to this question.

The adjusted ratios of adverse events reported in SRS are based on very low numbers of reported events and very large numbers of prescriptions. For example, about 40 adverse events per 30 million prescriptions were reported for temazepam and about 1,000 adverse events per 50 million prescriptions were reported for Halcion, resulting in adverse event rates of roughly 10 per 1 million prescriptions for temazepam and 200 per 1 million prescriptions for Halcion (see Table 3-14). Converting numbers of prescriptions to approximate numbers of patients is difficult. Estimating the probability that an actual adverse event will be reported to FDA is much more difficult, even if one considers only the most serious and disturbing events. These speculations lead to the very considerations that FDA tries to deal with in assessing the signal that an SRS analysis might be imparting.

TABLE 3-14 Aggregate Number of Domestic Spontaneous Reports, Reporting Rates, and Reporting Rate Ratios for Certain Adverse Behavioral Reactions to Halcion and Temazepam for First 7 Years of Marketing of Each Drug, as Reported in SRS

 

Halcion

Temazepam

Reporting Rate Ratios

Adverse Event

No. (%)

Reporting Rate

No. (%)

Reporting Rate

A

B

Confusion

322 (17.0)

6.1

16 (6.9)

0.5

12.2

5.7

Amnesia

293 (15.5)

5.6

3 (1.3)

0.1

56

27.8

Bizarre behavior

109 (5.8)

2.1

2 (0.9)

0.1

21

15.5

Agitation

113 (6.0)

2.1

10 (4.3)

0.3

7

3.2

Hallucinations

138 (7.3)

2.6

10 (4.3)

0.3

8.7

3.9

NOTE: Data are for 1981 through 1987 for temazepam and 1983 through 1989 for Halcion and are based on 1,895 total domestic spontaneous reports for Halcion and 231 for temazepam. Reporting rates are based on 52,695,000 prescriptions for Halcion and 30,047,000 prescriptions for temazepam. Rates are per million prescriptions. Ratios are reporting rate for Halcion divided by reporting rate for temazepam (A) and ratio calculated with a doubling of reports for temazepam (B).

SOURCE: Wysowski and Barash (1991).

The IOM committee is left with what seems to be strongly suggestive evidence from SRS data that, among users of Halcion, there is some group of patients who, by personal characteristics, prescriptive pattern, or medication use, do experience CNS-related adverse events not seen at the same rates as those seen in patients taking comparator drugs. The rates of these adverse events in the Halcion group or among the various groups taking other drugs must be so small as to escape detection statistically in any of the variety of controlled studies

Suggested Citation:"Assessment of Safety Data." 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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mounted so far. The alternative to this explanation is that the ratios of adverse events from SRS data are subject to biases that have at this point escaped close analysis or eluded the key to an alternative explanation. It is also possible that the use of concomitant medications could be involved in causing or otherwise confounding the expression of adverse events.

LITERATURE REVIEW

The IOM committee reviewed published literature pertinent to the safety of Halcion and constructed tables that are intended to provide relevant information from each paper. The review is based on publications that were referred to in the FDA task force report (U.S. Food and Drug Administration, 1996) and the Public Citizen petition (1992). These papers have been supplemented with additional papers, citations for which are provided at the bottom of the relevant tables (see Appendix B, Tables B-1 through B-10). The tables and the following discussion are organized to address the following areas of interest: pharmacokinetic and pharmacodynamic issues regarding the comparability of triazolam to other benzodiazepines; amnestic effects of Halcion; possible anxiogenic or insomniac effects associated with Halcion administration or withdrawal; ataxic, disinhibition, and psychotogenic, confusion, or dissociative effects; and other potential adverse events. The committee does not include the Wysowski and Barash paper (1991) in this review because that analysis is discussed in the preceding section.

Pharmacokinetic and Pharmacodynamic Issues Regarding the Comparability of Triazolam to Other Benzodiazepines

The information considered in this section is summarized in Table B-1. The topics covered in this section are important for the consideration of whether Halcion is a compound that could be expected to have a uniquely risky pharmacodynamic profile. They are also important for future considerations of the question of whether adequate comparisons of triazolam to other benzodiazepines have been conducted.

Pharmacokinetic Issues

Four factors that substantially contribute to the behavioral effects of benzodiazepines are (1) their affinity for benzodiazepine receptors, (2) their lipophilicity, (3) their status as agonists or antagonists, and (4) their levels in plasma and the brain.

Affinity for Benzodiazepine Receptors

Triazolam has a high affinity for benzodiazepine receptors relative to the other benzodiazepines currently used clinically in the United States. In a binding study (Richelson et al., 1991) conducted with human cortical tissue, it has greater affinity than clonazepam (4 times), lorazepam (8 times), desalkylflurazepam (the active metabolite of flurazepam and quazepam; 16 times), diazepam

Suggested Citation:"Assessment of Safety Data." 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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and alprazolam (~20 times), oxazepam (~70 times), and flurazepam and temazepam (>100 times) (see Table B-2). Generally, the affinity ratios fit the relative amounts administered clinically, although the dose of triazolam used in comparison studies is generally relatively greater than that suggested by the affinity ratios based on binding to cortical tissue. For example, consistent with the binding data, 0.5 mg of triazolam appears to be similar to 60 mg of temazepam in terms of sedation (Rush et al., 1993). At these doses, triazolam produces relatively less cognitive impairment than temazepam. However, this pattern is not always found when the ratio of the triazolam dose/temazepam dose is less favorable for triazolam.

One complicating factor is that there are several benzodiazepine receptor subtypes with different receptor affinities and affinities for different anatomical locations. The importance of this effect Was illustrated in a study by Sanger and Benavides (1993) (see Table B-3 ). Although the order of affinity of benzodiazepines in the rat cortex and cerebellum is relatively consistent, most benzodiazepines have markedly less affinity for spinal cord benzodiazepine receptors because a different subgroup of receptors is expressed there. In particular, triazolam appears to bind to benzodiazepine receptor subtypes with relatively equal potency. However, zolpidem shows greater potency for subtypes bearing the alpha-1 and gamma-2 receptor subunits (Faure-Halley et al., 1993; Graham et al., 1996; Ramsey-Williams and Carter, 1996). Because triazolam has binding affinity in the brain and spinal cord comparable to those of most benzodiazepines, it is relatively more potent in the spinal cord than most benzodiazepines. The significance of spinal cord benzodiazepine receptors relative to that of brain benzodiazepine receptors is not known.

Another important issue in considering the affinity of a drug for its receptors is the issue of active metabolites. Triazolam has two active metabolites, alpha-hydroxy-triazolam and 4-hydroxy-triazolam, both of which have significant affinities for benzodiazepine receptors (Sethy and Harris, 1982; Richelson et al., 1991). Both metabolites are extensively converted to the glucuronide in plasma and are present as the unbound form (the form that can enter the brain) in negligible amounts in plasma (Eberts et al., 1981; Mauri et al., 1993). Although there is no evidence that these metabolites contribute to the acute behavioral effects of triazolam, studies have not ruled out the accumulation of metabolites with long-term administration.

In vivo binding data for humans obtained from position emission spectroscopy or single photon emission computerized tomography (SPECT) studies would be helpful for advancing the discussion of differences in drug affinity between triazolam and other drugs in different regions of the brain. However, these studies have not yet been conducted.

Lipophilicity

The time course of the availability of benzodiazepines to brain benzodiazepine receptors is highly dependent on their lipophilicity, which allows them to cross the blood-brain barrier (Arendt et al., 1987; Miller et al., 1988) (see Table B-4). In this regard, triazolam is moderately liphophilic relative to other benzodiazepines. Midazolam and diazepam appear to be more lipophilic. The lipophilicity of triazolam is comparable to that of lorazepam and alprazolam.

Agonist Status

Triazolam is a full agonist of benzodiazepine receptors, as are most of the other benzodiazepines studied.

Suggested Citation:"Assessment of Safety Data." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
×
Levels in Plasma

Two issues are of particular importance with regard to the levels of benzodiazepines in plasma: time to peak concentration and plasma clearance.

Peak plasma triazolam levels are reached quite rapidly, but not distinctively so among benzodiazepines. Zolpidem may reach peak levels the quickest, with some studies suggesting that peak levels are reached in. approximately 0.5 hour (Monti et al., 1994). Peak plasma triazolam and flurazepam levels are reached in approximately 1.0 hour (Greenblatt et al., 1989). However, flurazepam is much less potent than its metabolite desalkylflurazepam, which achieves peak levels later. Plasma temazepam levels peak in 1.5 hours, achieving peak levels more slowly than the other drugs mentioned. The rapidity with which peak levels are achieved in plasma is important for the behavioral effects of a drug. It is well known, for example, that more rapid onset is associated with the increased euphoric effects of drugs of abuse, as exemplified by the reduced abuse potential of methadone compared with that of heroin, Similarly, the more rapidly that peak levels are achieved in blood, the more 'rapidly sleep may be induced.

Triazolam has a plasma half-life of 2 to 3 hours. This is comparable to that of zolpidem (Greenblatt et al., 1989; Monti et al., 1994). Together, they have the shortest half-lives of the routinely administered hypnotic agents. A short half-life reduces the risk of carryover sedation and cognitive impairment, whereas it increases the risk of adverse events due to withdrawal. It should be noted that the short plasma half-life of triazolam might allow for more time without significant receptor occupancy between doses. Although this has yet to be demonstrated by in vivo receptor methods, if true this quality might be associated with reduced physical dependence with long-term drug administration.

Several factors alter the plasma half-life of triazolam. Pharmacokinetic interactions with other medications is a major issue for many medications. Triazolam is metabolized by P-450 CYP 3A4, an hepatic enzyme. Several drugs and foods, including ketoconazole, diltiazem, serotoninergic antidepressants, and grapefruit juice, inhibit this enzyme and produce dose-related increases in the plasma half-life of triazolam (Hukkinen et al., 1995; yon Moltke et al., 1996; Kosuge et al., 1997). One study failed to show the interaction with fluoxetine (Wright et al., 1992). Other drugs, such as rifampin, induce P-450 CYP 3A4 and substantially reduce blood triazolam levels (Villikka et al., 1997). Drug interactions are of significant clinical importance for triazolam, and doses should be adjusted accordingly. Among FDA-approved medications, however, this issue is not unique to Halcion.

Other issues influence Plasma clearance. Plasma triazolam levels are doubled in elderly individuals, and therefore recommended doses are reduced for this group (Greenblatt et al., 1991). Cirrhosis does not appear to influence triazolam levels in blood (Robin et al., 1993).

Pharmacodynamic Interactions

Pharmacodynamic interactions are also important for benzodiazepines and have been shown to affect the response to triazolam as well. Metabolites of progesterone stimulate brain gamma-aminobutyric acid type A receptors. Consistent with this finding, progesterone appears to potentiate the effects of triazolam in postmenopausal women (McAuley et al., 1995). However, it is not yet clear that variability in progesterone and neurosteroid levels during the

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

menstrual cycle are associated with altered sensitivity to triazolam (Rukstalis and de Wit, 1995). Similarly, ethanol comparably potentiates the behavioral effects of both triazolam and zopiclone in humans (Kuitunen, 1994). Caffeine reduces many of the cognition-impairing effects of triazolam in a dose-dependent manner (Rush et al., 1994).

Unique Effects of Triazolobenzodiazepines on Locus Coeruleus Neurons

The Public Citizen petition highlights potential unique effects of triazolobenzodiazepines upon locus coeruleus activity. The suggestion arises from three principal sources: (1) the initial impression that alprazolam had unique efficacy against panic disorder; (2) data indicating that benzodiazepines inhibited locus coeruleus neuron firing; and (3) clinical data suggesting that benzodiazepines, particularly alprazolam, reduced yohimbine-induced panic in subjects with panic disorder.

Given recent findings, these arguments are not as compelling as they may have been in 1992. First, all benzodiazepine anxiolytic compounds (diazepam, lorazepam, clonazepam, and alprazolam) have been shown to be effective in the treatment of panic disorder when adjusting for differences in the potency of each compound. Thus, alprazolam is not unique in this regard (Krystal et al., 1996).

Second, the initial reports of benzodiazepine inhibition of locus coeruleus neuron activation indicated rather modest effects that emerged at rather high benzodiazepine doses (Grant et al., 1980; Beck and Fibiger, 1995). It is not clear that triazolobenzodiazepines are uniquely potent in this regard (Laurent et al., 1983; Nakane et al., 1994). In addition, there are questions about whether the effects of benzodiazepines on noradrenergie neuron activity are direct or indirect (Simson and Weiss, 1989).

Third, studies by Krystal and colleagues (1996) suggest that triazolobenzodiazepines do not potently block the methoxyhydroxyphenylglycol (MHPG) increases produced by yohimbine. This finding suggests that the benzodiazepine effect is upstream from the locus coeruleus and that the primary effects of benzodiazepine withdrawal would not be via locus coeruleus activation.

Summary

Triazolam is a potent, broad-spectrum benzodiazepine agonist with a relatively short plasma half-life. Basic animal and clinical studies do not suggest a profile for this medication that is inconsistent with the information presented to FDA at the time of the FDA review in 1992. Its pharmacokinetic and pharmacodynamic profiles are associated with benefits and risks that are particular to the intended use of this medication. The studies reviewed here, however, suggest that most differences between triazolam (Halcion) and other benzodiazepines can be eliminated by manipulating the parameters of drug administration. In humans, when this type of parity is achieved, the effects of triazolam may be indistinguishable from those of other benzodiazepines (Oliveto et al., 1994).

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

Consideration of Amnestic Effects of Halcion

The information discussed in this section is summarized in Table B-5. Several levels are considered: expected dose-related anterograde memory impairment, and unexpected amnestic events evident only in subjective reports. Concern that Halcion might uniquely produce the latter type of amnesia was raised (Krystal et al., 1995).

Performance of Memory Tasks After Single and Multiple Doses

All benzodiazepines have dose-related amnestic effects. These have been demonstrated by impairment in performance of a variety of the memory tasks listed in Table B-5. Several studies indicated that information that could not be recalled after a delay could not be recalled at testing 24 hours later (Greenblatt et al., 1989; Milgrom et al., 1994). Similarly, a nighttime dose of 0.5 mg of Halcion, but not 30 mg of temazepam, had residual amnestic effects in the morning (Bixler et al., 1991). Interpretation of the comparisons of amnestic effects across drugs is difficult because of differences between routinely used doses and doses that actually produce comparable sedative or amnestic effects. This was illustrated by Rush et al. (1993), who suggested that the sedative effects of 0.5 mg of Halcion per 70-kg person are equivalent to those of 60 mg of temazepam per 70-kg person, but that the amnestic effects of Halcion are less than those of temazepam at these doses. However, the sedative and amnestic effects of 0.5 mg of Halcion per 70-kg person are greater than those of 30 mg of temazepam per 70-kg person. The bottom line of these studies appears to be that Halcion produces dose-related impairment in performance of memory tasks. This impairment appears to be roughly comparable to that found after the administration of other benzodiazepines, when adjusting for their relative receptor affinities. When comparing benzodiazepines on the basis of typically prescribed doses, Halcion appears to have greater amnestic effects. This is presumably because typically prescribed doses overestimate the dose of Halcion for comparison purposes.

Repeated dosing may differentially affect the amnestic properties of short- and long-acting benzodiazepines. Roehrs et al. (1983) found that single doses of Halcion at 0.5 mg had greater anterograde amnestic effects than flurazepam at 30 mg. However, after 6 days of dosing, the memory impairments associated with flurazepam became progressively worse and equivalent to those of Halcion. The increasing amnestic effects of flurazepam may have been consistent with the accumulation of this drug in the blood with chronic administration. This change did not occur with Halcion, consistent with the absence of drag accumulation with chronic administration. As a result, the report of Roehrs et al. (1983) raises the possibility that long-term treatment with Halcion or other short-acting benzodiazepines might spare subjects the progressive memory impairment that might be associated with long-term treatment with a long-acting medication. Among the publications reviewed, that of Roehrs et al. (1983) was the. only study that directly compared the time course of amnestic effects from short- and long-acting benzodiazepines. This finding awaits replication.

Suggested Citation:"Assessment of Safety Data." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
×
Spontaneous Reports of Memory Impairment

Of the studies that directly evaluated subjective reports of memory disturbances, the report by Bixler et al. (1991) stands out for consideration. In that study, subjects received 0.5 mg of Halcion, 30 mg of temazepam, or placebo for a total of 5 nights. It is important to note that this 30-mg dose of temazepam is approximately half of the equivalent of the 0.5-mg dose for Halcion. Drug administration was divided into two sessions (initially, either 3 or 4 days of drug treatment, then 2 days of placebo, and then 1 to 2 days of active drug). Five of six subjects receiving Halcion reported daytime episodes of amnesia or subjective memory impairment, no subjects receiving temazepam reported any events, and one subject receiving placebo reported an amnestic event.

One other study documented spontaneous reports of memory impairment during chronic treatment with Halcion (Fleming et al., 1990). In that study, 4 of 24 of subjects treated with 7.5 mg of zopiclone and 3 of 24 patients treated with 0.25 mg of Halcion reported memory impairment. These reports are the basis of the concern raised by these investigators in their petition to FDA. The magnitude and frequency of amnestic effects in the study of Bixler et al. (1991) are of concern. However, the high frequency of these severe effects is not evident in the other studies reviewed. Furthermore, the comparison of the low, nontherapeutically equivalent dose of 30 mg of temazepam with 0.5 mg of Halcion may have biased the study of Bixler et al. (1991) against Halcion.

Halcion and State-Dependent Learning

One report suggests that Halcion facilitates the recall of dissociative experiences in a state-dependent learning model (Weingartner et al., 1995a). State-dependent learning is a term applied to the tendency for the retrieval of learned information to be impaired when the behavioral state while learning (e.g., while on a benzodiazepine) is different from the behavioral state when retrieval occurs (e.g., while off of a benzodiazepine). State-dependent learning effects are generally small. However, they may contribute to the apparent anterograde memory impairment. For example, information learned while traveling after ingesting Halcion might be more difficult to recall when one has not taken Halcion. This hypothesis has yet to be tested.

Summary

Halcion produces dose-related amnestic effects. Particularly when higher doses are taken at night, these effects may persist into the morning. Depending on one's selection of comparator doses of other drugs, Halcion is either more amnestic than, or as amnestic as other benzodiazepines with comparable levels of benzodiazepine receptor occupancy. The controlled clinical trials do not resolve the frequency of clinically significant amnestic episodes among patients treated with Halcion, particularly at 0.5-mg dose or higher.

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

Review of Data Regarding Possible Anxiogenic or Insomniac Effects Associated with Halcion Administration or Withdrawal

The information discussed in this section is summarized in Table B-6. This section reviews reports that suggest that the use of Halcion as a hypnotic agent is associated with (1) an increase in daytime anxiety or (2) withdrawal-related anxiety or sleep disturbance.

Halcion Effects on Daytime Anxiety

Studies provide conflicting data regarding the possibility that Halcion is acutely anxiolytic (Pinnock et al., 1985; Stopperich et al., 1993). Studies also provide conflicting data on the effects of repeated administration. Some studies suggest that Halcion use as a hypnotic agent reduces daytime anxiety (Mauri et al., 1993; Saletu et al., 1994). Others (Bliwise et al., 1988; Scharf, 1993; Monti et al., 1994) suggest that use of other benzodiazepines or related agents, but not Halcion, as hypnotic agents reduces daytime anxiety.

Of most concern are studies that report increased daytime anxiety. Kales et al. (1986) noted a significantly higher rate of ''excitatory events" including nervousness, anxiety, and hyperarousal among six subjects administered 0.5 mg of Halcion compared with the rate of such events among subjects given 15 mg of quazepam (both drugs were given on a short-term basis). Adam and Oswald (1988) reported a 52 percent increase in daytime anxiety on a visual analog scale for subjects treated with 0.5 mg of Halcion but not for those treated with placebo or lormetazepam. These anxiogenic effects are difficult to interpret because the effects of treatment, but not the treatment-time interaction, are significant. The authors do not present the raw data, compare baseline anxiety values between their groups, or use baseline anxiety values as a covariate. As a result, it is possible that their finding reflects a baseline difference between groups. Limited information about baseline differences between their groups also makes it difficult to evaluate the finding that 7 of 40 subjects receiving Halcion, but not those receiving placebo or lormetazepam, had panic attacks during the study. Two other studies reported infrequent anxiety-related adverse events among subjects receiving Halcion, but there is no indication of a greater frequency of adverse events for Halcion than for comparator benzodiazepines (Roger et al., 1993; Monti et al., 1994).

Withdrawal-Related Anxiety or Insomnia Following Short- and Long-Term Halcion Use
Rebound Anxiety

Pinnock et al. (1985) did not find evidence of increased anxiety 6 hours postoperatively in subjects treated with Halcion preoperatively. However, several studies report increases in anxiety following the termination of Halcion administration with short- and long-term treatments (Lee and Lader, 1988). Some studies suggest that withdrawal-related anxiety is not greater for Halcion than for zopiclone (Fleming et al., 1990).

Suggested Citation:"Assessment of Safety Data." Institute of Medicine. 1997. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: The National Academies Press. doi: 10.17226/5940.
×
Rebound Insomnia

Several studies describe increased rates of insomnia following discontinuation of Halcion treatment, even after only a few nights of treatment (Kales et al., 1986; Mamelak et al., 1990; Mauri et al., 1993). In general, the duration of rebound insomnia is limited to the first three nights of discontinuation (Adam and Oswald, 1988; Mouret et al., 1990; Elie et al., 1990; Monti et al., 1994). Several of these studies suggest that the magnitude of impairment with Halcion is greater than that with comparator benzodiazepines (Monti et al., 1994). The level of sleep impairment following termination of Halcion treatment in insomniac subjects does not generally exceed the initial level of sleep impairment (McCluskey et al., 1991). Furthermore, the degree of rebound insomnia following the discontinuation of Halcion treatment. appears to be more closely associated with the magnitude of clinical benefit than the duration of drug exposure in insomniac subjects (Merlotti et al., 1991). These data suggest that a component of the rebound insomnia is a return to the pretreatment level of insomnia. However, other data support the rebound insomnia model. For example, tapering the cessation of Halcion treatment reduces the cessation-related decline in sleep quality (Roehrs et al., 1992).

An issue facing the comparison of short- and long-half-life benzodiazepines is the possibility that long-acting benzodiazepines may not produce comparable levels of acute rebound anxiety. The short-half-life agents produce a relatively short period of sleep disruption. In contrast, there may be a less severe, but more protracted, disruption of sleep associated with withdrawal from long-acting benzodiazepines (Kales et al, 1982; Gillin et al., 1989; Mitler et al., 1984).

Summary

The published literature has documented both anxiolytic and anxiogenic effects in relatively small populations of individuals administered Halcion, Halcion does not appear to be as effective as longer-acting benzodiazepines for reducing daytime anxiety, and it may be associated with substantial increases in anxiety. Clinically significant anxiety increases appear to be relatively infrequent. However, the frequency of these reactions cannot be adequately assessed from the data published in the literature. Similarly, there appears to be increased risk of sleep impairment after the discontinuation of Halcion administration. The frequency of severe or protracted impairment is rare, but it is also impossible to determine this frequency from the data available in the literature. Overall, the data published in the literature do not contradict FDA or IOM analyses discussed elsewere in this report.

Ataxia, Disinhibition, and Psychotogenic, Confusional, or Dissociative Effects of Halcion

On the basis of data published in the literature, there do not appear to be compelling data singling out Halcion use as a risk factor for falls (see Table B-7). There are insufficient data to base a reconsideration of FDA approval of Halcion on the basis of published data on behavioral dyscontrol following Halcion administration (see Table B-8). The data from published studies consisting of case reports of the emergence of paranoia, hallucinations, or

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

confusion indicate that these conditions are infrequent consequences of Halcion administration (Wehli et al., 1985; Kales et al., 1986; Adam and Oswald, 1988) (see Tables B-9 and B-10).

Consideration of Other Potential Adverse Effects

The information discussed in this section is summarized in Table B-10. This section reviews several issues. raised in the published literature.

Early Termination of Use

Two reports indicate higher rates of early terminations of use after Halcion use than after use of comparator drugs (Fleming et al., 1990; Roger et al., 1993). Another report failed to find evidence of excessive terminations after Halcion use relative to that after zolpidem use (Hajak et al., 1994). These data do not permit the development of conclusions regarding an increased incidence of termination of use associated with Halcion use compared with that of other benzodiazepines.

Adverse Effects Defined Generally

Two studies (Wehli et al., 1985; Fleming et al., 1990) reported increased rates of adverse events in general associated with Halcion use relative to the rates associated with the use of comparator drugs. However, the difference between Halcion and the comparator drugs in the study of Wehli et al. (1985) was limited to mild side effects. Other studies failed to find differences between Halcion and comparator drugs (Roger et al., 1993; Hajak et al., 1994; Jacobsen et al., 1994) or did not note any significant or unexpected adverse effects (Thorpy et al., 1992; Mauri et al., 1993).

Other Adverse Effects

A recent report suggests an advantage of short- versus long-half-life benzodiazepines regarding driving safety among elderly subjects (Hemmelgarn et al., 1997). That study reported a 50 percent increase in the number of injurious motor vehicle crashes among elderly drivers during the first 7 days of use of long-half-life benzodiazepines compared with the numbers among elderly drivers Using short-half-Fife benzodiazepines or a placebo. The risk remained increased after continuous long-half-life benzodiazepine use for up to 1 year.

Suggested Citation:"Assessment of Safety Data." 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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Summaries and Meta-Analyses

In the time since the introduction of Halcion, a growing number of studies have reviewed the safety and efficacy of Halcion. These reviews have supported both its relative safety and efficacy (Greenblatt et al., 1984; Jonas et al., 1992; Klett, 1992; Rothschild, 1992; Mendelson and Jain, 1995; Lobo and Greene, 1997) or concluded that serious questions regarding the safety and efficacy of Halcion remain (Kales et al., 1996). These reports echo two concerns about the published literature: (1) essentially all studies evaluate only a single dose of Halcion or its comparator drug, which makes it difficult to equate Halcion doses with the doses of other medications on the basis of equal potency, and (2) most trials with a single dose of Halcion have used doses that are relatively larger (in terms of anticipated receptor occupancy) than that of the drug with which it is compared. The net. result is that many trials appear to be biased in favor of associating adverse effects with Halcion (Lobo and Greene, 1997). Overall, the reviews do not convincingly support the existence of an unexpected clinical profile for Halcion.

Closing Comments

The bulk of the published reports related to Halcion's safety were not designed to evaluate the relative frequency of rare, but serious, side effects. A small number of these studies suggest that Halcion use is associated with frequent and serious side effects. The frequency or severity of these side effects is not replicated broadly. in the published studies. However, the presence of these serious side effects warrants the review of other data that might provide a better understanding of these effects, which are of concern. The published studies, however, do not provide convincing evidence that there is associated with Halcion a unique or serious health risk relative to those associated with other benzodiazepines or benzodiazepine-like hypnotic agents. There is the possibility that, relative to other benzodiazepines, individuals receiving Halcion tend to remain on higher doses for longer than the recommended duration (Martinez-Cano et al., 1996). Use patterns may interact with the pharmacologic properties to give rise to increased rates of adverse effects. Even if this is true, however, this conclusion cannot be evaluated on the basis of the published literature. Kales and colleagues (1996) raised the concern that the available data from both controlled trials and SRS might be inadequate to evaluate the effects of Halcion on autobiographical memory (amnestic events). To the committee's knowledge, this phenomenon has not received direct attention in a published study and could be evaluated in a controlled trial. However, the subsequent modification to the labeling of Halcion reflects an integration of reports of serious, but infrequent, adverse effects of this drag into clinical practice.

CONCLUSIONS AND RECOMMENDATIONS

It is important to note that the conclusions and recommendations are based on a review of the available public information. Various types of data were reviewed and evaluated: (1)

Suggested Citation:"Assessment of Safety Data." 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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randomized, controlled (dose and duration) clinical trials, (2) spontaneous reports of adverse events, (3) survey data, and (4) the published literature. The committee did not review original, raw data or case reports but, rather, the data that were summarized in the New Drug Application and other sources. The committee's analyses were based on these summary data.

Clinical Trials and Surveillance

The committee is confident in the quality and adequacy of the data from clinical trials (pre- and postmarketing). supporting the safety of using Halcion within the current labeling guidelines. The committee recognizes, however, that the lack of significant adverse events reported from clinical trials appear to conflict with the numbers and types of adverse events (e.g., anterograde amnesia, confusion) that have appeared in the SRS of FDA and in some case reports in the literature. Many factors contribute to this apparent conflict (which is not uncommon among drugs), including the nature and design of clinical trials and external events that can affect the reporting of adverse events.

It is important to note that the statistical power to detect rare events is necessarily limited in controlled clinical trials because such trials include a small number of subjects compared with the number of patients using the drug in the postmarketing period, and subjects admitted to the trials must conform to carefully defined inclusion and exclusion criteria, narrowing the likely range of adverse events; rare events are unlikely to be detected in sample populations of a few hundred subjects. In addition, the treatment regimens in these trials are designed to avoid untoward or adverse events that might be expected to occur with higher doses or with dose dependent or duration-dependent use.

With respect to surveillance and reports of adverse events, the committee notes that apparent inconsistencies in the data from clinical trials and spontaneous reports are likely to occur for the reasons stated above, and concludes the following:

  • The popularity and consequent widespread use of Halcion produced large at-risk populations from which spontaneous reports of adverse events emerged.

  • Many people take Halcion (and other hypnotic drugs) for more than a year and at dosages above those recommended in the labeling.

  • In general, the types and frequencies of reported adverse events are subject to many external influences, including media attention, marketing, litigation, differential reporting rates, ability to connect drug use to a health event, and other factors, all of which affect the accuracy of interpreting the results.

Recommendation. 5: Improve Surveillance, Analysis, and Integration of Findings. The committee recommends that FDA develop improved methods for integrating the findings of clinical trials and postmarketing surveillance, and for resolving discrepancies in the interpretation of data from spontaneous reports, clinical case reports, and controlled clinical trials. This would include the reestablishment of a biostatistics and epidemiology advisory committee (in addition to having biostatistics and epidemiology expertise on the other advisory committees) that

Suggested Citation:"Assessment of Safety Data." 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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would be charged with the rapid and thorough assessment of the potential health risks suggested by reports of adverse events, identification and resolution of conflicts that may arise in the review of clinical trial and surveillance data, and the provision of expert advice on the maintenance and operation of effective postmarketing surveillance systems.

Suggested Citation:"Assessment of Safety Data." 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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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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