Halcion An Independent Assessment of Safety and Efficacy Data (1997) / Chapter Skim
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Assessment of Safety Data
Assessment of Safety Data
Pages 49-93
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From page 49... ...
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.
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. 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.
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with a Duration of Treatment of 1 to 92 days Medical Event Drowsiness/sedation Dizziness Headache Tiredness Nervousness Impaired coordination Depression Insomnia Confusion Excitement Euphoria Memory impairment Tremor Concentration difficulty Vasomotor disturbances Halcion (n = 3,982) Flurazepam Placebo Othera (n= 1,295)
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0 1 (2.9) 0 O O Nervousness Tiredness Paresthesia Dysesthesia Insomnia Impaired coordination Memory impairment Confi~sion Disonentation Vasomotor disturbances Oerealization Dream abnormalities Euphoria Fear Intellectual impairment Irritability Shakiness Depression 12 (9.9)
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SOURCE: The Upjohn Company (1992~.
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54 HALCION: AN INDEPENDENT ASSESSMENT TABLE 3-3 CNS-related Medical Events for Adult Insomniac Subjects, 4 to 6 arid 12 to 13 Weeks of Treatment 4 6 Weeks' Duration Triazolam 0.25 mg (n = 54) vs Flurazepam 30 mg (n = 27)
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SOURCE: The Upjohn Company (1992~.
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0 3 (15.8) Memory impairment 1 (2.2)
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ASSESSMENT OF SAFETY DATA TABLE 3-5 CNS-Related Medical Events for Geriatric Subjects, 1 to 2 arid 4 Weeks of Treatment 1-2 Weeks' Duration Triazolam 0.25 mg (n = 35) vs Flurazepam 15 mg (n= 58)
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c Includes Protocols 6004, 6016, 6042, 6043, and 6044. SOURCE: The Upjohn Company (1992~.
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, 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.
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From page 60... ...
, with expected rates ranging from 1.4 to 5.0 percent for nongeriatric 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 ma.
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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 0 0.00 impairment 0.125 0.02 0.25 0.00 0.s 0.01 o.ooo 0.001 0.001 0.006 0.026 0.001 0 0.003 15 0.007 30 0.00 0.000 0.000 0.00 0.000 0.000 0.00 0.000 0.000 Impaired 0 0.02 0.013 0.012 0 0.02 0.014 0.036 coordination 0.125 0.00 0.020 0.022 15 0.03 0.25 0.04 0.030 0.038 30 0.06 0.5 0.08 0.064 0.095 Confusion 0 0.00 0.003 0.006 0 0.125 0.00 0.003 0.005 15 0.25 0.01 0.003 0.004 30 0.5 0.00 0.003 0.003 0.028 0.071 0.050 0.127 0.00 0.002 0.017 0.01 0.001 0.013 o.oo 0.001 0.010 a The data used in these analyses were extracted Tom tabular data from the Upjohn Company, 1992; pp.
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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.
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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 ~ for Halcion versus flurazepam and placebo in clinical trials of longer duration that study the higher doses of Halcion in nongeriatric populations (see Table 3-74. A notable exception was a risk ratio of approximately 7 to ~ for Halcion versus placebo in Tong-term studies (Halcion, 10.6 percent; flurazepam, 4.]
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of Subjects (%) Risk Ratios for Dropouts Triazolam/ Triazolam/ Subject Group Triazolam Flurazepam Placebo Flurazepam Placebo All subjects 63/1,168 15/607 16/566 2.2a 1.9a (5.4)
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of Subjects (%) Risk Ratios for Dropouts Subject Group Triazolam/ Triazolam/ Triazolam Flurazepam Placebo Flurazepam Placebo All subjects 145/1,168 58/607 39/566 l.3a l.8a (12.4)
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la Memory impairment 0.7 o.oa o.oa 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. ~0.0 0.2 a Statistically significant when compared to Halcion by chi-square analysis or the Fisher exact test,p<0.05.
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, 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.
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See Appendix A, Tables A-1 through A-13, for more specific information concerning dropout rates. SOURCE: Laughren and Lee ~ 19929.
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See Appendix A, Tables A-1 through A-13, for more specific information concerning dropout rates. SOURCE: Laughren and Lee ~ 1992~.
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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.
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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 nongeriatric 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.
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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 Tower than the percentage of geriatric subjects receiving flurazepam who withdrew (13.5 percent, see Table 3-~.
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The rates of toxicity for the comparator drug, 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.
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Sleep latency to stage 2 decreased, and total sleep time increased with increased doses. The medical events were infrequent, and none was serious.
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A noteworthy event is the rates of "memory problems," in which 0.4 and I.! percent of the subjects receiving Halcion at 0.25 and 0.50 ma, respectively, reported this adverse event, whereas 0.2 to 0.3 percent of the subjects receiving flurazepam and oxazepam, respectively, reported this adverse event.
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77 ^ ^ ^ ^ oo .
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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.
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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)
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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 Reporting Rate Temazepam Ratios Adverse Event Reporting Reporting No.
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Tables B-l 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 HaTcion administration or withdrawal; ataxic, disinhibition, and psychotogenic, confusional, or dissociative effects; and other potential adverse events.
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From page 83... ...
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.
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From page 84... ...
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.
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Caffeine reduces many of the coanition-imcairina effects of triazolam in a dose-dependent manner (Rush et al., 1994~. Unique Effects of Triazolobenzodiazepines on Locus Coeruleus Neurons ~,!
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. 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.
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From page 88... ...
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 Tormetazepam, 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., ~ 993; Monti et al., ~ 994~.
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et al., 19941. 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., 19911.
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reported increased rates of adverse events in gerenal 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.
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From page 91... ...
essentially all studies evaluate only a single dose of Halcion or its comparator drug, which makes it difficult to equate HaTcion 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)
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From page 92... ...
, 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.
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ASSESSMENT OF SAFETY DATA 93 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 ciata, and the provision of expert advice on the maintenance and operation of effective postmarketing surveillance systems.
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