Pill Pushing©

Halcion - Sweet dreams are made of this - (3/1/2017)

By Dr. Ron Gasbarro

The drug in question: Halcion (triazolam)

Society at the time
The year was 1982. The Falklands War began as Argentina invaded and occupied the islands. Cal Ripken, Jr. played the first of what eventually became his record-breaking streak of 2,632 consecutive Major League Baseball games for the Baltimore Orioles. The Chicago Tylenol murders occurred when 7 people in the Chicago area died after ingesting capsules laced with potassium cyanide, after which safety packaging was used in everything from baby food to Boost™. 

American singers Kelly Clarkson and LeAnn Rimes were born. American actor John Belushi died at 33 from a drug overdose, while actor Vic Morrow, 53, was decapitated when a helicopter fell on him and 2 child actors on the set of Twilight Zone: The Movie. The first compact discs (CDs) were produced in Germany and just in time: Michael Jackson’s Thriller was released making it the best-selling album of all time. Synthpop reached its commercial peak with bands such as Orchestral Manoeuvres in the Dark, Ultravox, Soft Cell, Depeche Mode, Duran Duran, Spandau Ballet, and even the esoteric Kraftwerk, enjoying top 10 hits.  And in 1982, the next and arguably most notorious of the benzodiazepines were introduced to Americans: Halcion®.

The good, the bad, and the ugly
Halcion is a central nervous system (CNS) depressant in the benzodiazepine class. Its pharmacologic characteristics are similar to other benzodiazepines, such as Valium® (diazepam), Librium® (chlordiazepoxide), Dalmane® (flurazepam) and Xanax® (alprazolam), but it is generally only used as a sedative to treat severe insomnia. In addition to its hypnotic properties, triazolam also has amnesic, anxiolytic, sedative, anticonvulsant and muscle relaxant aspects. This drug is not effective for patients who suffer from frequent awakenings or early awakening, due to its short half-life (1-2 hours) [Rickles, 1986] as compared to flurazepam, which can have a half-life of over 100 hours [Roth, 1980] – extremely dangerous in the elderly. The drug is used to correct circadian rhythms, especially when used for jet lag [Buxton, 2000]. Its onset of action is roughly 15 to 30 minutes, so it should be taken right before bedtime. 

Pharmacologically, triazolam does not generate active metabolites. Besides being a short-acting benzodiazepine, it is lipophilic and is metabolized hepatically via oxidative pathways. The main pharmacological effects of triazolam are the enhancement of gamma-aminobutyric acid (GABA) at the GABAA receptor [Oelschläger, 1989]. GABA is an amino acid found in the CNS that functions as a suppressive neurotransmitter.

Benzodiazepines, such as triazolam, require special precaution if used in the elderly, during pregnancy, in children, alcoholics, or other drug-dependent individuals and individuals with comorbid psychiatric disorders [Authier, 2009]. Triazolam belongs to the Pregnancy Category X of the US Food and Drug Administration (FDA), meaning that it is known to have the potential to cause birth defects.

A pharmaceutical nightmare 
The Pink Sheet is a publication based in New York City that reports both the trends that shape the dynamics of the global pharmaceutical and biotech sectors as well as the exclusive, proprietary data behind these trends. On May 7, 1984, The Pink Sheet reported a story entitled “Upjohn’s Xanax and Halcion volume gains add $60 million to drug sales in 1983” [Pink Sheet, 1984]. Upjohn, the company that manufactured the sleeping pill stated that "Halcion made excellent penetration in its first full year on the US market, capturing a 16% share of new prescriptions.” Both drugs were blockbusters for the company, except that Xanax is still a widely used anxiolytic agent, whereas Halcion is almost non-existent today. Why?

The first inkling that a problem existed with Halcion was that the approved dosage may have been too high. Before Halcion reached the US market, it had undergone an eventful approval process [National Academies Press, 1997]. Upon reviewing the New Drug Application (NDA), the chief medical review officer expressed concern about both efficacy and safety, including (1) high rates of amnesia and confusion, lack of coordination, and other CNS-related side effects associated with Halcion (0.5 to 1.0 mg) compared with those associated with either flurazepam or placebo; (2) possible diminished effectiveness with repeated administration; (3) "rebound insomnia" during withdrawal; and (4) possible unique safety or efficacy profiles uncharacteristic of those for other benzodiazepines. These concerns were not sufficient, however, to prevent an FDA Psychopharmacologic Agents Advisory Committee (now named the Psychopharmacologic Drugs Advisory Committee [PDAC]) from recommending in 1977 that Halcion should be approved for clinical use. The approval was delayed, however, by a request from the Division of Neuropharmacological Drug Products for additional preclinical animal studies and human bioavailability data. When FDA approved Halcion for clinical use in November 1982, reports of possible problems with the drug had already appeared in Europe.

In 1979, a Dutch pharmacologist, C. van der Kroef, revealed a neurological “syndrome” associated with Halcion, prompting Upjohn to withdraw it from the Dutch market. In 1983, Upjohn introduced a 0.125mg tablet to join the 0.25mg and 0.5mg dosage forms. By 1988, Upjohn discontinued production of the 0.5mg tablet based on safety concerns and the package insert was changed to reflect the lower dosage forms. 

In time, the side effects of Halcion started to get the attention of the press. On August 18, 1991, Newsweek magazine published a story [Cowley, 1991] that encapsulates the magnitude of the Halcion problem that led to the FDA forcing Upjohn to strengthen the warning language on the package insert: 
“When Officer Reg Browne walked into the room, 83-year-old Mildred Coats was stretched out on her bed, clutching a cheery birthday card in her left hand. Several towels had been placed gently around her head to absorb the blood from spilling from 8 gunshot wounds. Anticipating a heated domestic dispute, Browne had donned a bulletproof vest before leaving the sheriff's office in Hurricane, Utah. But he didn't get a chance to use it. The old woman's daughter, 57-year-old Ilo Grundburg, was waiting calmly to hand him a written confession. ‘I didn't kill her because I didn't love her,’ Grundburg explained. ‘I loved her very much.’

Grundburg was arrested, charged with second-degree murder, jailed and then moved to a Salt Lake City mental hospital for psychiatric testing. But she never had to stand trial. After examining her, a pair of court-appointed psychiatrists testified that Grundburg had been involuntarily intoxicated when she killed her mother. Like more than 7 million other Americans, she had been taking the prescription drug Halcion to help her sleep. Though the drug is intended only for a short-term use, her doctor prescribed it for much of the preceding year, and she had grown increasingly agitated and paranoid while taking it. Because she had no clear motive for the murder and little memory of it, the experts concluded she hadn't acted voluntarily. Prosecutors responded by asking the court to dismiss the case. On Feb. 7, 1989, Ilo Grundburg went free.

Out of custody and off the drug, Grunburg got herself a lawyer. In a $21 million civil suit, she and her daughter, Janice Gray, charged that Halcion is a "defective drug" and that Upjohn, its Michigan-based manufacturer, failed to warn regulators and the public of its "severe and sometimes fatal adverse reactions." The company responded that it was "in no way negligent" and that the murder was "in no way caused by the drug Halcion." But last week, on the eve of the trial that would have brought a long, public airing of Halcion's disputed safety record, Upjohn blinked. In a terse press statement, the company announced it had "reached a resolution" with Grundberg and that the "details of the resolution shall remain confidential." The settlement spares the company what could have been a bruising battle with an unhappy customer. But it won't quiet the controversy surrounding the most widely prescribed sleeping pill in the world.”

On May 24, 1992, Newsweek magazine ran another story that involved Halcion and homicide [Newsweek, 1992]. “That Nila Wacaser stabbed her two young sons to death in a motel room was never in dispute. The Kansas City woman confessed to the crime in 1987 and received a death sentence in 1988. Before she could be executed, however, the Missouri Supreme Court threw out the conviction on a technicality and ordered a new trial. Two weeks ago Wacaser was back in court to mount a new defense. Citing her history of psychiatric troubles, her lawyers argued that Halcion, the sleep remedy she was receiving at the time of the crime, had unleashed a rage she might otherwise have checked. The argument failed--Wacaser was found guilty on May 8 and committed suicide the next morning--but the case may fuel the controversy surrounding the world's most widely prescribed sleeping pill. For the trial produced evidence that Upjohn, the maker of Halcion, has brushed aside its own scientists' safety concerns.”

Since initial experiments don't always reveal a drug's dangers, the Food and Drug Administration maintains a system of "postmarketing surveillance." Doctors and drug companies pass along patients' complaints, regardless of merit, and the agency watches for patterns. The FDA's epidemiologists have long worried about the number of Halcion users reporting psychiatric disturbances such as anxiety, memory loss, hostility, even psychosis. In 1989, after two agency studies showed that Halcion was spawning more than its share of such reports, the FDA convened an advisory panel to examine the trend and hear what Upjohn knew about it. Speaking for the company, Dr. Roy Drucker, a vice president, cautioned that spontaneous reports provide only a signal of possible trouble. He added that "there is no information available to the Upjohn Company, outside this meeting, that would tend to substantiate that signal." The committee accepted Drucker's assertion and voted not to impose special restrictions on the drug. Upjohn has since used the same argument to deflect countless questions about Halcion's safety. But according to a former company scientist, there's more to the story.

From the time Halcion hit the US market in 1982 until shortly before he left Upjohn in 1990, Dr. William Barry directed the company's own postmarketing surveillance program. In portions of a taped deposition shown during the Wacaser trial this month, he made clear that by 1989 he had detected the same trends as the FDA scientists and had spent years voicing concern. Barry testified that as early as 1983, he had written a memo describing an unexpected number of amnesia complaints from Halcion users; in 1984, he determined from an in-house study that people on high doses were reporting more amnesia, confusion, and hallucinations than people on low doses. (One wouldn't expect to see such a pattern if the problems were unrelated to the drug.) Barry also testified that he later urged the company to consider stronger warnings about such reactions as paranoia, psychosis and homicidal behavior.”

The impact on society
Today, the package insert includes this information [Halcion, 2016]:
WARNINGS 
Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after a careful evaluation of the patient. The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. 

Worsening of insomnia or the emergence of new thinking or behavior abnormalities may be the consequence of an unrecognized psychiatric or physical disorder. Such findings have emerged during the course of treatment with sedative-hypnotic drugs. Because some of the important adverse effects of sedative-hypnotics appear to be dose-related, it is important to use the smallest possible effective dose, especially in the elderly. Complex behaviors such as “sleep-driving” (i.e., driving while not fully awake after ingestion of a sedative-hypnotic, with amnesia for the event) have been reported. These events can occur in sedative-hypnotic-naïve as well as in sedative-hypnotic-experienced persons. 

Although behaviors such as sleep-driving may occur with sedative-hypnotics alone at therapeutic doses, the use of alcohol and other CNS depressants with sedative-hypnotics appears to increase the risk of such behaviors, as does the use of sedative-hypnotics at doses exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontinuation of sedative-hypnotics should be strongly considered for patients who report a “sleep-driving” episode. Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sedative-hypnotic. As with sleep-driving, patients usually do not remember these events.

More terrifying information for prescribers and patients
An increase in daytime anxiety has been reported for triazolam after as few as 10 days of continuous use. In some patients, this may be a manifestation of interdose (that is, between bedtime doses) withdrawal. If increased daytime anxiety is observed during treatment, discontinuation of treatment may be advisable.

A variety of abnormal thinking and behavior changes have been reported to occur in association with the use of benzodiazepine hypnotics including triazolam. Some of these changes may be characterized by decreased inhibition, e.g., aggressiveness and extroversion that seem excessive, similar to that seen with alcohol and other CNS depressants, such as the sedative-hypnotics. Other kinds of behavioral changes have also been reported, for example, bizarre behavior, agitation, hallucinations, depersonalization. In primarily depressed patients, the worsening of depression, including suicidal thinking, has been reported in association with the use of benzodiazepines.

It can rarely be determined with certainty whether a particular instance of the abnormal behaviors listed above is drug-induced, spontaneous in origin, or a result of an underlying psychiatric or physical disorder. Nevertheless, the emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation.

Because of its depressant CNS effects, patients receiving triazolam should be cautioned against engaging in hazardous occupations requiring complete mental alertness such as operating machinery or driving a motor vehicle. For the same reason, patients should be cautioned about the concomitant ingestion of alcohol and other CNS depressant drugs during treatment with triazolam tablets. As with some, but not all benzodiazepines, anterograde amnesia of varying severity and paradoxical reactions have been reported following therapeutic doses of triazolam. Data from several sources suggest that anterograde amnesia may occur at a higher rate with triazolam than with other benzodiazepine hypnotics.

Where the drug is today
From the time of its approval, Halcion had been associated with a large number of reports of adverse events. Indeed, there was sufficient concern about the safety of the drug to cause Public Citizen, a consumer advocacy group, to submit petitions in 1991 and 1992 requesting that FDA remove Halcion from the US market. In 1997, those petitions were denied by the FDA. Although rarely used, Halcion, now as generic triazolam remains on the US market. However, over the last few decades, newer and albeit “safer” sedatives have become available to American consumers.  

Ron Gasbarro, PharmD, is a registered pharmacist, medical writer, and principal at Rx-Press.com. Visit him at www.rx-press.com

References
Authier N, Balayssac D, Sautereau M, et al. Benzodiazepine dependence: focus on withdrawal syndrome.  Ann Pharm Fr. 2009;67:408-13. 

Buxton OM, Copinschi G, Van Onderbergen A, Karrison TG, Van Cauter E. A benzodiazepine hypnotic facilitates adaptation of circadian rhythms and sleep-wake homeostasis to an eight hour delay shift simulating westward jet lag. Sleep. 2000;23:915-27.

Cowley G. Sweet dreams or nightmare? Newsweek. August 18, 1991.

Halcion tablets [package insert]. New York, NY: Pharmacia & Upjohn Co.; 2016. 

National Academies Press, The. Halcion: An Independent Assessment of Safety and Efficacy Data. Washington, DC: National Academy of Sciences; 1997.

Newsweek staff. Fueling the fire over Halcion. Newsweek. May 24, 1992.

Oelschläger H. Chemical and pharmacologic aspects of benzodiazepines. Schweiz Rundsch Med Prax. 1989;78(27–28):766–72.

Rickels K. The clinical use of hypnotics: indications for use and the need for a variety of hypnotics. Acta Psychiatrica Scandinavica Suppl. 1986;74(S332):132–41. 

Roth T, Hartse KM, Zorick FJ, Kaffeman ME. The differential effects of short- and long-acting benzodiazepines upon nocturnal sleep and daytime performance. Arzneimittelforschung. 1980;30(5a):891-4.


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