By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
The FDA has approved the first orally dissolving, self-administered sublingual film for the acute treatment of agitation associated with schizophrenia or bipolar disorders. Dexmedetomidine is an alpha-2 adrenergic agonist originally approved in 1999 for use in ICUs in intubated and mechanically ventilated patients and procedural sedation in non-intubated adults.1 The sublingual film is distributed as Igalmi.
INDICATIONS
Dexmedetomidine can be prescribed for the acute management of agitation associated with schizophrenia or bipolar I or II disorder.2
DOSAGE
The recommended dose (given sublingually or buccally) is based on agitation severity (mild, moderate, or severe) and the patient population.2 For adults with mild or moderate agitation, the initial dose is 120 mcg; 180 mcg is recommended for severe agitation. For those with mild or moderate hepatic impairment, the dose is 90 mcg and 120 mcg, respectively. For severe hepatic impairment, the doses are 60 mcg and 90 mcg. For geriatric patients (age 65 years and older) with mild, moderate, or severe agitation, the dose is 120 mcg. If agitation persists, up to two additional doses (generally, a lower dose) may be given at least two hours apart. The maximum total daily dose ranges from 180 mcg to 240 mcg, depending on patient status and agitation severity. The drug should be given under the supervision of a healthcare provider. No food or drink should be given for at least 15 minutes after sublingual administration and one hour after buccal administration. The film may be cut in half to provide 60 mcg and 90 mcg strengths. Dexmedetomidine is available as 120 mcg and 180 mcg sublingual films.
POTENTIAL ADVANTAGES
Dexmedetomidine provides the first orally dissolving, self-administered drug for the acute treatment for schizophrenia or bipolar disorder-associated agitation. Intramuscular (IM) olanzapine injection is FDA-approved for this indication.
POTENTIAL DISADVANTAGES
Dexmedetomidine causes dose-dependent hypotension, orthostatic hypotension, and bradycardia.2 In clinical studies, 18%, 16%, and 9% of patients treated with 180 mcg, 120 mcg, and placebo, respectively, experienced orthostatic hypotension (decrease in systolic blood pressure of ≥ 20 mmHg or ≥ 10 mmHg of diastolic blood pressure). Bradycardia (≤ 50 beats per minute) also has been observed in 6% to 7% of patients vs. 1% for placebo. Vital signs should be assessed before administration of additional doses. Dexmedetomidine prolongs QT intervals and should be avoided in patients with a history of torsades de pointes, other arrhythmias, symptomatic bradycardia, hypokalemia or hypomagnesemia, or on medications known to prolong QT interval. The most frequently reported adverse reaction is somnolence (22% to 23% vs. 6% for placebo).2 The safety and efficacy have not been established beyond 24 hours from the initial dose.
COMMENTS
The effectiveness of dexmedetomidine was evaluated in two randomized, double-blind, placebo-controlled, fixed-dose studies. One study included subjects with schizophrenia, schizoaffective, or schizophreniform disorder (n = 380), and the other study included subjects with bipolar I or II disorder (n = 378).2,3 Subjects were randomized to receive a single dose of dexmedetomidine (180 mcg, 120 mcg) or placebo. The primary efficacy endpoint was mean change from baseline at two hours for the Positive and Negative Syndrome Scale, Excited Component (PEC) total score. This investigator-rated instrument consisted of five items: poor impulse control, tension, hostility, uncooperativeness, and excitement. Each item scored from 1 to 7 (absent, minimal, mild, moderate, moderate-severe, severe, extremely severe). Clinically agitated is a PEC score of ≥ 14. In study 1, dexmedetomidine 180 mcg and 120 mcg showed a mean difference from placebo of 5.5 and 3.7 points, respectively, from a baseline of 17.5 PEC score. Decrease in agitation was statistically significant at 20 minutes with the higher dose and 30 minutes for the lower dose. In study 2, mean reduction was 5.4 and 4.1 points, respectively, relative to placebo. Significant decrease in agitation began 20 minutes after treatment for both doses.
CLINICAL IMPLICATIONS
It is estimated that up to 25% of patients with schizophrenia or bipolar disorder experience episodes of agitation.4 These can occur 10 to 17 times annually. Initial treatment is with non-pharmacological (verbal and nonverbal) de-escalation.5 Pharmacologic options include first- and second-generation antipsychotics, benzodiazepines, ketamine, and combinations (e.g., haloperidol and promethazine), with the goal of calming rather than sedating.3,5,6 Its ultimate role will be defined with more clinical experience. There are no published comparative studies with IM olanzapine. Igalmi is set for a second quarter launch. Pricing is unavailable.
REFERENCES
- Department of Health and Human Services. Precedex (dexmedetomidine) safety and drug utilization review. March 10, 2016.
- BioXcel Therapeutics, Inc. Igalmi prescribing information. April 2022.
- Preskorn SH, Zeller S, Citrome L, et al. Effect of sublingual dexmedetomidine vs placebo on acute agitation associated with bipolar disorder: A randomized clinical trial. JAMA 2022;327:727-736.
- BioXcel Therapeutics. BioXcel Therapeutics announces FDA approval of Igalmi (dexmedetomidine) sublingual film for acute treatment of agitation associated with schizophrenia or bipolar I or II disorder in adults. April 6, 2022.
- Ward K, Citrome L. The treatment of acute agitation associated with schizophrenia or bipolar disorder: Investigational drugs in early stages of their clinical development, and their clinical context and potential place in therapy. Expert Opin Investig Drugs 2020;29:245-257.
- Zareifopoulos N, Panayiotakopoulos G. Treatment options for acute agitation in psychiatric patients: Theoretical and empirical evidence. Cureus 2019;11:e6152.
Dexmedetomidine can be prescribed for the acute management of agitation associated with schizophrenia or bipolar I or II disorder.
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