How to treat agitation in social settings

Abstract

The present disclosure relates to a method for treating agitation in a patient with schizophrenia or bipolar disorder in a non-clinical setting, comprising oromucosally administering to the patient an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof. In various embodiments, a caregiver administers the dexmedetomidine or a pharmaceutically acceptable salt thereof to the patient, or the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 405,452, filed September 11, 2022, and U.S. Provisional Application No. 63 / 504,109, filed May 24, 2023, the contents of which are incorporated by reference in their entireties as if set forth herein.

[0002] Technical Field The present disclosure relates to a method for treating agitation in a patient with schizophrenia or bipolar disorder in a non-clinical setting, comprising oromucosal administration of an effective amount of dexmedetomidine, or a pharmaceutically acceptable salt thereof, via a caregiver or informant, or via self-administration by the patient. The agitation can be mild to moderate. [Background technology]

[0003] Agitation, manifested as motor restlessness and an accompanying mental state of tension, is a serious medical problem that can be present in some psychiatric disorders and can rapidly escalate into aggressive behavior. Patients with neuropsychiatric disorders, such as schizophrenia and bipolar disorder, are prone to acute agitation episodes, especially when their illness worsens. This is a common reason for emergency department visits and institutionalization, and unless recognized early and managed effectively, it can rapidly escalate into potentially dangerous situations, including physical violence. Prolonged hospitalization is not a desirable option because it confines patients to the hospital. Frequent outpatient visits also present numerous logistical obstacles and are impractical. The key to safety is early intervention to prevent agitation from progressing to aggression and violence. Therefore, there is a need for caregivers or informants (e.g., family members) to assess and consider the condition of such agitated patients in nonclinical settings (e.g., at home) so that they can provide timely anti-agitation treatment to calm the patient and prevent recurrence of agitated episodes.

[0004] The methods described herein improve medical services in non-clinical settings, such as in-home, group homes, assisted living facilities, correctional facilities, hospices, or long-term care facilities, by allowing a greater proportion of patients to be treated at a much lower cost than if they were still receiving inpatient services.

[0005] The technical effect of the disclosed methods is to enable caregivers or information providers and individuals to collect objective data with minimal inconvenience to the patient, correlate patterns and changes in said data with the individual's mental health status, and adjust and, if necessary, change said individual's dosing or other treatment plan based on patterns in said data and changes in said individual's type, response, and activity level. The overall result is reduced strain on the healthcare system and better patient outcomes. Summary of the Invention

[0006] The present disclosure provides a method of treating agitation in a patient with schizophrenia or bipolar disorder in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof to the patient at a dose of about 60 micrograms, wherein the patient is 18 years of age or older.

[0007] The present disclosure provides a method of treating agitation in a patient with schizophrenia or bipolar disorder in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof to the patient at a dose of about 80 micrograms, wherein the patient is 18 years of age or older.

[0008] In embodiments, the present disclosure provides a method of treating agitation in a patient with schizophrenia or bipolar disorder in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof to the patient at a total daily dose of about 60 micrograms to about 360 micrograms, wherein the patient is 18 years of age or older.

[0009] In embodiments, the present disclosure provides a method of treating agitation in a patient with schizophrenia or bipolar disorder in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof to the patient at a total daily dose of about 60 micrograms to about 180 micrograms, wherein the patient is 18 years of age or older.

[0010] In embodiments, schizophrenia comprises schizoaffective disorder or schizophreniform disorder. In embodiments, bipolar disorder comprises bipolar disorder I or bipolar disorder II.

[0011] In various embodiments, the dexmedetomidine or pharmaceutically acceptable salt thereof is administered by a caregiver or information provider of the patient. In various embodiments, the caregiver or information provider is a family member or family friend. In various embodiments, the caregiver or information provider is a person employed by or for the patient. In various embodiments, the caregiver or information provider maintains physical proximity to the patient for at least 8 hours after administration of the dexmedetomidine or pharmaceutically acceptable salt thereof. In various embodiments, the dexmedetomidine or pharmaceutically acceptable salt thereof is self-administered by the patient.

[0012] In embodiments, the non-clinical setting is a home, hi embodiments, the non-clinical setting is a group home, an assisted living facility, a correctional facility, a hospice, or a long-term care facility.

[0013] In embodiments, the patient experiences no more than two episodes of agitation per week.

[0014] In various embodiments, the patient experiences at least one episode of agitation in the past month. For example, the patient may have at least one episode per month, at least two episodes per month, or at least three episodes of agitation per month. In various embodiments, the non-clinical setting may have an upper limit on episodes within a given period. For example, the patient may have a maximum of one, a maximum of two, a maximum of three, a maximum of four, a maximum of five, or a maximum of six episodes of agitation per month.

[0015] In embodiments, the agitation is mild or moderate. In embodiments, the agitation is acute. In embodiments, the agitation is not severe.

[0016] In various embodiments, the route of administration is oral mucosal (sublingual, buccal, or gingival). In various embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in an oral mucosal dosage form selected from the group consisting of a film, a wafer, a patch, a lozenge, a gel, a spray, a tablet, and a drop. In various embodiments, the dosage form is a thin film. In various embodiments, the dosage form is a sublingual film. In various embodiments, the dosage form is a buccal film. In various embodiments, the dosage form is a gingival film.

[0017] In various embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered as a single dose per day. In various embodiments, the total daily dose may be administered submucosally in the oral cavity multiple times (e.g., 1 to 4 times) at appropriate intervals (e.g., at least 0.5 hours apart) to achieve the desired effect, as a single unit dose, as multiple unit doses, or as a fraction (e.g., half of a unit dose) of one or more unit doses, or a combination thereof, to achieve the desired effect.

[0018] In various embodiments, a total daily dose of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt) is administered as the first dose and any second dose.

[0019] In various embodiments, the first dose is about 60 micrograms, about 70 micrograms, about 80 micrograms, about 90 micrograms, about 100 micrograms, about 110 micrograms, about 120 micrograms, or about 180 micrograms of dexmedetomidine hydrochloride. In various embodiments, the first dose is 60 micrograms of dexmedetomidine hydrochloride. In various embodiments, the first dose is 80 micrograms of dexmedetomidine hydrochloride.

[0020] In embodiments, the second dose is administered at least about 2 hours after administration of the first dose if the PEC score does not improve by more than 2. In embodiments, the patient is hemodynamically stable.

[0021] In various embodiments, the second dose is administered at least about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about 5.5 hours, about 6 hours, about 6.5 hours, about 7 hours, about 7.5 hours, about 8 hours, about 8.5 hours, about 9 hours, about 9.5 hours, about 10 hours, about 10.5 hours, about 11 hours, about 11.5 hours, about 12 hours, about 12.5 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours after administration of the first dose.

[0022] In various embodiments, the optional second dose is about 60 micrograms, about 70 micrograms, about 80 micrograms, about 90 micrograms, about 100 micrograms, about 110 micrograms, about 120 micrograms, or about 180 micrograms of dexmedetomidine hydrochloride. In various embodiments, the optional second dose is about 60 micrograms of dexmedetomidine hydrochloride. In various embodiments, the optional second dose is 80 micrograms of dexmedetomidine hydrochloride.

[0023] In embodiments, the present disclosure provides a method of treating acute agitation in a patient with schizophrenia in a non-clinical setting, comprising administering to the patient, via a caregiver or information provider, a total daily dose of about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, mucosally (e.g., sublingually, bucally, or gingivally).

[0024] In embodiments, the present disclosure provides a method of treating acute agitation in a patient with schizophrenia in a non-clinical setting, comprising administering to the patient, via a caregiver or information provider, a dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, mucosally (e.g., sublingually, bucally, or gingivally).

[0025] In embodiments, the present disclosure provides a method of treating acute agitation in a patient with schizophrenia in a non-clinical setting, comprising administering to the patient, via a caregiver or information provider, a dose of about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, mucosally (e.g., sublingually, bucally, or gingivally).

[0026] In various embodiments, the present disclosure provides a method of treating acute agitation in a patient with bipolar disorder (e.g., bipolar disorder Type I or bipolar disorder Type II) in a non-clinical setting, comprising administering to the patient, via a caregiver or information provider, a total daily dose of about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, mucosally (e.g., sublingually, bucally, or gingivally).

[0027] In various embodiments, the present disclosure provides a method of treating acute agitation in a patient with bipolar disorder (e.g., bipolar disorder Type I or bipolar disorder Type II) in a non-clinical setting, comprising administering to the patient, via a caregiver or information provider, a total daily dose of about 60 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, mucosally (e.g., sublingually, bucally, or gingivally).

[0028] In various embodiments, the present disclosure provides a method of treating acute agitation in a patient with bipolar disorder (e.g., bipolar disorder type I or bipolar disorder type II) in a non-clinical setting, comprising administering to the patient, via a caregiver or information provider, a dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, mucosally (e.g., sublingually, bucally, or gingivally).

[0029] In various embodiments, the present disclosure provides a method of treating acute agitation in a patient with bipolar disorder (e.g., bipolar disorder Type I or bipolar disorder Type II) in a non-clinical setting, comprising administering to the patient, via a caregiver or information provider, a dose of about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, mucosally (e.g., sublingually, bucally, or gingivally).

[0030] In embodiments, the present disclosure provides a method of treating acute agitation in a patient with schizophrenia in a non-clinical setting, comprising self-administering by the patient an oromucosal dosage form comprising about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0031] In embodiments, the present disclosure provides a method of treating acute agitation in a patient with schizophrenia in a non-clinical setting, comprising administering about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient.

[0032] In embodiments, the present disclosure provides a method of treating acute agitation in a patient with schizophrenia in a non-clinical setting, comprising self-administering by the patient an oromucosal dosage form comprising about 60 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0033] In embodiments, the present disclosure provides a method of treating acute agitation in a patient with schizophrenia in a non-clinical setting, comprising administering an oromucosal dosage form comprising about 60 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient.

[0034] In embodiments, the present disclosure provides a method of treating acute agitation in a patient with schizophrenia in a non-clinical setting, comprising self-administration by the patient of an oromucosal dosage form comprising about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0035] In embodiments, the present disclosure provides a method of treating acute agitation in a patient with schizophrenia in a non-clinical setting by administering an oromucosal dosage form comprising about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient.

[0036] In embodiments, the present disclosure provides a method of treating acute agitation in a patient with schizophrenia in a non-clinical setting, comprising self-administration by the patient of an oromucosal dosage form comprising about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0037] In embodiments, the present disclosure provides a method of treating acute agitation in a patient with schizophrenia in a non-clinical setting by administering an oromucosal dosage form comprising about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient.

[0038] In embodiments, the present disclosure provides a method of treating acute agitation in a patient with bipolar disorder (e.g., bipolar disorder Type I or bipolar disorder Type II) in a non-clinical setting, comprising self-administration by the patient of an oromucosal dosage form comprising about 60 micrograms to about 360 micrograms of dexmedetomidine, or a pharmaceutically acceptable salt thereof.

[0039] In embodiments, the present disclosure provides a method of treating acute agitation in a patient with bipolar disorder (e.g., bipolar disorder Type I or bipolar disorder Type II) in a non-clinical setting, comprising administering an oromucosal dosage form comprising about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient.

[0040] In embodiments, the present disclosure provides a method of treating acute agitation in a patient with bipolar disorder (e.g., bipolar disorder Type I or bipolar disorder Type II) in a non-clinical setting, comprising self-administration by the patient of an oromucosal dosage form comprising about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0041] In embodiments, the present disclosure provides a method of treating acute agitation in a patient with bipolar disorder (e.g., bipolar disorder Type I or bipolar disorder Type II) in a non-clinical setting, comprising administering an oromucosal dosage form comprising about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient.

[0042] In embodiments, the present disclosure provides a method of treating acute agitation in a patient with bipolar disorder (e.g., bipolar disorder Type I or bipolar disorder Type II) in a non-clinical setting, comprising self-administration by the patient of an oromucosal dosage form comprising about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0043] In embodiments, the present disclosure provides a method of treating acute agitation in a patient with bipolar disorder (e.g., bipolar disorder type I or bipolar disorder type II) in a non-clinical setting, comprising administering an oromucosal dosage form comprising about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient.

[0044] In embodiments, the present disclosure provides a two-stage method of treating acute agitation in a patient with bipolar disorder (eg, bipolar disorder type I or bipolar disorder type II).

[0045] In various embodiments, the first phase comprises administering to the patient, under the supervision of a physician, a unit dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the oral mucosa (e.g., sublingually, bucally, or gingivally), and the duration of the first phase is at least 8 hours.

[0046] In various embodiments, the second phase comprises administering to the patient, under non-physician supervision (in a non-clinical setting), a unit dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the oral mucosa (e.g., sublingually, bucally, or gingivally), and the duration of the second phase is up to 12 weeks.

[0047] In embodiments, the present disclosure provides a method of treating acute agitation in a patient with bipolar disorder (e.g., bipolar disorder type I or bipolar disorder type II), the method comprising: (a) administering to a patient under the supervision of a physician a unit dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the oral mucosa (e.g., sublingually, bucally, or gingivally) for at least 8 hours; (b) administering to the patient under non-physician supervision (in a non-clinical setting) a unit dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the oral mucosa (e.g., sublingually, bucally, or gingivally) for up to 12 weeks.

[0048] In embodiments, the present disclosure provides a two-stage method for treating acute agitation in a patient with schizophrenia.

[0049] In various embodiments, the first phase comprises administering to the patient, under the supervision of a physician, a unit dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the oral mucosa (e.g., sublingually, bucally, or gingivally), and the duration of the first phase is at least 8 hours.

[0050] In various embodiments, the second phase comprises administering to the patient, under non-physician supervision (in a non-clinical setting), a unit dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the oral mucosa (e.g., sublingually, bucally, or gingivally), and the duration of the second phase is up to 12 weeks.

[0051] In embodiments, the present disclosure provides a method of treating acute agitation in a patient with schizophrenia, the method comprising: (a) administering to a patient under the supervision of a physician a unit dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the oral mucosa (e.g., sublingually, bucally, or gingivally) for at least 8 hours; (b) administering to the patient under non-physician supervision (in a non-clinical setting) a unit dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the oral mucosa (e.g., sublingually, bucally, or gingivally) for up to 12 weeks.

[0052] In embodiments, the oral mucosal dosage form is selected from the group consisting of a film, a wafer, a patch, a lozenge, a gel, a spray, a tablet, and a drop. In embodiments, the dosage form is a sublingual, or buccal, or gingival film.

[0053] In various embodiments, administration of an oromucosal dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof provides an anti-agitation effect within about 30 minutes after administration. In various embodiments, administration of an oromucosal dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof provides an anti-agitation effect within about 20 minutes after administration. In various embodiments, administration of an oromucosal dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof provides an anti-agitation effect within about 15 minutes after administration.

[0054] In embodiments, agitation is treated without inducing significant sedation. In embodiments, treatment is effective with reduced or no side effects (e.g., cardiac or respiratory side effects).

[0055] In embodiments, patients achieve a mean change in PEC score of greater than -7 relative to baseline within 30 minutes of administration. In embodiments, patients achieve an improvement in CGI-I score to about 1 (very improved) or about 2 (much improved). In embodiments, agitation, as measured by the Agitation and Sedation Scale (ACES), is reduced to 2 (moderate agitation), 3 (mild agitation), or 4 (normal behavior) 30 minutes after administration.

[0056] In embodiments, a caregiver or informant is alerted to the patient's impending agitation episode via an Ecological Momentary Assessment (EMA) device or other remotely enabled device. In embodiments, the EMA device is monitored by the caregiver or informant. In embodiments, the EMA device comprises the caregiver's or informant's smartphone or tablet with an application installed to report patient observations.

[0057] In embodiments, the caregiver or information is altered via an Ecological Momentary Assessment (EMA) device or other remotely enabled device to reduce the patient's agitation.

[0058] In embodiments, the alert is received in the form of a text message, call, sound, or window flashing / display on the caregiver or information provider device.

[0059] In embodiments, patient observations are recorded from one or more wearable devices (or wearable sensors) worn / placed / attached to the patient's body.

[0060] In embodiments, the wearable device (or wearable sensor) is in contact with the patient and may be selected from an iPhone (BYOD or provisioned), an accelerometer, a gyroscope, a portable device, a digital device, a smart fabric, a band, and an actuator like an Apple Watch or iWatch, a patch such as an MC10 patch, a sensor like a Microsoft Kinect, etc. In embodiments, the wearable device is a bracelet, an anklet, a shoe, an armband, a thigh band, or a mitten. In embodiments, the wearable device is a smartwatch, a ring, a patch, a conductive tattoo, a head wearable. In embodiments, the wearable device is a wrist-worn multi-sensor device with network capabilities (e.g., a wearable watch such as an Apple watch).

[0061] In embodiments, the patient, caregiver, or informant records observations in an agitation episode diary for each episode of agitation. In embodiments, the agitation episode diary includes questions based on safety information, emergency service use, use of other concomitant medications, and drowsiness. In embodiments, the agitation episode diary includes questions based on efficacy information (Yes / No), mCGI-S, CGI-C, Agitation Behavior Scale (informant only), use of study medication, or use of rescue medication after taking the study medication.

[0062] In embodiments, the present disclosure provides individual unit oral mucosal film dosage forms provided as a kit, the kit comprising: (i) about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) instructions for administering (i) to a patient with schizophrenia or bipolar disorder in need thereof; The dosage form is administered to treat acute agitation in a patient in a non-clinical setting.

[0063] In embodiments, the present disclosure provides individual unit oral mucosal film dosage forms provided as a kit, the kit comprising: (iii) about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; (iv) instructions for administering (i) to a patient with schizophrenia or bipolar disorder in need thereof; The dosage form is administered to treat acute agitation in a patient in a non-clinical setting.

[0064] In embodiments, the present disclosure provides individual unit oral mucosal film dosage forms provided as a kit, the kit comprising: (i) about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) instructions for administering (i) to a patient with schizophrenia or bipolar disorder in need thereof; The dosage form is administered in a non-clinical setting to treat mild to moderate agitation in patients. [Brief explanation of the drawings]

[0065] [Figure 1] 1 shows the mean change from baseline over time in PEC total score in patients with schizophrenia and / or bipolar disorder treated with a sublingual film containing dexmedetomidine hydrochloride (60 μg) compared to the placebo group. [Figure 2] 1 shows the proportion of responders over time in the PEC total score in patients with schizophrenia and / or bipolar disorder treated with a sublingual film containing dexmedetomidine hydrochloride (60 μg) compared to the placebo group. [Figure 3] 1 shows the change in CGI scores over time in patients with schizophrenia and / or bipolar disorder treated with a sublingual film containing dexmedetomidine hydrochloride (60 μg) compared to a placebo group. [Figure 4] 1 shows the proportion of responders over time in CGI-I scores in patients with schizophrenia and / or bipolar disorder treated with a sublingual film containing dexmedetomidine hydrochloride (60 μg) compared to a placebo group. [Figure 5A]1 shows the mean change from baseline over time in PEC total score by primary diagnosis in a subgroup of patients (n=129) with schizophrenia treated with a sublingual film containing dexmedetomidine hydrochloride (60 μg) compared to the placebo group. [Figure 5B] 1 shows the mean change from baseline in PEC total score by primary diagnosis in the subgroup of patients with bipolar disorder (n=72) treated with a sublingual film containing dexmedetomidine hydrochloride (60 μg) compared with the placebo group (n=43). DETAILED DESCRIPTION OF THE INVENTION

[0066] Abbreviation: Abbreviation ACES: Agitation and Sedation Rating Scale AEoSI: Adverse Event of Special Interest AE: adverse event BID: Twice a day BMI: Body Mass Index CGI-I: Clinical Global Impression-Improvement CGI-S: Clinical Global Impression-Severity C-SSRS: Columbia-Suicide Severity Rating Scale Dex or DEX: dexmedetomidine DSM: Diagnostic and Statistical Manual of Mental Disorders ECG: electrocardiogram EDA: electrodermal activity EMA: Ecological Momentary Assessment HAM-D (or HDRS): Hamilton Depression Rating Scale MINI: Mini-Interview for Mental Illnesses for DSM-5 MW: molecular weight mm: millimeters mcg: microgram μg: microgram PANSS: Positive and Negative Symptom Scale PCRS: Placebo-Controlled Reminder Script PEC:PANSS excitement items PK: Pharmacokinetics SAE: Serious Adverse Event SAP: Statistical Analysis Plan SBP: systolic blood pressure SL: sublingual TEAE: Treatment-emergent adverse event TSQM: Treatment Satisfaction Questionnaire for Drug Therapy wt%: weight percent YMRS: Young Mania Rating Scale

[0067] Definition: Throughout this specification, numerical ranges are provided for certain quantities. These ranges should be understood to include all subranges within that range. Thus, a range of "50 to 80" includes all possible ranges within that range (e.g., 51 to 79, 52 to 78, 53 to 77, 54 to 76, 55 to 75, 60 to 70, etc.). Furthermore, every value within a given range may be an endpoint of the range encompassed thereby (e.g., the range 50 to 80 includes ranges with endpoints of 55 to 80, 50 to 75, etc.).

[0068] The term "a" or "an" refers to one or more of that entity. Thus, the terms "a" (or "an"), "one or more," and "at least one" are used interchangeably herein. In addition, reference to an "agent" by the indefinite article "a" or "an" does not exclude the possibility that more than one of the agents is present, unless the context clearly requires that one, and only one, of the agents be present. As used herein, "about" means ±10% of the indicated numerical value.

[0069] As used herein, the term "comprise" and its conjugations as used in the specification and claims are used in their open-ended sense, meaning that the items that follow the word are included, but items not specifically mentioned are not excluded. The disclosure may, as appropriate, "comprise," "consist," or "consist essentially of" the steps, elements, and / or reagents recited in the claims.

[0070] The term "pharmaceutically acceptable salt" refers to salts that are known to be non-toxic and are commonly used in pharmaceutical literature. Typical inorganic acids used to form such salts include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, hypophosphorous acid, and the like. Salts derived from organic acids, such as aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic and hydroxylalkandioic acids, aromatic acids, and aliphatic and aromatic sulfonic acids, may also be used. A preferred salt is the hydrochloride salt.

[0071] The term "effective amount" is interchangeable with "therapeutically effective dose" or "therapeutically effective amount" and refers to an amount sufficient to produce a desired effect. An effective amount is sufficient to cause improvement in a patient's condition (e.g., agitation). An effective amount may be administered in one or more administrations, applications, or dosages.

[0072] The terms "formulation" and "composition" are used interchangeably unless a different meaning is clearly intended.

[0073] The term "unit dose," "unit dosage," or "unit dosage form" means a physically discrete unit containing a predetermined amount of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0074] The term "pharmaceutically acceptable carrier" refers to a pharmacologically inactive substance to be used as a carrier. As used herein, the phrases "carrier" and "excipient" are used interchangeably unless otherwise clearly intended to have different meanings. The term "film" herein includes thin films of any shape, including rectangular, square, or other desired shapes. The film can be of any desired thickness and size so that it can be conveniently placed on the patient's oral mucosa (i.e., sublingually, buccally, or gingivally). For example, the film can be a relatively thin film having a thickness of about 20 micrometers to about 200 micrometers, or a somewhat thicker film having a thickness of about 20 micrometers to about 1000 micrometers. In various embodiments, the film can be even thicker, for example, having a thickness of greater than about 30 millimeters (mm).

[0075] The term "self-supporting" herein means that the film maintains its structural integrity during handling without the need for a support layer. Some flexibility in the film is intended and may be desirable.

[0076] As used herein, the term "therapeutic" refers to treatment and / or prophylaxis, depending on the context.

[0077] As used herein, the terms "treat," "treating," or "treatment," with respect to a particular disease or disorder, include alleviating, ameliorating, alleviating, or inhibiting the symptoms and / or pathology of the disease or disorder. Treatment may be measured as a level of reduction of at least 10% or more, preferably 20% or more, more preferably 40% or more, and even more preferably 60%.

[0078] As used herein, the term "agitation" refers to a disorder characterized by signs or symptoms of irritability, emotional outbursts, disordered thinking, or excessive motor and verbal activity, which may result from either dysfunction of specific brain regions, such as the frontal lobe, or dysfunction of neurotransmitter systems, such as the noradrenergic system. In embodiments, agitation may be caused by noradrenergic hyperarousal. As used herein without limitation, the term "signs and / or symptoms of agitation" includes excessive motor activity (e.g., pacing, rocking, marking, pointing, restlessness, repetitive stereotypes), verbal aggression (e.g., yelling, speaking excessively loudly, using abusive language, shrieking, yelling, threatening others), and physical aggression (e.g., grabbing, shoving, pushing, clenching fists, resisting, hitting others, kicking objects or people, scratching, biting, throwing objects, hitting oneself, slamming doors, tearing objects, and destroying property). In the present disclosure, an agitated patient may also exhibit aggression. Agitation may be acute. Agitation may be mild to moderate. An occurrence of "agitation" is referred to herein as an "agitated episode" or "agitated event."

[0079] The term "acute agitation" means agitation that occurs rapidly and has a sudden onset. Acute agitation can be associated with, for example, neurodegenerative and neuropsychiatric disorders, but it can be particularly present in neuropsychiatric conditions. If acute agitation is left untreated, it can lead to chronic agitation.

[0080] The term "mild agitation" includes low levels of symptoms and little impairment of function, "moderate agitation" includes some significant symptoms that interfere with functioning to some extent, and "severe agitation" includes agitated symptoms that interfere with all functioning.

[0081] The term "schizoaffective disorder" refers to a chronic mental health condition characterized primarily by symptoms of schizophrenia, such as hallucinations or delusions, and symptoms of mood disorders, such as mania and depression.

[0082] The term "schizophreniform disorder" refers to a type of psychosis with symptoms similar to those of schizophrenia but lasting less than six months. Symptoms of both disorders can include delusions, hallucinations, disorganized speech, disorganized or catatonic behavior, and social withdrawal.

[0083] The term "mania" refers to a psychological state in which a person experiences irrational euphoria, extremely intense mood, hyperactivity, and delusions. Mania (or a manic episode) is a common symptom of bipolar disorder. Mild or less severe forms of mania, which last for a short period (usually a few days), are called hypomania.

[0084] Terms such as "without significant sedation," "does not induce significant sedation," or "does not cause significant sedation" mean that the patient experiences a level of sedation equal to or less than Level 3 on the Ramsay Sedation Scale, meaning sedated but responsive to commands. In embodiments, dexmedetomidine may be administered to achieve a Richmond Agitation Sedation Scale (RASS)-1 ("mild sedation").

[0085] The term "significantly reduced" refers to a level of reduction of at least 10% or more, preferably 20% or more, more preferably 40% or more, even more preferably 60% or more, still more preferably 80% or more, and 90% or more compared to a control.

[0086] The terms "oral mucosal delivery" or "oral mucosal administration" and the like refer to administration to the oral mucosa, including delivery across any tissue of the oral cavity, pharynx, larynx, trachea, or upper gastrointestinal tract, and particularly including delivery across sublingual, buccal, gingival, and palatal mucosal tissues.

[0087] The term "sublingual" literally means "under the tongue" and refers to the method of administering a substance via the mouth in such a way that the substance is rapidly absorbed via the blood vessels located under the tongue rather than via the digestive tract. Sublingual absorption occurs through the highly vascularized sublingual mucosa, which allows the substance to reach the blood circulation directly, thereby allowing direct systemic administration unaffected by the gastrointestinal system and avoiding undesirable hepatic first-pass metabolism.

[0088] The term "buccal" refers to administration of the dosage form to the gums and inner lips or cheeks.

[0089] The term "gingival" refers to administration of a dosage form to the gingiva (gums) found in the human oral cavity, which surrounds part of the teeth.

[0090] As used herein, the term "clinical setting" refers to any service or treatment that must be administered by a medical professional or that must be diagnosed by a medical professional.

[0091] The term "non-clinical setting" is synonymous with "home care setting" or "home setting," "social setting," "outpatient care," or "outpatient" and refers to any service or treatment that does not require a medical professional to diagnose or administer. Typically, a non-clinical setting is outside of a hospital, e.g., a home, group home, assisted living facility, rehabilitation facility, hospice, or long-term care facility.

[0092] As used herein, the term "caregiver" refers to a person who cares for a patient with bipolar I disorder, bipolar II disorder, schizophrenia, schizoaffective disorder, or schizophreniform disorder. A caregiver can be, for example, a family member, a friend, or a social worker, or a paid person, depending on the patient's situation.

[0093] As used herein, the term "EDA" refers to electrical skin activity / response, also known as skin conductance response (an older term is "galvanic skin response").

[0094] The term "baseline" in medicine refers to information or other initial known values ​​found at the beginning of a study that are used for comparison with later data. The concept of a baseline is essential in everyday medical practice to establish relative, rather than absolute, meaning for data. PANSS-EC, also known as PEC, for patients with schizophrenia.

[0095] The term "heart rate variability" refers to the variation in the time intervals between heartbeats and reflects an individual's current health status.

[0096] As used herein, the term "EMA" or "Ecological Momentary Assessment" refers to the repeated sampling of a patient's current behavior and experiences in real time in their natural environment. The repeated measurements of data are used to analyze important characteristics of the dynamics of a phenomenon.

[0097] As used herein, the terms "wearable device" or "wearable sensor" refer to any device that can be worn / placed / attached to a patient's body and that can detect and process signals related to sympathetic nervous system activity and / or motor activity. This device can interface (e.g., remotely or otherwise) with any suitable corresponding device, such as an end-user display terminal, and will typically include a transducer, a transducer control module, a communication device, and a monitoring system or computer database. Physiological measurements can also be measured using both standard technology and miniaturized wearable devices, such as, for example, network-capable sensor devices (e.g., waist-worn, wrist-worn, finger-worn, etc.) (e.g., iPhones).

[0098] As used herein, the term "informant" refers to a person who is present most (but not all) of the time to assist in recording data and remind patients to take their medications. An informant merely informs, i.e., they report on the patient's condition but do not provide care.

[0099] As used herein, the term "EEG" refers to electroencephalography (EEG). EEG is an electrophysiological monitoring method for recording the electrical activity of the brain. EEG reflects the underlying electrical activity of neurons and provides information about the oscillations of neuronal populations, pathways of information flow, and neural activity networks. Active Agent:

[0100] Dexmedetomidine has the IUPAC name (+)4-(S)-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole. Dexmedetomidine as the monohydrochloride salt is primarily used as a drug for sedation of patients undergoing treatment in intensive care settings or to sedate patients before and / or during surgical and other procedures. The drug is currently sold under the trademark name "PRECEDEX®."

[0101] Pharmaceutically acceptable salts of dexmedetomidine that may be included herein generally include any suitable salt that has been or can be approved for human administration by the U.S. FDA or other appropriate foreign or domestic agency. Non-limiting examples of suitable pharmaceutically acceptable salts include salts of inorganic acids, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrosulfic acid, and hydroiodic acid. Other examples include salts derived from non-toxic organic acids, including acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid, or combinations of these acid salts. Exemplary salts include dexmedetomidine hydrochloride, dexmedetomidine hydrobromide, dexmedetomidine sulfate, dexmedetomidine sulfonate, dexmedetomidine phosphate, dexmedetomidine nitrate, dexmedetomidine formate, dexmedetomidine citrate, dexmedetomidine tartrate, dexmedetomidine malate, dexmedetomidine benzoate, dexmedetomidine salicylate, dexmedetomidine ascorbate, etc. In various embodiments, a deuterated form of dexmedetomidine or a pharmaceutically acceptable salt thereof may be included. Dosage:

[0102] In various embodiments, the dose of dexmedetomidine or a pharmaceutically acceptable salt thereof is in the range of about 5 micrograms to about 360 micrograms. Examples of suitable doses include about 5 micrograms to about 340 micrograms, about 5 micrograms to about 320 micrograms, about 5 micrograms to about 300 micrograms, about 5 micrograms to about 280 micrograms, about 5 micrograms to about 270 micrograms, about 5 micrograms to about 260 micrograms, about 5 micrograms to about 250 micrograms, about 5 micrograms to about 240 micrograms, about 5 micrograms to about 230 micrograms, about 5 micrograms to about 220 micrograms, about 5 micrograms to about 210 micrograms, about 5 micrograms to about 200 micrograms, about 5 micrograms to about 190 micrograms, about 5 micrograms to about 180 micrograms, about 5 micrograms to about 170 micrograms, about 5 micrograms to about 160 micrograms, and about 5 micrograms to about 280 micrograms. The dose may range from about 100 micrograms to about 150 micrograms, about 5 micrograms to about 140 micrograms, about 5 micrograms to about 130 micrograms, about 5 micrograms to about 120 micrograms, about 5 micrograms to about 110 micrograms, about 5 micrograms to about 100 micrograms, about 10 micrograms to about 90 micrograms, about 10 micrograms to about 80 micrograms, about 10 micrograms to about 70 micrograms, about 10 micrograms to about 60 micrograms, about 10 micrograms to about 50 micrograms, about 10 micrograms to about 40 micrograms, about 10 micrograms to about 35 micrograms, about 15 micrograms to about 35 micrograms, about 20 micrograms to about 50 micrograms, about 25 micrograms to about 40 micrograms, or about 25 micrograms to 35 micrograms. This dose may be administered once or more times daily (including two, three, four, five, or six times daily). In various embodiments, the dose of dexmedetomidine or a pharmaceutically acceptable salt thereof may be administered twice daily. The dose may be administered to a patient "as needed" in one, two, or more doses per day.

[0103] In various embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered oromucosally (e.g., sublingually, bucally, or gingivally). In various embodiments, the unit dose of dexmedetomidine or a pharmaceutically acceptable salt thereof is about 10 micrograms, about 15 micrograms, about 20 micrograms, about 25 micrograms, about 30 micrograms, about 35 micrograms, about 40 micrograms, about 45 micrograms, about 50 micrograms, about 55 micrograms, about 60 micrograms, about 65 micrograms, about 70 micrograms, about 75 micrograms, about 80 micrograms, about 85 micrograms, about 90 micrograms, about 95 micrograms, about 100 micrograms, about 110 micrograms, about 120 micrograms, about 130 micrograms, about 140 micrograms, about 150 micrograms, about 160 micrograms, about 170 micrograms, or about 180 micrograms.

[0104] In various embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 30 micrograms. In various embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 40 micrograms. In various embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 50 micrograms. In various embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 60 micrograms. In various embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 70 micrograms. In various embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 80 micrograms. In various embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 90 micrograms. In various embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 100 micrograms. In various embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 110 micrograms. In various embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 120 micrograms. In various embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 130 micrograms. In various embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 140 micrograms. In various embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 150 micrograms. In various embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 160 micrograms.In various embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 170 micrograms. In various embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 180 micrograms. In various embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 190 micrograms. In various embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 200 micrograms. In various embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 210 micrograms. In various embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 220 micrograms. In various embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 230 micrograms. In various embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 240 micrograms. In various embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 260 micrograms. In various embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 280 micrograms. In various embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 300 micrograms. In various embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 320 micrograms. In various embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 340 micrograms.In various embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 360 micrograms.

[0105] The dosage of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) can depend on various factors, such as the type and severity of the condition, the general health of the particular patient, the particular form of dexmedetomidine being administered, and the particular formulation used to treat the patient. Methods and Administration:

[0106] In embodiments, the present disclosure provides a method of treating agitation in a patient with schizophrenia or bipolar disorder in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof to the patient at a dose of about 60 micrograms.

[0107] In embodiments, the present disclosure provides a method of treating agitation in a patient with schizophrenia or bipolar disorder in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof to the patient at a dose of about 80 micrograms.

[0108] In embodiments, the present disclosure provides a method of treating agitation in a patient with schizophrenia or bipolar disorder in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof to the patient at a dose of about 60 micrograms, wherein the patient is 18 years of age or older.

[0109] In embodiments, the present disclosure provides a method of treating agitation in a patient with schizophrenia or bipolar disorder in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof to the patient at a dose of about 80 micrograms, wherein the patient is 18 years of age or older.

[0110] In embodiments, the present disclosure provides a method of treating agitation in a patient with schizophrenia or bipolar disorder in a non-clinical setting, comprising administering dexmedetomidine, or a pharmaceutically acceptable salt thereof, to the patient in a total daily dose of about 60 micrograms to about 360 micrograms.

[0111] In embodiments, the present disclosure provides a method of treating agitation in a patient with schizophrenia or bipolar disorder in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof to the patient at a total daily dose of about 60 micrograms to about 360 micrograms, wherein the patient is 18 years of age or older.

[0112] In embodiments, the present disclosure provides a method of treating agitation in a patient with schizophrenia or bipolar disorder in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof to the patient in a total daily dose of about 60 micrograms to about 180 micrograms.

[0113] In embodiments, the present disclosure provides a method of treating agitation in a patient with schizophrenia or bipolar disorder in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof to the patient at a total daily dose of about 60 micrograms to about 180 micrograms, wherein the patient is 18 years of age or older.

[0114] In embodiments, the present disclosure provides a method of treating agitation in a patient with schizophrenia or bipolar disorder in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof to the patient at a total daily dose of about 80 micrograms to about 360 micrograms, wherein the patient is 18 years of age or older.

[0115] In embodiments, the present disclosure provides a method of treating acute agitation in a patient with schizophrenia or bipolar disorder in a non-clinical setting, comprising administering dexmedetomidine, or a pharmaceutically acceptable salt thereof, to the patient in a total daily dose of about 60 micrograms to about 360 micrograms.

[0116] In embodiments, the present disclosure provides a method of treating acute agitation in a patient with schizophrenia or bipolar disorder in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof to the patient at a total daily dose of about 60 micrograms to about 360 micrograms, wherein the patient is 18 years of age or older.

[0117] In embodiments, the present disclosure provides a method of treating acute agitation in a patient with schizophrenia or bipolar disorder in a non-clinical setting, comprising administering dexmedetomidine, or a pharmaceutically acceptable salt thereof, to the patient in a total daily dose of about 60 micrograms to about 180 micrograms.

[0118] In embodiments, the present disclosure provides a method of treating acute agitation in a patient with schizophrenia or bipolar disorder in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof to the patient at a total daily dose of about 60 micrograms to about 180 micrograms, wherein the patient is 18 years of age or older.

[0119] In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered by a caregiver or information provider of the patient. In embodiments, the caregiver or information provider is a family member or a family friend. In embodiments, the caregiver or information provider is dedicated to the patient. In embodiments, the caregiver or information provider is a social worker. In embodiments, the caregiver or information provider is a person employed by or for the patient. In embodiments, the caregiver or information provider maintains physical proximity to the patient for at least 8 hours after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0120] In various embodiments, the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient.

[0121] In embodiments, bipolar disorders include bipolar I disorder, bipolar II disorder, and bipolar mania. In embodiments, the bipolar disorder is bipolar I disorder. In embodiments, the bipolar disorder is bipolar II disorder. In embodiments, the bipolar disorder is bipolar mania.

[0122] In embodiments, schizophrenia includes schizoaffective disorder and schizophreniform disorder. In embodiments, schizophrenia is schizoaffective disorder. In embodiments, schizophrenia is schizophreniform disorder.

[0123] In embodiments, the patient experiences periodic episodes of agitation. In embodiments, the patient has a score of 4 or greater on at least one of the five items of the PEC at baseline. In embodiments, the patient has a total score of 14 or greater on the five items of the PEC at baseline. In embodiments, the patient has a score of 4 or less on the C-SSRS at baseline.

[0124] In embodiments, the agitation is mild or moderate. In embodiments, the agitation is not severe.

[0125] In various embodiments, the route of administration is oral mucosal (sublingual, buccal, or gingival). In various embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in an oral mucosal dosage form selected from the group consisting of a film, a wafer, a patch, a lozenge, a gel, a spray, a tablet, and a drop. In various embodiments, the dosage form is a thin film. In various embodiments, the dosage form is a sublingual film. In various embodiments, the dosage form is a buccal film. In various embodiments, the dosage form is a gingival film. Suitable films are described in U.S. Pat. No. 10,792,246, incorporated herein by reference in its entirety for all purposes.

[0126] In various embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered as a single dose per day. In various embodiments, the total daily dose may be administered submucosally in the oral cavity multiple times (e.g., 1 to 4 times) at an appropriate interval (e.g., at least 0.5 hours apart) to achieve the desired effect, as a single unit dose, multiple unit doses, or as a fraction (e.g., half of a unit dose) of one or more unit doses, or a combination thereof. In various embodiments, the dose of dexmedetomidine or a pharmaceutically acceptable salt thereof may be administered twice daily, for example, two 60 microgram unit doses administered approximately two hours apart to produce the effect of a 120 microgram dose.

[0127] In various embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (eg, dexmedetomidine hydrochloride) is administered as a first dose and an optional second dose.

[0128] In various embodiments, the first dose is about 60 micrograms, about 70 micrograms, about 80 micrograms, about 90 micrograms, about 100 micrograms, about 110 micrograms, about 120 micrograms, or about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof. In various embodiments, the first dose is about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0129] In various embodiments, the first dose is about 60 micrograms, about 70 micrograms, about 80 micrograms, about 90 micrograms, about 100 micrograms, about 110 micrograms, about 120 micrograms, or about 180 micrograms of dexmedetomidine hydrochloride. In various embodiments, the first dose is about 60 micrograms of dexmedetomidine hydrochloride.

[0130] In embodiments, the second dose is administered at least 2 hours after the administration of the first dose if the PEC score does not improve by more than 2. In embodiments, the patient is hemodynamically stable.

[0131] In various embodiments, the optional second dose is about 60 micrograms, about 70 micrograms, about 80 micrograms, about 90 micrograms, about 100 micrograms, about 110 micrograms, about 120 micrograms, or about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof. In various embodiments, the optional second dose is about 60 micrograms, about 70 micrograms, about 80 micrograms, about 90 micrograms, about 100 micrograms, about 110 micrograms, about 120 micrograms, or about 180 micrograms of dexmedetomidine hydrochloride. In various embodiments, the optional second dose is about 60 micrograms of dexmedetomidine hydrochloride. In various embodiments, the optional second dose is 80 micrograms of dexmedetomidine hydrochloride.

[0132] In various embodiments, the second dose is administered at least about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about 5.5 hours, about 6 hours, about 6.5 hours, about 7 hours, about 7.5 hours, about 8 hours, about 8.5 hours, about 9 hours, about 9.5 hours, about 10 hours, about 10.5 hours, about 11 hours, about 11.5 hours, about 12 hours, about 12.5 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours after administration of the first dose.

[0133] In various embodiments, a rescue medication is optionally administered to the patient after the second dose of dexmedetomidine in the event of persistent or uncontrollable agitation. In various embodiments, the rescue medication is selected from a benzodiazepine (e.g., alprazolam, clonazepam, lorazepam, oxazepam, midazolam, triazolam, chlordiazepoxide, clorazepate, diazepam, estazolam, flurazepam, temazepam, quazepam), or an antipsychotic selected from the group consisting of, but not limited to, aripiprazole, olanzapine, quetiapine, chlorpromazine, cariprazine, asenapine, clozapine, lurasidone, risperidone, and ziprasidone. In various embodiments, the rescue medication is lorazepam in a dose of about 4 mg. In various embodiments, the rescue medication is oxazepam in a dose of about 60 mg. In embodiments, the rescue medication is chlorpromazine in a dose of about 300 mg.

[0134] In embodiments, the agitation is acute.

[0135] In embodiments, the patient experiences five or fewer episodes of agitation per week. In embodiments, the patient experiences three or fewer episodes of agitation per week. In embodiments, the patient experiences two or fewer episodes of agitation per week. In embodiments, the patient has experienced at least one episode of agitation in the past month.

[0136] In embodiments, the patient experiences no more than five episodes of agitation per month. In embodiments, the patient experiences no more than three episodes of agitation per month. In embodiments, the patient experiences no more than two episodes of agitation per month.

[0137] In embodiments, the present disclosure provides a method of treating acute agitation in a patient with schizophrenia in a non-clinical setting, comprising administering to the patient, via a caregiver or information provider, a total daily dose of about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, mucosally (e.g., sublingually, bucally, or gingivally).

[0138] In embodiments, the present disclosure provides a method of treating acute agitation in a patient with schizophrenia in a non-clinical setting, comprising administering to the patient, via a caregiver or information provider, a total daily dose of about 60 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, mucosally (e.g., sublingually, bucally, or gingivally).

[0139] In embodiments, the present disclosure provides a method of treating acute agitation in a patient with schizophrenia in a non-clinical setting, comprising administering to the patient, via a caregiver or information provider, about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, mucosally (e.g., sublingually, bucally, or gingivally).

[0140] In embodiments, the present disclosure provides a method of treating acute agitation in a patient with schizophrenia in a non-clinical setting, comprising administering to the patient, via a caregiver or information provider, about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, mucosally (e.g., sublingually, bucally, or gingivally).

[0141] In various embodiments, the present disclosure provides a method of treating acute agitation in a patient with bipolar disorder (e.g., bipolar disorder Type I or bipolar disorder Type II) in a non-clinical setting, comprising administering to the patient, via a caregiver or information provider, a total daily dose of about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, mucosally (e.g., sublingually, bucally, or gingivally).

[0142] In various embodiments, the present disclosure provides a method of treating acute agitation in a patient with bipolar disorder (e.g., bipolar disorder Type I or bipolar disorder Type II) in a non-clinical setting, comprising administering to the patient, via a caregiver or information provider, a total daily dose of about 60 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, mucosally (e.g., sublingually, bucally, or gingivally).

[0143] In various embodiments, the present disclosure provides a method of treating acute agitation in a patient with bipolar disorder (e.g., bipolar disorder type I or bipolar disorder type II) in a non-clinical setting, comprising administering to the patient, via a caregiver or information provider, about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, mucosally (e.g., sublingually, bucally, or gingivally).

[0144] In various embodiments, the present disclosure provides a method of treating acute agitation in a patient with bipolar disorder (e.g., bipolar disorder Type I or bipolar disorder Type II) in a non-clinical setting, comprising administering to the patient, via a caregiver or information provider, about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, mucosally (e.g., sublingually, bucally, or gingivally).

[0145] In embodiments, the present disclosure provides a method of treating acute agitation in a patient with schizophrenia in a non-clinical setting, comprising self-administering by the patient an oromucosal dosage form comprising about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0146] In embodiments, the present disclosure provides a method of treating acute agitation in a patient with schizophrenia in a non-clinical setting, comprising administering an oromucosal dosage form comprising about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient.

[0147] In embodiments, the present disclosure provides a method of treating acute agitation in a patient with schizophrenia in a non-clinical setting, comprising self-administration by the patient of an oromucosal dosage form comprising about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0148] In embodiments, the present disclosure provides a method of treating acute agitation in a patient with schizophrenia in a non-clinical setting, comprising an oromucosal dosage form comprising about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient.

[0149] In embodiments, the present disclosure provides a method of treating acute agitation in a patient with schizophrenia in a non-clinical setting, comprising self-administration by the patient of an oromucosal dosage form comprising about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0150] In embodiments, the present disclosure provides a method of treating acute agitation in a patient with schizophrenia in a non-clinical setting, comprising administering an oromucosal dosage form comprising about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient.

[0151] In embodiments, the present disclosure provides a method of treating acute agitation in a patient with bipolar disorder (e.g., bipolar disorder Type I or bipolar disorder Type II) in a non-clinical setting, comprising self-administration by the patient of an oromucosal dosage form comprising about 60 micrograms to about 360 micrograms of dexmedetomidine, or a pharmaceutically acceptable salt thereof.

[0152] In embodiments, the present disclosure provides a method of treating acute agitation in a patient with bipolar disorder (e.g., bipolar disorder Type I or bipolar disorder Type II) in a non-clinical setting, comprising administering an oromucosal dosage form comprising about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient.

[0153] In embodiments, the present disclosure provides a method of treating acute agitation in a patient with bipolar disorder (e.g., bipolar disorder Type I or bipolar disorder Type II) in a non-clinical setting, comprising self-administration by the patient of an oromucosal dosage form comprising about 60 micrograms to about 180 micrograms of dexmedetomidine, or a pharmaceutically acceptable salt thereof.

[0154] In embodiments, the present disclosure provides a method of treating acute agitation in a patient with bipolar disorder (e.g., bipolar disorder Type I or bipolar disorder Type II) in a non-clinical setting, comprising administering an oromucosal dosage form comprising about 60 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient.

[0155] In embodiments, the present disclosure provides a method of treating acute agitation in a patient with bipolar disorder (e.g., bipolar disorder Type I or bipolar disorder Type II) in a non-clinical setting, comprising self-administration by the patient of an oromucosal dosage form comprising about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0156] In embodiments, the present disclosure provides a method of treating acute agitation in a patient with bipolar disorder (e.g., bipolar disorder Type I or bipolar disorder Type II) in a non-clinical setting, comprising administering an oromucosal dosage form comprising about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient.

[0157] In embodiments, the present disclosure provides a method of treating acute agitation in a patient with bipolar disorder (e.g., bipolar disorder Type I or bipolar disorder Type II) in a non-clinical setting, comprising self-administration by the patient of an oromucosal dosage form comprising about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0158] In embodiments, the present disclosure provides a method of treating acute agitation in a patient with bipolar disorder (e.g., bipolar disorder type I or bipolar disorder type II) in a non-clinical setting, comprising administering an oromucosal dosage form comprising about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient.

[0159] In embodiments, the present disclosure provides a two-stage method of treating acute agitation in a patient with bipolar disorder (eg, bipolar disorder type I or bipolar disorder type II).

[0160] In various embodiments, the first phase comprises administering to the patient, under the supervision of a physician, a unit dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the oral mucosa (e.g., sublingually, bucally, or gingivally), and the duration of the first phase is at least 8 hours.

[0161] In embodiments, the duration of the first phase is at least about 8 hours, at least about 8.5 hours, at least about 9 hours, at least about 9.5 hours, at least about 10 hours, at least about 10.5 hours, at least about 11 hours, at least about 11.5 hours, at least about 12 hours, at least about 12.5 hours, at least about 13 hours, at least about 13.5 hours, at least about 14 hours, at least about 14.5 hours, at least about 15 hours, at least about 20 hours, at least about 22 hours, or at least about 24 hours.

[0162] In various embodiments, the second phase comprises administering to the patient, under non-physician supervision (in a non-clinical setting), a unit dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the oral mucosa (e.g., sublingually, bucally, or gingivally), and the duration of the second phase is up to 12 weeks.

[0163] In embodiments, the present disclosure provides a method of treating acute agitation in a patient with bipolar disorder (e.g., bipolar disorder type I or bipolar disorder type II), the method comprising: (a) administering to a patient under the supervision of a physician a unit dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the oral mucosa (e.g., sublingually, bucally, or gingivally) for at least 8 hours; (b) administering to the patient under non-physician supervision (in a non-clinical setting) a unit dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the oral mucosa (e.g., sublingually, bucally, or gingivally) for up to 12 weeks.

[0164] In embodiments, the present disclosure provides a two-stage method for treating acute agitation in a patient with schizophrenia.

[0165] In various embodiments, the first phase comprises administering to the patient, under the supervision of a physician, a unit dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the oral mucosa (e.g., sublingually, bucally, or gingivally), and the duration of the first phase is at least 8 hours.

[0166] In embodiments, the duration of the first phase is at least about 8 hours, at least about 8.5 hours, at least about 9 hours, at least about 9.5 hours, at least about 10 hours, at least about 10.5 hours, at least about 11 hours, at least about 11.5 hours, at least about 12 hours, at least about 12.5 hours, at least about 13 hours, at least about 13.5 hours, at least about 14 hours, at least about 14.5 hours, at least about 15 hours, at least about 20 hours, at least about 22 hours, or at least about 24 hours.

[0167] In various embodiments, the second phase comprises administering to the patient, under non-physician supervision (in a non-clinical setting), a unit dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the oral mucosa (e.g., sublingually, bucally, or gingivally), and the duration of the second phase is up to 12 weeks.

[0168] In embodiments, the present disclosure provides a method of treating acute agitation in a patient with schizophrenia or bipolar disorder in a non-clinical setting, comprising administering to the patient, via a caregiver or information provider, a dosage form comprising about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, to the oral mucosa (e.g., sublingually, bucally, or gingivally).

[0169] In embodiments, the present disclosure provides a method of treating acute agitation in a patient with schizophrenia or bipolar disorder in a non-clinical setting, comprising administering to the patient, via a caregiver or information provider, a dosage form comprising about 60 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, mucosally (e.g., sublingually, bucally, or gingivally).

[0170] In embodiments, the present disclosure provides a method of treating acute agitation in a patient with schizophrenia or bipolar disorder in a non-clinical setting, comprising administering to the patient, via a caregiver or information provider, a dosage form comprising about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, to the oral mucosa (e.g., sublingually, bucally, or gingivally).

[0171] In embodiments, the present disclosure provides a method of treating acute agitation in a patient with schizophrenia or bipolar disorder in a non-clinical setting, comprising administering to the patient, via a caregiver or information provider, a dosage form comprising about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, to the oral mucosa (e.g., sublingually, bucally, or gingivally).

[0172] In embodiments, the present disclosure provides a method of treating mild to moderate agitation in a patient with schizophrenia or bipolar disorder in a non-clinical setting, comprising self-administration by the patient of an oromucosal dosage form comprising about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0173] In embodiments, the present disclosure provides a method of treating mild to moderate agitation in a patient with schizophrenia or bipolar disorder in a non-clinical setting, comprising administering an oromucosal dosage form comprising about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient.

[0174] In embodiments, the present disclosure provides a method of treating mild to moderate agitation in a patient with schizophrenia or bipolar disorder in a non-clinical setting, comprising self-administration by the patient of an oromucosal dosage form comprising about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0175] In embodiments, the present disclosure provides a method of treating mild to moderate agitation in a patient with schizophrenia or bipolar disorder in a non-clinical setting, comprising administering an oromucosal dosage form comprising about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient.

[0176] In embodiments, the present disclosure provides a method of treating mild to moderate agitation in a patient with schizophrenia or bipolar disorder in a non-clinical setting, comprising self-administration by the patient of an oromucosal dosage form comprising about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0177] In embodiments, the present disclosure provides a method of treating mild to moderate agitation in a patient with schizophrenia or bipolar disorder in a non-clinical setting, comprising administering an oromucosal dosage form comprising about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient.

[0178] In various embodiments, the diagnosis of schizophrenia or bipolar disorder is made according to DSM-IV criteria. The Diagnostic and Statistical Manual of Mental Disorders (DSM) is a handbook widely used by clinicians and psychiatrists to diagnose mental illnesses. It includes descriptions, symptoms, and other criteria for diagnosing mental health disorders. DSM-IV was first published in 1994 and describes over 250 mental disorders. An updated version, called DSM-IV-TR, was published in 2000 (TR stands for "Text Revision"). This version adopted a multiaxial or multidimensional approach to diagnosing mental disorders.

[0179] In embodiments, the patient experienced at least one clinical symptom of agitation requiring intervention in the previous month (i.e., the month before treatment was initiated). In embodiments, the patient experienced two or three (or more) episodes of agitation in the previous month (i.e., the month before treatment was initiated). In embodiments, the patient was clinically administered a medication for agitation. In embodiments, the patient experienced at least one episode of agitation in the month before emergency visit or needing medical services (i.e., the month before treatment was initiated).

[0180] In embodiments, the patient suffers from one or more co-morbid psychiatric disorders. In embodiments, the patient does not suffer from other co-morbid psychiatric disorders.

[0181] In various embodiments, the patient is not taking other medications (eg, an alpha-1 noradrenergic blocker and an alpha-2 adrenergic agonist) concomitantly.

[0182] In various embodiments, the patient is between about 18 and about 75 years old, e.g., about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46 about 47 years old, about 48 years old, about 49 years old, about 50 years old, about 51 years old, about 52 years old, about 53 years old, about 54 years old, about 55 years old, about 56 years old, about 57 years old, about 58 years old, about 59 years old, about 60 years old, about 61 years old, about 62 years old, about 63 years old, about 64 years old, about 65 years old, about 66 years old, about 67 years old, about 68 years old, about 69 years old, about 70 years old, about 71 years old, about 72 years old, about 73 years old, about 74 years old, or about 75 years old, including all values ​​and ranges therebetween.

[0183] In various embodiments, the patient is over 75 years of age. In various embodiments, the patient is about 65 to about 80 years of age, e.g., about 76 years of age, about 77 years of age, about 78 years of age, about 79 years of age, about 80 years of age, including all values ​​and ranges therebetween. In various embodiments, the patient is about 75 to about 80 years of age, e.g., about 75 years of age, about 76 years of age, about 77 years of age, about 78 years of age, about 79 years of age, or about 80 years of age, including all values ​​and ranges therebetween. In various embodiments, the patient is over 80 years of age, e.g., about 81 years of age, about 82 years of age, about 83 years of age, about 84 years of age, about 85 years of age, about 86 years of age, about 87 years of age, about 88 years of age, about 89 years of age, about 90 years of age, about 91 years of age, about 92 years of age, about 93 years of age, about 94 years of age, about 95 years of age, about 96 years of age, about 97 years of age, about 98 years of age, about 99 years of age, or about 100 years of age, including all values ​​and ranges therebetween.

[0184] In embodiments, the oral mucosal dosage form is selected from the group consisting of a film, a wafer, a patch, a lozenge, a gel, a spray, a tablet, and a drop. In embodiments, the dosage form is a sublingual, or buccal, or gingival film.

[0185] In various embodiments, administration of dexmedetomidine, a pharmaceutically acceptable salt thereof, or an oromucosal dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof provides an anti-agitation effect within about 120 minutes of administration without causing significant sedation. In various embodiments, administration of dexmedetomidine, a pharmaceutically acceptable salt thereof, or an oromucosal dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof provides an anti-agitation effect within about 60 minutes of administration without causing significant sedation. In various embodiments, administration of dexmedetomidine, a pharmaceutically acceptable salt thereof, or an oromucosal dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof provides an anti-agitation effect within about 30 minutes of administration without causing significant sedation. In various embodiments, administration of dexmedetomidine, a pharmaceutically acceptable salt thereof, or an oromucosal dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof provides an anti-agitation effect within about 20 minutes of administration without causing significant sedation. In various embodiments, administration of dexmedetomidine, a pharmaceutically acceptable salt thereof, or an oromucosal dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof provides an anti-agitation effect within about 15 minutes of administration without causing significant sedation.

[0186] In embodiments, the treatment is effective without causing clinically significant cardiovascular effects. In embodiments, the treatment is effective with reduced or no side effects (e.g., respiratory side effects). PCT Publication No. 2018 / 126182, the disclosure of which is incorporated herein by reference, discloses the treatment of agitation in a patient by administering dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the agitation is effectively treated without causing significant sedation.

[0187] In various embodiments, clinical improvement in agitation is measured using the PANSS, ACES, and / or CGI-I scale. In various embodiments, reduction in agitation is assessed by the relative change in PEC score after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof. In various embodiments, reduction in agitation is assessed by the relative change in CGI-S4 stage (0-3) scale after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0188] In embodiments, the reduction in agitation is assessed after an appropriate period of time, such as 0.5 hours, 1 hour, 2 hours, 4 hours, or 6 hours, following administration of the first dose of dexmedetomidine or a pharmaceutically acceptable salt thereof. In embodiments, the reduction in agitation is assessed prior to administration of a rescue medication to the patient.

[0189] In various embodiments, the patient achieves a mean change in PEC score of greater than -2, -3, -4, -5, -6, -7, -8, -9, or -10 relative to baseline within 30 minutes of administering the composition. In various embodiments, the patient achieves a mean change in PEC score of greater than -7 relative to baseline within 2 hours of administering dexmedetomidine or a pharmaceutically acceptable salt thereof. In various embodiments, the reduction in PEC score is maintained for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof. In various embodiments, the patient experiencing agitation has a baseline score of about 14 or greater on the PEC scale.

[0190] In embodiments, patients achieve an improvement in CGI-I score to about 1 (very improved) or about 2 (much improved). In embodiments, agitation, as measured by the Agitation and Sedation Scale (ACES), is reduced to 2 (moderate agitation), 3 (mild agitation), or 4 (normal behavior) 30 minutes after administration. In embodiments, the improvement in score is sustained for a period of about 2 hours to about 6 hours. In embodiments, patients experiencing agitation have a baseline CGI-I score of about 3 or greater.

[0191] In various embodiments, agitation, as measured by the Agitation and Sedation Scale (ACES), is reduced to 2 (moderate agitation), 3 (mild agitation), or 4 (normal behavior) 30 minutes after administration of the composition. In various embodiments, agitation is reduced to 3 (mild agitation). For example, an improved ACES score may be achieved within about 5 minutes, about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 60 minutes, about 70 minutes, about 80 minutes, about 90 minutes, about 100 minutes, about 110 minutes, or about 120 minutes. In various embodiments, patients experiencing agitation have a baseline ACES score of about 3 or less.

[0192] In various embodiments, the improvement in ACES score lasts for about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0193] In embodiments, the reduction in PEC, CGI-S, and ACES scores is maintained for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours after administration. In embodiments, a single administration of dexmedetomidine or a pharmaceutically acceptable salt thereof treats agitation and maintains sedative effects for at least 12 hours.

[0194] In various embodiments, the methods described herein improve the remaining signs and symptoms of schizophrenia following administration of dexmedetomidine or a pharmaceutically acceptable salt thereof, as measured by a decrease in PEC score of greater than -7 relative to baseline.

[0195] In embodiments, the methods described herein provide an improvement in the duration of sedation, as measured using a decrease in ACES score of 2 or more, following administration of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0196] Wearable / EMA devices: Agitation in patients with neuropsychiatric or neurodegenerative disorders can lead to patients becoming uncooperative with treatment and potentially violent and aggressive, posing a danger to themselves and their caregivers or informants. By detecting signals that indicate a patient is becoming agitated, the present disclosure combines a diagnostic and therapeutic component with dexmedetomidine to prevent the onset of an agitated episode. Thus, according to the present disclosure, dexmedetomidine can be used as a prophylactic or preventative treatment.

[0197] In some embodiments, a caregiver or information provider is alerted to an impending agitation episode via an Ecological Momentary Assessment (EMA) device or other remotely enabled device. In some embodiments, the EMA device is monitored by the caregiver or information provider. In some embodiments, the EMA device comprises a caregiver's or information provider's smartphone or tablet with an application installed for reporting patient observations. In some embodiments, the application on the caregiver's or information provider's device provides prompts for reporting side effects after dexmedetomidine administration. In some embodiments, the application on the caregiver's or information provider's device provides prompts for reporting the absence or presence of agitation episodes. In some embodiments, the caregiver or information provider reports information regarding the frequency or number of agitation episodes on an application installed on the EMA device. In some embodiments, the EMA device may be an end-user terminal capable of alerting the caregiver via a sound / alarm and / or display. In some embodiments, the alert is received in the form of a text message, call, sound, or window flashing / display on the caregiver's or information provider's device. Suitable examples of such devices are described in PCT Publication Nos. 2021 / 055595, 2021 / 163482, and 2021 / 163482, the contents of which are incorporated herein by reference.

[0198] In embodiments, predicting an agitation episode (or event) includes determining a time period during which the patient's agitation episode will occur and also includes determining the severity of the patient's agitation episode. In embodiments, predicting includes comparing the physiological data to a baseline value of at least one physiological parameter. In embodiments, a signal / alert is generated when the physiological data exceeds a threshold value of the baseline value.

[0199] In various embodiments, an impending episode of agitation is diagnosed by steps including: monitoring one or more physiological signals of the patient's sympathetic nervous system activity using a wearable device (or sensor) placed on or attached to the patient's skin surface; identifying when the patient is likely to have an agitation episode through processing of incoming data at the wearable device; and transmitting a signal from the wearable device to an EMA device or remote compatible device monitored by a caregiver or information provider, alerting the patient to an impending agitation episode.

[0200] In embodiments, the reduction in agitation is alerted to a caregiver or informant via an Ecological Momentary Assessment (EMA) device or other remotely enabled device.

[0201] In embodiments, an alert is sent to the patient to self-administer an oral mucosal dosage form comprising dexmedetomidine or a salt thereof. In embodiments, a caregiver or information provider determines that the patient would benefit from administration of dexmedetomidine, and the caregiver or information provider alerts the patient to administer an oral mucosal dosage form comprising dexmedetomidine or a salt thereof.

[0202] In embodiments, patient observations are recorded from one or more wearable devices (or wearable sensors) worn / placed / attached to the patient's body.

[0203] In embodiments, the wearable device (or wearable sensor) is in contact with the patient and may be selected from an iPhone (BYOD or provisioned), an accelerometer, a gyroscope, a portable device, a digital device, a smart fabric, a band, and an actuator such as an Apple Watch or iWatch, a patch such as an MC10 patch, a sensor such as a Microsoft Kinect, a wireless communication network and power source, and data acquisition technology for processing and decision support, or any conventional or non-conventional device / sensor performing a similar function.

[0204] In embodiments, the wearable device is a bracelet, anklet, shoe, armband, thigh band, or mitten. In embodiments, the wearable device is a smartwatch, ring, patch, conductive tattoo, or head wearable. In embodiments, the wearable device is a wrist-worn multi-sensor device with network capabilities (e.g., a wearable watch such as an Apple watch).

[0205] In embodiments, the wearable device monitors changes in the patient's sympathetic nervous system activity by measuring EDA over time.

[0206] EDA is the phenomenon whereby the skin momentarily becomes more electrically conductive when an external or internal stimulus that physiologically arouses the body is encountered. EDA is considered one of the most responsive physiological indicators of stress response and arousal. Research into EDA has led to important tools such as EEG. Wearable devices placed on a patient's skin monitor EDA by recording changes in the patient's skin's electrical resistance. Changes in sympathetic nervous system activity cause a slight increase in sweating and a decrease in skin resistance (because sweat contains water and electrolytes). These changes in skin electrical resistance are recorded by the wearable or sensing device.

[0207] In various embodiments, electrodermal activity is measured by clipping a monitoring device onto a patient's fingers, attaching electrodes to the middle phalanges of adjacent fingers on the hand, and measuring / analyzing EDA waveforms. Data obtained by the clipped device is then transferred to a computer database to which the monitoring device is connected, the computer database including one or more early warning algorithms. Based on the analyzed data, the early warning algorithm predicts early signs of the patient's onset of agitation and, based on operation of the early warning algorithm, generates a patient alert / warning to a caregiver or information provider that an anti-agitation medication should be administered.

[0208] The wearable device can also monitor other physiological signals, including heart rate variability such as resting EEG, cognitive function assessments such as pupil size, salivary amylase secretion, blood pressure, pulse rate, respiratory rate, blood oxygen level, and other signals associated with increased sympathetic nervous system activity.

[0209] In various embodiments, the wearable device records and collects objective data on integrated physiological parameters (EDA, resting EEG, blood pressure, mobility / movement, memory / processing, speech / sleep patterns, social engagement, etc.) A baseline value is calculated for the patient and any changes in physiological parameters such as EDA and / or resting EEG levels are statistically classified on a defined scale (0 to 5).

[0210] In various embodiments, the wearable device transmits information related to the increase in sympathetic nervous activity and physical activity to an EMA device (e.g., a smartphone or tablet) or to a device (e.g., a computer database) monitored by a caregiver or information provider. In various embodiments, the wearable device includes one or more early warning algorithms, an alert unit, and a storage unit for storing data related to the one or more alerts provided by the alert unit, i.e., previously detected increases in sympathetic nervous activity, data related to the patient, predetermined tolerances and thresholds, etc. In various embodiments, the wearable device comprises a display unit for displaying the stored data or measurements of one or more parameters.

[0211] In some embodiments, the wearable device also detects the severity of the agitation (e.g., mild, moderate, or severe). In some embodiments, the wearable device predicts the probability that a particular patient will transition from mild to moderate agitation, and the wearable device may also predict the probability of a severity change. In some embodiments, the probability of a severity change may be measured using predictions of at least one machine learning model (e.g., an agitation state detection model) to create and / or define a sequence of events. In some embodiments, the probability of a severity change includes estimating the conditional probability of changing states using a conditional random field or similar approach.

[0212] In embodiments, the patient, caregiver, or informant records observations in an agitation episode diary for each episode of agitation. In embodiments, the agitation episode diary includes questions based on safety information, emergency service use, use of other concomitant medications, and drowsiness. In embodiments, the agitation episode diary includes questions based on efficacy information (Yes / No), mCGI-S, CGI-C, Agitation Behavior Scale (informant only), use of study medication, or use of rescue medication after taking the study medication.

[0213] Pharmaceutical Composition: The compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art. Typically, these methods include the step of bringing into association the active ingredient (e.g., dexmedetomidine or a pharmaceutically acceptable salt thereof) with the carrier, which constitutes one or more accessory ingredients.

[0214] In various embodiments, the dosage form comprises: (i) about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) one or more mucoadhesives; and (iii) one or more pharmaceutically acceptable excipients or carriers, The dosage form disintegrates within about 5 seconds to about 10 minutes of contact with the oral mucosa, and the dosage form is administered in a non-clinical setting for the treatment of patients with schizophrenia or bipolar disorder who are in an acutely agitated state.

[0215] In embodiments, the non-clinical setting is a home. In embodiments, the non-clinical setting is a group home, assisted living facility, rehabilitation facility, hospice, or long-term care facility. In embodiments, the dosage form is self-administered by the patient or administered by a caregiver or information provider.

[0216] In various embodiments, the dosage form comprises: (i) about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) one or more mucoadhesives; and (iii) one or more pharmaceutically acceptable excipients or carriers, The dosage form disintegrates within about 5 seconds to about 10 minutes of contact with the oral mucosa, and the dosage form is administered in a non-clinical setting for the treatment of patients with schizophrenia or bipolar disorder who are in an acutely agitated state.

[0217] In various embodiments, the dosage form comprises: (i) about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) one or more mucoadhesives; and (iii) one or more pharmaceutically acceptable excipients or carriers, The dosage form disintegrates within about 5 seconds to about 10 minutes of contact with the oral mucosa, and the dosage form is administered in a non-clinical setting for the treatment of patients with schizophrenia or bipolar disorder who are in an acutely agitated state.

[0218] In embodiments, the non-clinical setting is a home. In embodiments, the non-clinical setting is a group home, assisted living facility, rehabilitation facility, hospice, or long-term care facility. In embodiments, the dosage form is self-administered by the patient or administered by a caregiver or information provider.

[0219] In various embodiments, the oromucosal dosage form is a tablet, capsule, patch, film, sachet, wafer, powder, minitablet, pellet, paste, gel, ointment, cream, drops, liquid (e.g., solution, suspension, or emulsion), spray, microsphere, or nanoparticle, which can be formulated according to standard methods in the art.

[0220] In various embodiments, the composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof is administered to the oral mucosa (sublingually / buccally or gingivally) in the form of a tablet, film, spray, gel, or drops. In various embodiments, the composition is in the form of a tablet or a packed powder. In various embodiments, the composition is in the form of a film. In various embodiments, the composition is a thin film. In various embodiments, the film is placed sublingually near the base of the left or right tongue. In various embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered bucally in the form of a film, patch, or tablet, particularly a film. In various embodiments, the film is placed against the lip or inside of the cheek near the jawline.

[0221] In various embodiments, the dosage form is an oral mucosal tablet for sublingual or buccal or gingival administration. In various embodiments, the dosage form is lyophilized (or freeze-dried). Examples of oral mucosal dosage forms include those described in U.S. Patent Nos. 6,509,040, 7,972,621, 10,548,839, 9,775,819, 5,188,825, 5,631,023, 6,297,240, 6,413,549, 5,976,577, 6,156,339, 5,827,541, and 5,776,577, which are incorporated herein by reference in their entirety for all purposes. Nos. 29,958, 6,726,928, 9,192,580, 6,709,669, U.S. Patent Application Publication No. 20200138721, 20190276707, 20190314274, 20040156894, PCT Publication No. 1999038496, PCT Publication No. 2000044351, and U.S. Patent Application Publication No. 20090226522 and related patents / patent applications.

[0222] In various embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered to a patient by intranasal administration or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as a solution in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art.

[0223] In various embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered to a patient in a single dosage form. In various embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered to a patient in a single dosage form multiple times daily (e.g., two, three, four, five times daily, etc.).

[0224] In various embodiments, the composition is an intranasal spray, particularly a spray comprising dexmedetomidine or a pharmaceutically acceptable salt thereof, such as those described in PCT Publication No. 2013 / 090278, the contents of which are incorporated herein by reference.

[0225] In various embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered to a patient by the oral route. In various embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is orally administered in the form of a tablet, an orally disintegrating tablet (ODT), an effervescent tablet, a capsule, a pellet, a pill, a lozenge or troche, a powder, a dispersible granule, a cachet, an aqueous solution, a syrup, an emulsion, a suspension, a solution, a soft gel, a dispersion, or the like. In various embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is orally administered to a patient in the form of an orally disintegrating tablet.

[0226] In embodiments, the compositions or dosage forms are conveniently delivered to the patient on an "as needed" basis, in one, two, or more doses per day. In embodiments, the dosage forms effectively treat agitation in the patient without causing significant sedation.

[0227] Oral mucosal preparations (sublingual and / or buccal or gingival preparations) Suitable formulations for use in accordance with the present disclosure are described in U.S. Patent Application Publication No. 2020 / 0000717, which is incorporated herein by reference in its entirety for all purposes.

[0228] According to the present disclosure, dexmedetomidine or a pharmaceutically acceptable salt thereof can be formulated into a dosage form suitable for oral mucosal (e.g., sublingual, buccal, or gingival) administration. Such dosage forms include tablets, powders, pills, films, capsules, liquids, gels, syrups, slurries, suspensions, etc. In various embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is formulated as a film product.

[0229] Carriers suitable for inclusion in oral mucosal (e.g., sublingual, buccal, or gingival) formulations include, but are not limited to, sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffer solutions, emulsifiers, isotonic saline, pyrogen-free water, and combinations thereof. Carriers that dissolve readily in saliva may be preferred.

[0230] Oral mucosal (e.g., sublingual, buccal, or gingival) formulations may also include other pharmaceutically acceptable carriers and / or excipients, such as binders, lubricants, diluents, coating agents, disintegrants, barrier layer components, glidants, colorants, solubility enhancers, gelling agents, fillers, proteins, cofactors, emulsifiers, solubilizers, suspending agents, and mixtures thereof. Specific excipients that may be used in accordance with the present disclosure are known in the art and are described, for example, in Handbook of Pharmaceutical Excipients, fifth edition, 2005, edited by Rowe et al., McGraw Hill.

[0231] film Films suitable for sublingual or buccal or gingival administration according to the present disclosure comprise dexmedetomidine or a pharmaceutically acceptable salt thereof either (i) disposed in a polymer matrix or (ii) deposited on the surface of a polymer matrix, e.g., on the surface of a "placebo" film.

[0232] Polymer components of the film The polymer component is comprised of one or more water-soluble polymers within the film matrix and / or as part of drug-containing deposits (e.g., one or more droplets) on the surface of the polymer. In various embodiments, the polymer component is comprised of a single water-soluble polymer. In various embodiments, the polymer component is comprised of two or more water-soluble polymers, including two or more of the same water-soluble polymers with different molecular weights.

[0233] The polymer component in the film matrix is ​​of suitable composition and present in an amount sufficient to ensure rapid disintegration of the film matrix in the oral mucosa. For example, the presence of the polymer component may enable the film matrix to completely disintegrate in the oral mucosa in about 15 seconds to about 180 seconds, e.g., about 30 seconds to about 180 seconds (including about 120 seconds). The polymer component in the film matrix also provides sufficient strength to the film (i.e., the film is self-supporting).

[0234] When present in one or more droplets of the dexmedetomidine composition deposited on the surface of a polymer matrix / substrate, the polymer component may comprise, for example, the water-soluble polymer hydroxypropyl cellulose; however, different water-soluble polymers are also contemplated, as described in the definitions of "first water-soluble polymer" and "second water-soluble polymer" herein below. For example, the polymer component may comprise one, two, or three hydroxypropyl celluloses having different molecular weights. Conveniently, the molecular weights of the different hydroxypropyl celluloses may range from (i) less than about 60,000 daltons (e.g., from about 5,000 daltons to about 49,000 daltons), (ii) from about 90,000 daltons to about 200,000 daltons, and (iii) from about 200,000 daltons to about 500,000 daltons. Two or more hydroxypropyl celluloses may be mixed in any suitable ratio to achieve a desired droplet viscosity. The viscosity of the dexmedetomidine composition solution or suspension can be measured using a Brookfield viscometer equipped with a small sample adapter at a temperature of 25°C and can range from about 5 cps to about 3700 cps. For example, the viscosity can range from about 5 cps to about 500 cps, about 6 cps to about 200 cps, about 6 cps to about 100 cps, or about 6 cps to about 50 cps. In some embodiments of the present disclosure, the viscosity of the dexmedetomidine composition solution or suspension is about 6 cps to about 20 cps at 25°C and a shear rate of about 7 (1 / sec).

[0235] In embodiments, (i) about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt); (ii) one or more water-soluble polymers; and (iii) polyethylene oxide; and (iv) optionally, one or more pharmaceutically acceptable carriers; The film is administered in a non-clinical setting by a caregiver or informant to a patient with schizophrenia or bipolar disorder who is in an acutely agitated state. In embodiments, the agitation is mild to moderate. In embodiments, the agitation is not severe.

[0236] In embodiments, (i) about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt); (ii) one or more water-soluble polymers; and (iii) polyethylene oxide; and (iv) optionally, one or more pharmaceutically acceptable carriers; The film is self-administered in a non-clinical setting by a patient with schizophrenia or bipolar disorder who is in a state of acute agitation. In embodiments, the agitation is mild to moderate. In embodiments, the agitation is not severe.

[0237] In embodiments, (i) about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt); (ii) one or more water-soluble polymers; and (iii) polyethylene oxide; and (iv) optionally, one or more pharmaceutically acceptable carriers; The film is self-administered in a non-clinical setting by a patient with schizophrenia or bipolar disorder who is in a state of acute agitation. In embodiments, the agitation is mild to moderate. In embodiments, the agitation is not severe.

[0238] In embodiments, (i) about 90 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt); (ii) one or more water-soluble polymers; and (iii) polyethylene oxide; and (iv) optionally, one or more pharmaceutically acceptable carriers; The film is administered in a non-clinical setting by a caregiver or informant to a patient with schizophrenia or bipolar disorder who is in an acutely agitated state. In embodiments, the agitation is mild to moderate. In embodiments, the agitation is not severe.

[0239] In embodiments, (i) about 90 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt); (ii) one or more water-soluble polymers; and (iii) polyethylene oxide; and (iv) optionally, one or more pharmaceutically acceptable carriers; The film is self-administered in a non-clinical setting by a patient with schizophrenia or bipolar disorder who is in a state of acute agitation. In embodiments, the agitation is mild to moderate. In embodiments, the agitation is not severe.

[0240] In embodiments, (i) about 120 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt); (ii) one or more water-soluble polymers; and (iii) polyethylene oxide; and (iv) optionally, one or more pharmaceutically acceptable carriers; The film is administered in a non-clinical setting by a caregiver or informant to patients with schizophrenia or bipolar disorder who are in an acutely agitated state.

[0241] In embodiments, the film is self-administered in a non-clinical setting by a patient in an acutely agitated state. In embodiments, the agitation is mild to moderate. In embodiments, the agitation is not severe.

[0242] In embodiments, (i) about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt); (ii) one or more water-soluble polymers; and (iii) polyethylene oxide; and (iv) optionally, one or more pharmaceutically acceptable carriers; The film is administered in a non-clinical setting by a caregiver or informant to a patient with schizophrenia or bipolar disorder who is in an acutely agitated state. In embodiments, the film is self-administered by the patient in a non-clinical setting. In embodiments, the agitation is mild to moderate. In embodiments, the agitation is not severe.

[0243] Medical Kit: The present disclosure provides individual unit dosage forms provided as a kit comprising a composition described herein in a container, with or without instructions for administration to a patient in need thereof, in various embodiments, the composition is a film for oral mucosal administration to a patient in a non-clinical setting.

[0244] In embodiments, the present disclosure provides individual unit oral mucosal film dosage forms provided as a kit, the kit comprising: (i) about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) instructions for administering (i) to a patient with schizophrenia or bipolar disorder in need thereof; The dosage form is administered to treat acute agitation in a patient in a non-clinical setting.

[0245] In embodiments, the present disclosure provides individual unit oral mucosal film dosage forms provided as a kit, the kit comprising: (i) about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) instructions for administering (i) to a patient with schizophrenia or bipolar disorder in need thereof; The dosage form is administered in a non-clinical setting to treat mild to moderate agitation in patients.

[0246] In embodiments, the present disclosure provides individual unit oral mucosal film dosage forms provided as a kit, the kit comprising: (i) about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) instructions for administering (i) to a patient with schizophrenia or bipolar disorder in need thereof; The dosage form is administered in a non-clinical setting to treat mild to moderate agitation in patients.

[0247] In embodiments, the present disclosure provides individual unit oral mucosal film dosage forms provided as a kit, the kit comprising: (i) about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) instructions for administering (i) to a patient with schizophrenia or bipolar disorder in need thereof; The dosage form is administered in a non-clinical setting to treat mild to moderate agitation in patients.

[0248] In embodiments, the agitation is not severe. In embodiments, the dosage form is administered to the patient via a caregiver or information provider. In embodiments, the dosage form is self-administered by the patient.

[0249] In various embodiments, the film dosage form comprises about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., hydrochloride). In various embodiments, the film dosage form comprises about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., hydrochloride). In various embodiments, the film dosage form comprises about 90 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., hydrochloride). In various embodiments, the film dosage form comprises about 120 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., hydrochloride). In various embodiments, the film dosage form comprises about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., hydrochloride). In various embodiments, the dosage form is administered sublingually. In various embodiments, the dosage form is administered bucally. In various embodiments, the dosage form is administered gingivally.

[0250] In embodiments, the kit includes a package insert containing instructions for using the compositions described herein to treat agitation in a patient. In embodiments, the agitation is acute. In embodiments, the agitation is mild to moderate.

[0251] In various embodiments, the total daily dose of dexmedetomidine is administered as a first dose and an optional second dose.

[0252] In various embodiments, a kit containing dexmedetomidine or a pharmaceutically acceptable salt thereof is provided as two dosage forms, with one dosage form administered followed by the other dosage form at an appropriate interval (e.g., two or more hours). In various embodiments, the two film dosage forms may be packaged separately and provided in the same or different containers. In various embodiments, one or both dosage forms contain about 60 micrograms of dexmedetomidine hydrochloride. In various embodiments, the dosage form contains about 120 micrograms of dexmedetomidine hydrochloride. In various embodiments, the dosage form contains about 180 micrograms of dexmedetomidine hydrochloride.

[0253] In various embodiments, the kits include containers, including, but not limited to, bottles, vials (e.g., dual-chamber vials), syringes (e.g., single- or dual-chamber syringes), and test tubes. The containers may be formed from a variety of materials, such as glass or plastic. In various embodiments, the kits may include a label or package insert (e.g., on or associated with the container).

[0254] The label or package insert may indicate that a compound contained therein may be useful or intended for treating acute agitation in patients with schizophrenia or bipolar disorder.

[0255] Specific Embodiments Embodiment 1. A method of treating agitation in a patient with schizophrenia or bipolar disorder in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof to the patient at a dose of about 60 micrograms, wherein the patient is 18 years of age or older.

[0256] Embodiment 2. A method of treating agitation in a patient with schizophrenia or bipolar disorder in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof to the patient at a dose of about 80 micrograms, wherein the patient is 18 years of age or older.

[0257] Embodiment 3. A method of treating acute agitation in a patient with schizophrenia in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof to the patient at a total daily dose of about 60 micrograms to about 360 micrograms, wherein the patient is 18 years of age or older.

[0258] Embodiment 4. A method of treating acute agitation in a patient with bipolar disorder in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof to the patient at a total daily dose of about 60 micrograms to about 360 micrograms, wherein the patient is 18 years of age or older.

[0259] Embodiment 5. A method of treating acute agitation in a patient with schizophrenia in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof to the patient at a total daily dose of about 60 micrograms to about 180 micrograms, wherein the patient is 18 years of age or older.

[0260] Embodiment 6. A method of treating acute agitation in a patient with bipolar disorder in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof to the patient at a total daily dose of about 60 micrograms to about 180 micrograms, wherein the patient is 18 years of age or older.

[0261] Embodiment 7. The method of any one of embodiments 1-6, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered by a caregiver or informant of the patient.

[0262] Embodiment 8. The method of embodiment 7, wherein the caregiver or informant is a family member, a family friend, a social worker, or any person recruited by or for the patient.

[0263] Embodiment 9. The method of any one of embodiments 1-6, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient.

[0264] Embodiment 10. The method of embodiment 1, 2, or 4, wherein the bipolar disorder comprises bipolar I disorder, bipolar II disorder, and bipolar mania.

[0265] Embodiment 11. The method of any one of embodiments 1-3, wherein the schizophrenia includes schizoaffective disorder and schizophreniform disorder.

[0266] Embodiment 12. The method of any one of embodiments 1-11, wherein the agitation is mild or moderate.

[0267] Embodiment 13. The method of any one of embodiments 1 to 11, wherein the agitation is not severe.

[0268] Embodiment 14. A method of treating acute agitation in a patient with schizophrenia in a non-clinical setting, comprising administering to the patient, via a caregiver or information provider, a total daily dose of about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, administered orally (e.g., sublingually, bucally, or gingivally).

[0269] Embodiment 15. A method of treating acute agitation in a patient with schizophrenia in a non-clinical setting, comprising administering to the patient, via a caregiver or informant, a dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, mucosally (e.g., sublingually, bucally, or gingivally).

[0270] Embodiment 16. A method of treating acute agitation in a patient with schizophrenia in a non-clinical setting, comprising administering to the patient, via a caregiver or informant, a dose of about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, mucosally (e.g., sublingually, bucally, or gingivally).

[0271] Embodiment 17. A method of treating acute agitation in a patient with bipolar disorder in a non-clinical setting, comprising administering to the patient, via a caregiver or information provider, a total daily dose of about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, administered orally (e.g., sublingually, bucally, or gingivally).

[0272] Embodiment 18. A method of treating acute agitation in a patient with bipolar disorder in a non-clinical setting, comprising administering to the patient, via a caregiver or information provider, a dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, mucosally (e.g., sublingually, bucally, or gingivally).

[0273] Embodiment 19. A method of treating acute agitation in a patient with bipolar disorder in a non-clinical setting, comprising administering to the patient, via a caregiver or information provider, a dose of about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, mucosally (e.g., sublingually, bucally, or gingivally).

[0274] Embodiment 20. A method of treating acute agitation in a patient with schizophrenia in a non-clinical setting, comprising administering an oromucosal dosage form comprising about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient.

[0275] Embodiment 21. A method of treating acute agitation in a patient with bipolar disorder in a non-clinical setting, comprising administering an oromucosal dosage form comprising about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient.

[0276] Embodiment 22. A method of treating acute agitation in a patient with bipolar disorder in a non-clinical setting, comprising administering an oromucosal dosage form comprising about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient.

[0277] Embodiment 23. A method of treating acute agitation in a patient with bipolar disorder in a non-clinical setting, comprising administering an oromucosal dosage form comprising about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or pharmaceutically acceptable salt thereof is self-administered by the patient.

[0278] Embodiment 24. A method of treating mild to moderate agitation in a patient with schizophrenia or bipolar disorder in a non-clinical setting is provided, comprising administering to the patient, via a caregiver or information provider, a dosage form comprising about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, mucosally (e.g., sublingually, bucally, or gingivally).

[0279] Embodiment 25. A method of treating mild to moderate agitation in a patient with schizophrenia or bipolar disorder in a non-clinical setting is provided, comprising administering to the patient, via a caregiver or information provider, a dosage form comprising about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, mucosally (e.g., sublingually, bucally, or gingivally).

[0280] Embodiment 26. A method of treating mild to moderate agitation in a patient with schizophrenia or bipolar disorder in a non-clinical setting is provided, comprising administering to the patient, via a caregiver or information provider, a dosage form comprising about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, mucosally (e.g., sublingually, bucally, or gingivally).

[0281] Embodiment 27. A method of treating mild to moderate agitation in a patient with schizophrenia in a non-clinical setting, comprising administering an oromucosal dosage form comprising about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient.

[0282] Embodiment 28. A method of treating mild to moderate agitation in a patient with schizophrenia in a non-clinical setting, comprising administering an oromucosal dosage form comprising about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient.

[0283] Embodiment 29. A method of treating mild to moderate agitation in a patient with schizophrenia in a non-clinical setting, comprising administering an oromucosal dosage form comprising about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient.

[0284] Embodiment 30. A method of treating mild to moderate agitation in a patient with bipolar disorder (bipolar I disorder or bipolar II disorder) in a non-clinical setting, comprising administering an oromucosal dosage form comprising about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient.

[0285] Embodiment 31. A method of treating mild to moderate agitation in a patient with bipolar disorder in a non-clinical setting, comprising administering an oromucosal dosage form comprising about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient.

[0286] Embodiment 32. A method of treating mild to moderate agitation in a patient with bipolar disorder in a non-clinical setting, comprising administering an oromucosal dosage form comprising about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient.

[0287] Embodiment 33. A method of treating acute agitation in a patient with bipolar disorder (e.g., bipolar disorder type I or bipolar disorder type II), comprising: (a) administering to the patient under the supervision of a physician a unit dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the oral mucosa (e.g., sublingually, bucally, or gingivally) for at least 8 hours (Step 1); (b) administering to the patient under non-physician supervision (in a non-clinical setting) a unit dose of about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the oral mucosa (e.g., sublingually, bucally, or gingivally) for up to 12 weeks (a second step).

[0288] Embodiment 34. A method of treating acute agitation in a patient with schizophrenia, comprising: (a) administering to the patient under the supervision of a physician a unit dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the oral mucosa (e.g., sublingually, bucally, or gingivally) for at least 8 hours (Step 1); (b) administering to the patient under non-physician supervision (in a non-clinical setting) a unit dose of about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the oral mucosa (e.g., sublingually, bucally, or gingivally) for up to 12 weeks (a second step).

[0289] Embodiment 35. The method of any one of embodiments 1 to 34, wherein the patient experiences periodic episodes of agitation.

[0290] Embodiment 36. The method of any one of embodiments 1 to 34, wherein the patient has a score of 4 or greater on at least one of the five items of the PEC at baseline.

[0291] Embodiment 37. The method of any one of embodiments 1 to 34, wherein the patient has a PEC five-item total score of 14 or greater at baseline.

[0292] Embodiment 38. The method of any one of embodiments 1 to 34, wherein the patient has a C-SSRS score of 4 or less.

[0293] Embodiment 39. The method of any one of embodiments 1 to 34, wherein the patient experiences no more than two episodes of agitation per week.

[0294] Embodiment 40. The method of any one of embodiments 1 to 34, wherein the patient suffers from one or more co-morbid psychiatric disorders.

[0295] Embodiment 41. The method of any one of embodiments 1 to 34, wherein the patient does not suffer from one or more co-morbid psychiatric disorders.

[0296] Embodiment 42. The method of any one of embodiments 1 to 34, wherein the patient is not taking any other medications concomitantly.

[0297] Embodiment 43. The method of any one of embodiments 1 to 34, wherein the patient is about 18 to about 75 years old.

[0298] Embodiment 44. The method of any one of embodiments 1 to 34, wherein the patient is about 75 years of age or older.

[0299] Embodiment 45. The method of any one of embodiments 1 to 34, wherein the route of administration is oral mucosa (sublingual, buccal, or gingival).

[0300] Embodiment 46. The method of embodiment 45, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in an oromucosal dosage form selected from the group consisting of a film, a wafer, a patch, a lozenge, a gel, a spray, a tablet, and drops.

[0301] Embodiment 47. The method of embodiment 45, wherein the dosage form is a thin film.

[0302] Embodiment 48. The method of embodiment 46 or 47, wherein the dosage form is a sublingual film.

[0303] Embodiment 49. The method of embodiment 46 or 47, wherein the dosage form is a buccal film.

[0304] Embodiment 50. The method of embodiment 46 or 47, wherein the dosage form is a gingival film.

[0305] Embodiment 51 The method of any one of the preceding embodiments, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered as a single dose per day.

[0306] Embodiment 52. The method of any one of the preceding embodiments, wherein a total daily dose of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., hydrochloride) is administered as a first dose and an optional second dose.

[0307] Embodiment 53. The method of embodiment 52, wherein the first dose is about 30 micrograms, about 40 micrograms, about 50 micrograms, about 60 micrograms, about 70 micrograms, about 80 micrograms, about 90 micrograms, about 100 micrograms, about 110 micrograms, about 120 micrograms, or about 180 micrograms of dexmedetomidine hydrochloride.

[0308] Embodiment 54. The method of embodiment 52 or 53, wherein the first dose is about 60 micrograms of dexmedetomidine hydrochloride.

[0309] Embodiment 55. The method of embodiment 52 or 53, wherein the first dose is about 80 micrograms of dexmedetomidine hydrochloride.

[0310] Embodiment 56. The method of embodiment 52, wherein the second dose is administered at least about 2 hours after administration of the first dose if the PEC score does not improve by more than 2 points.

[0311] Embodiment 57. The method of embodiment 54 or 56, wherein the second dose is administered at least about 0.5 hours, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about 5.5 hours, about 6 hours, about 6.5 hours, about 7 hours, about 7.5 hours, about 8 hours, about 8.5 hours, about 9 hours, about 9.5 hours, about 10 hours, about 10.5 hours, about 11 hours, about 11.5 hours, about 12 hours, about 12.5 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours after administration of the first dose.

[0312] Embodiment 58. The method of embodiment 52, 56, or 57, wherein the optional second dose is about 30 micrograms, about 40 micrograms, about 50 micrograms, about 60 micrograms, about 70 micrograms, about 80 micrograms, about 90 micrograms, about 100 micrograms, about 110 micrograms, about 120 micrograms, or about 180 micrograms of dexmedetomidine hydrochloride.

[0313] Embodiment 59. The method of embodiment 52 or 58, wherein the optional second dose is about 60 micrograms.

[0314] Embodiment 60. The method of embodiment 52 or 58, wherein the optional second dose is about 80 micrograms.

[0315] Embodiment 61. The method of any one of the preceding embodiments, wherein administration of dexmedetomidine, a pharmaceutically acceptable salt thereof, or an oromucosal dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt form thereof provides an anti-agitation effect within about 30 minutes after administration.

[0316] Embodiment 62. The method of any one of the preceding embodiments, wherein administration of dexmedetomidine, a pharmaceutically acceptable salt thereof, or an oromucosal dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt form thereof provides an anti-agitation effect within about 90 minutes after administration.

[0317] Embodiment 63. The method of any one of the preceding embodiments, wherein administration of dexmedetomidine, a pharmaceutically acceptable salt thereof, or an oromucosal dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof provides an anti-agitation effect within about 120 minutes after administration.

[0318] Embodiment 64. The method of any one of the preceding embodiments, wherein the agitation is treated without inducing significant sedation.

[0319] Embodiment 65. The method of any one of the preceding embodiments, wherein the treatment is effective with reduced or no side effects (e.g., cardiac or respiratory side effects).

[0320] Embodiment 66. The method of any one of the preceding embodiments, wherein the clinical improvement in agitation is measured using the PANSS, ACES, and / or CGI-I scales.

[0321] Embodiment 67. The method of any one of the preceding embodiments, wherein the reduction in agitation is assessed by the relative change in PEC score after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0322] Embodiment 68. The method of any one of the preceding embodiments, wherein the reduction in agitation is assessed by the relative change in the CGI-S4 stage (0 to 3) scale following administration of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0323] Embodiment 69. The method of any one of the preceding embodiments, wherein the patient achieves a mean change in PEC score relative to baseline of greater than -7 within 30 minutes of administration.

[0324] Embodiment 70. The method of any one of the preceding embodiments, wherein the patient achieves an improvement in CGI-I score to about 1 (very improved) or about 2 (much improved).

[0325] Embodiment 71. The method of any one of the preceding embodiments, wherein the agitation is reduced to 2 (moderate agitation), 3 (mild agitation), or 4 (normal behavior) 30 minutes after administration as measured by the Agitation and Sedation Scale (ACES).

[0326] Embodiment 72. The method of any one of the preceding embodiments, wherein the reduction in PEC, CGI-S, and ACES scores is maintained for at least 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours after administration.

[0327] Embodiment 73. The method of any one of the preceding embodiments, wherein a single administration of dexmedetomidine or a pharmaceutically acceptable salt thereof treats agitation and maintains sedative effects for at least 12 hours.

[0328] Embodiment 74. The method of any one of the preceding embodiments, wherein administration of dexmedetomidine provides an improvement in the duration of sedation, as measured using a decrease in ACES score of 2 or more, after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof.

[0329] Embodiment 75. The method of any one of the preceding embodiments, wherein administration of dexmedetomidine improves residual signs and symptoms of schizophrenia after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof, as measured by a decrease in PEC score of greater than −2 relative to baseline.

[0330] Embodiment 76. The method of any one of the preceding embodiments, wherein the caregiver or information provider is alerted of the impending agitation episode via an ecological momentary assessment (EMA) device or other remotely enabled device.

[0331] Embodiment 77. The method of any one of the preceding embodiments, wherein the reduction in agitation is alerted to the caregiver or information provider via an ecological momentary assessment (EMA) device or other remotely enabled device.

[0332] Embodiment 78. The method of any one of the preceding embodiments, wherein the reduction in agitation is assessed after an appropriate period, such as 0.5 hours, 1 hour, 2 hours, 4 hours, or 6 hours, following administration of the first dose of dexmedetomidine.

[0333] Embodiment 79. The method of any one of the preceding embodiments, wherein a rescue medication is optionally administered to the patient after the second dose of dexmedetomidine.

[0334] Embodiment 80. The method of any one of the preceding embodiments, wherein the reduction in agitation is assessed prior to administration of the rescue medication to the patient.

[0335] Embodiment 81. The method of embodiment 76 or 77, wherein the method includes a wearable device (or wearable sensor) in contact with the patient.

[0336] Embodiment 82. The method of embodiment 81, wherein the wearable device (or wearable sensor) may be selected from an iPhone (BYOD or provisioned), an accelerometer, a gyroscope, a portable device, a digital device, a smart fabric, a band, and an actuator such as an Apple Watch or iWatch, a patch such as an MC10 patch, a sensor such as a Microsoft Kinect, etc.

[0337] Embodiment 83. The method of embodiment 81 or 82, wherein the wearable device can be attached to the patient as a bracelet, anklet, shoe, armband, thigh band, or mitten.

[0338] Embodiment 84. The method described in embodiment 81 or 82, wherein the wearable device is a wrist-worn multi-sensor device with network functionality (e.g., a wearable watch such as an Apple watch).

[0339] Embodiment 85. The method of embodiment 76 or 77, wherein the EMA device comprises a smartphone or tablet having an application installed for reporting patient observations.

[0340] Embodiment 86. The method of embodiment 85, wherein the application on the caregiver's or information provider's EMA device provides a prompt to report the absence or presence of an episode of agitation.

[0341] Embodiment 87. The method described in embodiment 85, wherein the caregiver or information provider reports information regarding the frequency or number of agitation episodes on an application installed on an EMA device.

[0342] Embodiment 88. The method of embodiment 81, wherein the wearable device detects the severity of agitation (e.g., mild, moderate, or severe).

[0343] Embodiment 89. The method of embodiment 81, wherein the wearable device predicts the probability that a particular patient will progress from mild to moderate to severe agitation.

[0344] Embodiment 90. The method of embodiment 81, wherein the wearable device predicts the probability of a change in severity.

[0345] Embodiment 91. The method of embodiment 90, wherein the probability of the severity change can be measured using predictions of at least one machine learning model (e.g., an agitation detection model) to create and / or define a sequence of events.

[0346] Embodiment 92. The method of any one of the preceding embodiments, wherein the patient, caregiver, or informant records observations in an agitation episode diary for each episode of agitation.

[0347] Embodiment 93. The method of any one of the preceding embodiments, wherein the agitation episode diary includes questions based on safety information, use of emergency services, use of other concomitant medications, and drowsiness.

[0348] Embodiment 94. The method of any one of the preceding embodiments, wherein the agitation episode diary includes questions based on efficacy information (Yes / No) after taking a study medication, mCGI-S, CGI-C, Agitation Behavior Scale (informant only), use of study medication, or rescue medication use.

[0349] Embodiment 95. An oromucosal dosage form for the treatment of patients with schizophrenia or bipolar disorder in an acute agitated state in a non-clinical setting, comprising: (i) about 5 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) one or more mucoadhesives; and (iii) one or more pharmaceutically acceptable excipients or carriers; The oral mucosal dosage form disintegrates within about 5 seconds to about 10 minutes after coming into contact with the oral mucosa.

[0350] Embodiment 96. An oromucosal dosage form for the treatment of patients with schizophrenia or bipolar disorder in an acute agitated state in a non-clinical setting, comprising: (i) about 60 micrograms to about 300 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) one or more mucoadhesives; and (iii) one or more pharmaceutically acceptable excipients or carriers; The oral mucosal dosage form disintegrates within about 5 seconds to about 10 minutes after coming into contact with the oral mucosa.

[0351] Embodiment 97. An oromucosal dosage form for the treatment of patients with schizophrenia or bipolar disorder in an acute agitated state in a non-clinical setting, comprising: (i) about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) one or more mucoadhesives; and (iii) one or more pharmaceutically acceptable excipients or carriers; The oral mucosal dosage form disintegrates within about 5 seconds to about 10 minutes after coming into contact with the oral mucosa.

[0352] Embodiment 98. An oromucosal dosage form for the treatment of patients with schizophrenia or bipolar disorder in an acute agitated state in a non-clinical setting, comprising: (i) about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) one or more mucoadhesives; and (iii) one or more pharmaceutically acceptable excipients or carriers; The oral mucosal dosage form disintegrates within about 5 seconds to about 10 minutes after coming into contact with the oral mucosa.

[0353] Embodiment 99. An oromucosal dosage form for the treatment of patients with schizophrenia or bipolar disorder in an acute agitated state in a non-clinical setting, comprising: (i) about 120 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) one or more mucoadhesives; and (iii) one or more pharmaceutically acceptable excipients or carriers; The oral mucosal dosage form disintegrates within about 5 seconds to about 10 minutes after coming into contact with the oral mucosa.

[0354] Embodiment 100. An oromucosal dosage form for the treatment of a patient with schizophrenia or bipolar disorder in an acute agitated state in a non-clinical setting, comprising: (i) about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) one or more mucoadhesives; and (iii) one or more pharmaceutically acceptable excipients or carriers; The oral mucosal dosage form disintegrates within about 5 seconds to about 10 minutes after coming into contact with the oral mucosa.

[0355] Embodiment 101. The oromucosal dosage form of any of embodiments 95 to 100, wherein the non-clinical setting is a home or group home, an assisted living facility, a rehabilitation facility, a hospice, or a long-term care facility.

[0356] Embodiment 102. The oromucosal dosage form of embodiments 95-100, wherein the dosage form is self-administered by the patient.

[0357] Embodiment 103. The oromucosal dosage form of any one of embodiments 95 to 100, wherein the dosage form is administered by the caregiver or the information provider.

[0358] Embodiment 104. The oral mucosal dosage form of any one of embodiments 95 to 100, wherein the oral mucosal dosage form is a tablet, capsule, patch, film, sachet, wafer, powder, minitablet, pellet, paste, gel, ointment, cream, drops, liquid (e.g., solution, suspension, or emulsion), spray, microsphere, or nanoparticle.

[0359] Embodiment 105. The oral mucosal dosage form of embodiment 104, wherein the dosage form is an oral mucosal film (sublingual or buccal or gingival).

[0360] Embodiment 106. The oral mucosal dosage form of embodiment 105, wherein the dosage form is an oral mucosal tablet.

[0361] Embodiment 107. The oral mucosal dosage form of embodiment 106, wherein the tablet is freeze-dried.

[0362] Embodiment 108. An oral mucosal dosage form according to any one of embodiments 95 to 107, wherein the dosage form is advantageously delivered to the patient on an "as needed" basis, in one, two or more doses per day.

[0363] Embodiment 109. An oromucosal dosage form according to any one of embodiments 95 to 107, wherein the dosage form effectively treats agitation in a patient without causing significant sedation.

[0364] Embodiment 110. A self-supporting dissolvable film, comprising: (i) about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt); (ii) one or more water-soluble polymers; and (iii) polyethylene oxide; and (iv) optionally, one or more pharmaceutically acceptable carriers; The self-supporting dissolvable film is administered in a non-clinical setting by a caregiver or informant to a schizophrenic or bipolar patient in an acutely agitated state.

[0365] Embodiment 111. A self-supporting dissolvable film, comprising: (i) about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt); (ii) one or more water-soluble polymers; and (iii) polyethylene oxide; and (iv) optionally, one or more pharmaceutically acceptable carriers; The self-supporting dissolvable film, wherein the film is self-administered in a non-clinical setting by a patient with schizophrenia or bipolar disorder in an acutely agitated state.

[0366] Embodiment 112. A self-supporting dissolvable film, comprising: (i) about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt); (ii) one or more water-soluble polymers; and (iii) polyethylene oxide; and (iv) optionally, one or more pharmaceutically acceptable carriers; The self-supporting dissolvable film, wherein the film is self-administered in a non-clinical setting by a patient with schizophrenia or bipolar disorder in an acutely agitated state.

[0367] Embodiment 113. A self-supporting dissolvable film, comprising: (i) about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt); (ii) one or more water-soluble polymers; and (iii) polyethylene oxide; and (iv) optionally, one or more pharmaceutically acceptable carriers; The self-supporting dissolvable film is administered in a non-clinical setting by a caregiver or informant to a schizophrenic or bipolar patient in an acutely agitated state.

[0368] Embodiment 114. A self-supporting dissolvable film, comprising: (i) about 120 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt); (ii) one or more water-soluble polymers; and (iii) polyethylene oxide; and (iv) optionally, one or more pharmaceutically acceptable carriers; The self-supporting dissolvable film is administered in a non-clinical setting by a caregiver or informant to a patient with schizophrenia or bipolar disorder in an acutely agitated state.

[0369] Embodiment 115. A self-supporting dissolvable film, comprising: (i) about 120 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt); (ii) one or more water-soluble polymers; and (iii) polyethylene oxide; and (iv) optionally, one or more pharmaceutically acceptable carriers; The self-supporting dissolvable film, wherein the film is self-administered in a non-clinical setting by a patient with schizophrenia or bipolar disorder in an acutely agitated state.

[0370] Embodiment 116. An individual unit oral mucosal film dosage form provided as a kit, comprising: (i) about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) instructions for administering (i) to a patient with schizophrenia or bipolar disorder in need thereof; The kit, wherein the dosage form is administered to treat acute agitation in the patient in a non-clinical setting.

[0371] Embodiment 117. An individual unit oral mucosal film dosage form provided as a kit, comprising: (i) about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) instructions for administering (i) to a patient with schizophrenia or bipolar disorder in need thereof; The kit, wherein the dosage form is administered to treat mild to moderate agitation in the patient in a non-clinical setting.

[0372] Embodiment 118. The kit of embodiment 116 or 117, wherein the dosage form is administered to the patient via a caregiver or information provider.

[0373] Embodiment 119. The kit of embodiment 116 or 117, wherein the dosage form is self-administered by the patient.

[0374] Embodiment 120. The kit of embodiment 116, wherein the kit comprises a package insert containing instructions for using the dosage form for the treatment of acute agitation in a patient.

[0375] Embodiment 121. The kit or oromucosal dosage form of any one of embodiments 97 to 120, wherein the bipolar disorder includes bipolar I disorder, bipolar II disorder, and bipolar mania.

[0376] Embodiment 122. The kit or oromucosal dosage form of any one of embodiments 97 to 120, wherein the schizophrenia includes schizoaffective disorder and schizophreniform disorder.

[0377] Embodiment 123. A kit according to any one of embodiments 96 to 122, wherein the kit comprises dexmedetomidine or a pharmaceutically acceptable salt thereof provided as two dosage forms for administering one dosage form followed by the other dosage form at an appropriate time interval.

[0378] Embodiment 124. The kit of embodiment 123, wherein the two film dosage forms are packaged separately and provided in the same container.

[0379] Embodiment 125. The kit of embodiment 123, wherein the two film dosage forms are packaged separately and provided in different containers.

[0380] Embodiment 126. The kit of any one of embodiments 116-125, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is present in an amount of about 60 micrograms, about 70 micrograms, about 80 micrograms, about 90 micrograms, about 100 micrograms, about 110 micrograms, about 120 micrograms, or about 180 micrograms.

[0381] Embodiment 127. The kit of any one of embodiments 116 to 126, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is present in an amount of about 60 micrograms.

[0382] Embodiment 128. The kit of any one of embodiments 116 to 126, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is present in an amount of about 80 micrograms.

[0383] Embodiment 129. A kit described in any one of embodiments 116 to 128, wherein the film dosage form is administered sublingually, bucally, or gingivally.

[0384] Embodiment 130. The method, oromucosal dosage form, or kit of any one of the preceding embodiments, wherein the agitation is mild to moderate.

[0385] Embodiment 131. The method, oromucosal dosage form, or kit of any one of the preceding embodiments, wherein the agitation is not severe.

[0386] The details of the present disclosure, its objects and advantages are explained in more detail below with reference to non-limiting exemplary examples. [Example]

[0387] Example 1: To determine the efficacy and safety of dexmedetomidine hydrochloride sublingual film evaluated for home use in a multicenter, double-blind, placebo-controlled study for agitation associated with schizophrenia and bipolar disorder

[0388] the purpose: Main purpose: Part 1: To determine whether a 60 microgram dose of dexmedetomidine hydrochloride sublingual film effectively reduced symptoms of agitation, as assessed using the Positive and Negative Symptom Scale-Agitation Item (PEC) change from baseline compared with the change from baseline for placebo.

[0389] Part 2: To assess the safety of dexmedetomidine hydrochloride sublingual film when used in the home setting based on serious adverse events (SAEs) and treatment-emergent adverse events (TEAEs) collected by both informants and clinical investigators.

[0390] Secondary Objectives: Part 1: To determine overall clinical improvement after administration of study treatment as measured by the Clinical Global Impression-Improvement scale (CGI-I). To determine overall clinical improvement after drug administration as measured by the modified Clinical Global Impression-Severity scale (mCGI-S) administered by the investigator. Describe duration of sedation as measured by PEC and ACES. To determine the safety profile of dexmedetomidine hydrochloride sublingual film as assessed by TEAEs, serious TEAEs, vital sign measurements, electrocardiogram (ECG), and clinical laboratory results. Describe overall tolerability in terms of reporting of treatment-emergent adverse events.

[0391] Part 2: - Assess relief of signs and symptoms of agitation based on the modified CGI-S scale 2 hours after administration of the study treatment or before administering rescue medication, whichever occurs first. To determine the number / frequency of agitation episodes and the number and frequency of agitation episodes that are treated in the home setting. To determine the number of interactions with emergency services resulting from agitation episodes (specifically, hospitalizations, emergency room visits, urgent care visits, and law enforcement interventions).

[0392] Exploratory purpose: Part 1: To describe patients' opinions regarding the taste, acceptability, and preference of dexmedetomidine hydrochloride sublingual film. To evaluate patient satisfaction with dexmedetomidine hydrochloride sublingual film in the treatment of agitation episodes. The Treatment Satisfaction Questionnaire for Medication (TSQM) will be administered for this purpose at the end of the treatment period.

[0393] Part 2: To evaluate patient satisfaction with dexmedetomidine hydrochloride sublingual film in the treatment of agitation episodes. The Treatment Satisfaction Questionnaire for Medication (TSQM) will be administered for this purpose at the end of the treatment period.

[0394] Primary endpoint Part 1: Change in PEC score from baseline compared to placebo 2 hours after drug administration.

[0395] Part 2: Comparison of serious adverse events (SAEs) and TEAEs compared to placebo.

[0396] Secondary endpoints Part 1: · CGI-I assesses overall clinical improvement after drug administration. The mCGI-S assesses global clinical improvement after medication administration. Duration of remission is measured by PEC and ACES. The safety profile of dexmedetomidine hydrochloride sublingual film will be measured by adverse event (AE) reporting, vital sign measurements, ECG, and clinical laboratory results. Overall tolerability of the oral film will be assessed by TEAE reporting and local site (oral / sublingual) tolerability.

[0397] Part 2: Reduction of signs and symptoms of agitation will be assessed by the modified CGI-S score 2 hours after drug administration. Number and frequency of agitation episodes. · Number of interactions with emergency services related to agitation episodes reported by informants.

[0398] Exploratory endpoints Part 1: Patients' opinions regarding taste, acceptability, and liking of the study treatment will be assessed using a preference questionnaire. To assess patient satisfaction with dexmedetomidine hydrochloride sublingual film in the treatment of agitation episodes using the TSQM.

[0399] Part 2: To assess patient satisfaction with dexmedetomidine hydrochloride sublingual film in the treatment of agitation episodes using the TSQM.

[0400] Study Design: This is a Phase 3, randomized, double-blind, placebo-controlled, two-part study evaluating the efficacy, safety, and tolerability of a 60 microgram dose of dexmedetomidine hydrochloride sublingual film in adult (18-75 years) men and women with acute agitation associated with a primary diagnosis of bipolar I disorder, bipolar II disorder, schizophrenia, schizoaffective disorder, or schizophreniform disorder. The first part of the study consisted of a 1-day clinic treatment period for patients experiencing an acute episode of agitation, followed by a post-treatment observation period. The second part of the study was a 12-week study to determine the safety of dexmedetomidine hydrochloride sublingual film when used in a home setting to treat patients' episodes of agitation.

[0401] Each patient may only participate in part of the study. All patients enrolled will be individuals who have not previously received a dose of dexmedetomidine hydrochloride sublingual film or IGALMI™ M.

[0402] Part 1: Clinic-Based Implementation: During the clinic study period, patients will be randomized 1:1 to receive 60 mcg dexmedetomidine hydrochloride sublingual film or a matching placebo. Eligible patients may be identified in outpatient clinics, mental health centers, psychiatric or emergency medical services (including medical / psychiatric observation units), or as newly admitted patients for acute agitation or patients already hospitalized for an underlying major psychiatric disorder. Patients will reside or be admitted to the clinical research facility where they will be under medical observation while undergoing screening procedures to assess eligibility, during treatment, and for at least an 8-hour post-treatment observation period.

[0403] Randomization will not be formally stratified, but the randomization scheme will be designed so that no more than 70% of patients in each arm of the study will have a primary diagnosis of bipolar disorder (bipolar I or bipolar II) or schizophrenia (including schizoaffective disorder and schizophreniform disorder).

[0404] Once eligibility is confirmed, patients are randomized to receive either a 60 microgram dexmedetomidine hydrochloride sublingual film or a matching placebo. Upon administration, patients are instructed on how to administer the dexmedetomidine hydrochloride film sublingually and that it must be held in the sublingual cavity until dissolved. Patients self-administer under the supervision of a trained staff member. If a patient is unable to self-administer, the event is recorded and the patient's participation is terminated.

[0405] Patients will also assess for local irritation in the area where the film is placed. Efficacy and safety assessments will be performed periodically before and after administration.

[0406] Every effort must be made to have the patient complete all protocol-defined evaluations.

[0407] Rescue medications may be administered if warranted by the patient's condition (as determined by the investigator). Rescue medications may be either benzodiazepines (lorazepam at a maximum dose of 4 milligrams (mg) or oxazepam at a maximum dose of 60 mg) or any antipsychotic except clozapine, pimozide, or prochlorperazine (maximum dose approximately equivalent to 300 mg of chlorpromazine as specified by BioXcel and selected by the investigator).

[0408] Patients are required to remain in the clinic for a minimum of 8 hours of observation after administration of study treatment.

[0409] Efficacy, safety, tolerability, and pharmacokinetics (PK) will be assessed at various times throughout the treatment period (see Table 1: Part 1 Implementation Schedule for details).

[0410] Part 2: Community (Home) Environment Implementation: During the home study period, patients will be randomized 1:1 to receive either a 60-microgram sublingual dexmedetomidine hydrochloride film or a matching placebo film if an agitation episode occurs at home. Eligible patients will be individuals who experience regular episodes of agitation associated with a primary diagnosis of bipolar disorder or schizophrenia. Additionally, patients will need a reliable informant available to participate in study administration when agitation episodes are treated with study medication and during monthly clinic visits. Randomization will not be formally stratified, but the randomization scheme will be designed so that no more than 70% of patients in each arm of the study will have a primary diagnosis of bipolar disorder (bipolar I or bipolar II) or schizophrenia (including schizoaffective disorder and schizophreniform disorder).

[0411] Once eligibility is confirmed, patients and informants are instructed on how to administer the study treatment sublingually and that the patient must hold the study treatment in the sublingual cavity until it dissolves. Patients self-administer under the supervision of the informant. If the patient is unable to self-administer during the first agitation episode in which treatment is attempted, the event will be recorded and the patient's participation will be terminated. Informants and patients are also trained at screening regarding their responsibilities during the study, how to assess the severity of agitation using the mCGI-S, and the circumstances under which the informant can recommend that the patient self-administer study treatment and rescue medication doses. Patients are trained on when they can administer study treatment and rescue medication based on their own perception. Ideally, the informant will be present when the study treatment is administered, but if the patient feels the need, they can self-administer the study treatment even in the informant's absence.

[0412] The informant will be responsible for recording the start and end times of the agitation event via the Ecological Momentary Assessment (EMA) application, along with the times when study treatment and rescue medication (if needed) were administered. At several time points (see Table 3: In-Home Informant Assessment), the informant and patient assessor will be asked to rate the severity of the agitation episode. The informant will record both ratings in the EMA application.

[0413] The informant will also record all adverse events (AEs) reported by the patient within 8 hours of study treatment administration or rescue medication administration (whichever occurs last), as well as medications taken by the patient within 4 hours before and 4 hours after administration.

[0414] The information provider also records any interactions with emergency services via the EMA application (specifically, hospital admissions, emergency room visits, urgent care visits, interventions by other emergency services such as ambulance services, and interventions by law enforcement agencies).

[0415] Additionally, informants are prompted once daily by the EMA application to ask whether any agitation episodes occurred that were not reported at the time they occurred and to identify whether such unreported episodes required emergency services intervention. Informants and patients are prompted twice daily by the EMA application to provide their current mCGI-S ratings (see Table 3, Patient and Informant Ratings at Home).

[0416] Patients and informants will return to the clinic for follow-up visits 1 and 2 months (28 and 56 days) after the baseline visit, and a final study visit at the end of the 3-month (84-day) study (see Table 2: Part 2 Event Schedule).

[0417] At randomization and at follow-up visits 1 and 2, patients will be dispensed two packages, each containing one 60 mcg strip of dexmedetomidine sublingual film or matching placebo. If both packages are used before the next scheduled clinic visit, the patient or informant will need to come to the clinic to obtain two additional packages.

[0418] The investigator will also provide the patient with a prescription for a rescue medication of the investigator's choice, which can be either a benzodiazepine (lorazepam up to 4 mg or oxazepam up to 60 mg) or any antipsychotic except clozapine, pimozide, or prochlorperazine (maximum dose approximately equivalent to 300 mg of chlorpromazine as specified by BioXcel and selected by the investigator).

[0419] Planned Patient Number: In Part 1 of the study, approximately 200 patients will be enrolled at up to 20 study sites in the United States. In Part 2, approximately 250 patient-informant dyads will be enrolled at up to 20 study sites in the United States. The same sites will participate in Parts 1 and 2. Patients may participate in only part of the study (Part 1 or Part 2). Patients in both parts of the study will not have been previously treated with dexmedetomidine sublingual film or IGALMI™.

[0420] Eligibility Diagnosis and Main Criteria: Phase 1: Inclusion Criteria (Part 1 and Part 2) 1. Male and female patients aged 18 to 75 years. 2. Patients who are able to read, understand, and provide written informed consent. 3. Patients meeting DSM-5 / 5-TR criteria for a primary diagnosis of bipolar I or bipolar II disorder, schizophrenia, schizoaffective disorder or schizophreniform disorder. 4. Patients who, in the opinion of the investigator, are in good general health prior to study entry based on a detailed medical history, physical examination, 12-lead ECG with rhythm strips, blood chemistry profile, hematology, and urinalysis. 5. Female participants (if of childbearing potential and sexually active) and male participants (if sexually active with a partner of childbearing potential) who agree to use medically acceptable, effective contraception throughout the study and for one week after completion of the study. Medically acceptable contraception methods that participants and / or their partners may use include abstinence, birth control pills or patches, spermicide-containing diaphragms, intrauterine devices (IUDs), foam or spermicide-containing condoms, spermicide vaginal suppositories, surgical sterilization, and progestin implants or progestin injections. Prohibited methods include rhythm methods, withdrawal, condoms only, or diaphragms only.

[0421] Additional inclusion criteria for patients enrolled in Part 1: 6. Patients who are clinically determined to be agitated at screening and baseline, with a total score of 14 or greater on the five items (poor impulse control, tension, hostility, uncooperativeness, and agitation) that make up the PANSS-Agitation Item (PEC). 7. Patients with a score of 4 or higher on at least one of the five PEC items at baseline.

[0422] Additional inclusion criteria for patients enrolled in Part 2: 8. Based on medical history, within the past month, the patient must have had at least one clinical episode of agitation requiring intervention (e.g., receipt of PRN medication for the episode, clinic visit, emergency room visit, emergency medical services intervention, law enforcement intervention). 9. Patient is able to understand and comply with study procedures, including completing the EMA application assessment. 10. The patient will have an informant who is able to read and write, provide written informed consent, and comply with study procedures, including the evaluation of the EMA application and completing other EMA application required procedures during the study. Finally, the informant must accompany the participant to monthly clinic visits and be interviewed by the investigator to assess the mean mCGI-S for the period since the investigator's previous mCGI-S assessment.

[0423] Exclusion Criteria (Part 1 and Part 2) 1. Patients with serious or unstable medical illnesses, including ongoing liver disease (moderate to severe liver impairment), renal disease, gastrointestinal disease, respiratory disease, cardiovascular disease (including ischemic heart disease and congestive heart failure), endocrine disease, or blood disease. 2. Comorbid psychiatric disorders are generally allowed. However, substance use disorders (within the past 2 years) are excluded if the substance involved is other than nicotine or caffeine. Mild cannabis use is allowed. Urinary tetrahydrocannabinol (THC) is not excluded if the investigator determines the severity of the cannabis use disorder to be mild. 3. The investigator believes that the patient has a history of episodes of agitation attributable to substance use. 4. A diagnosis of antisocial personality disorder, unstable personality disorder, or narcissistic personality disorder that precedes the diagnosis of schizophrenia or bipolar disorder or, in the opinion of the investigator, is independent of the signs and symptoms of schizophrenia or bipolar disorder. 5. Suicidal ideation as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS). Exclude patients with a score of 4 or greater (assessed as meeting the criteria for each scale item). Clinically significant risk of suicide based on the investigator's clinical opinion or a history of actual suicide attempt within the past year. 6. Active self-injurious behavior. 7. Female patients who have a positive pregnancy test at screening or are breastfeeding. 8. Patients currently receiving treatment with alpha-1 noradrenergic blockers (terazosin, doxazosin, tamsulosin, alfuzosin, or prazosin), alpha-2 adrenergic agonists, or other prohibited drugs. 9. Patients have hydrocephalus, a seizure disorder, or a history of significant head trauma, cerebral infarction, transient ischemic attack, subarachnoid hemorrhage, brain tumor, encephalopathy, meningitis, Parkinson's disease, or focal neurological findings. 10. History of syncope or other syncopal episodes, hypovolemia, signs of orthostatic hypotension, a decrease in SBP of 20 mmHg or more or a decrease in DBP of 10 mmHg or more at 1 or 3 minutes after standing after 5 minutes of supine rest, a heart rate of less than 55 beats / min at screening and baseline, or a systolic blood pressure of less than 100 mmHg or a diastolic blood pressure of less than 60 mmHg. 11. Patients with laboratory or ECG abnormalities deemed clinically significant by the investigator or qualified designee that were clinically relevant to the patient's participation in the study [high-degree atrioventricular block (≥2nd degree atrioventricular block without a pacemaker), diagnosis of sick sinus syndrome]. 12. Patients with a known personal or family history of hereditary long QT syndrome. 13. Patients who received an investigational drug within 30 days prior to the start of the study (30 days prior to the first dose in Phase 1, 30 days prior to Day 0 in Phase 2). 14. Patients who have previously received dexmedetomidine hydrochloride sublingual film (trade name IGALMI) either in a clinical trial or by prescription. 15. Patients who are deemed by the investigator to be inappropriate candidates for dexmedetomidine administration, e.g., patients with a history of allergic reaction to dexmedetomidine or who are deemed inappropriate to participate in the study for any reason.

[0424] Additional exclusion criteria for patients enrolled in Part 1: 16. Patients with agitation caused by acute intoxication, including positive confirmation of alcohol by breathalyzer or positive confirmation of drugs of abuse (excluding THC) during urine screening. 17. Use of benzodiazepines or other hypnotics or antipsychotics within 4 hours prior to study treatment.

[0425] Test product, dose, and method of administration: product: The product, dexmedetomidine hydrochloride, is a thin film formulation of dexmedetomidine for sublingual (SL) or buccal (BL) administration. Each dose delivers 60 micrograms of dexmedetomidine. The product is a small, solid-dose film formulation, approximately 286 mm2 in area and 0.7 mm thick, designed to completely dissolve in the sublingual cavity within 1 to 3 minutes. Patients receive one film strip to place under the tongue in the oral cavity.

[0426] Control treatment, dose, and mode of administration: A matching dose of placebo film will be taken sublingually as above.

[0427] Treatment duration: Part 1: 8 hours Part 2: 12 weeks

[0428] Evaluation criteria: Part 1: Efficacy: Evaluation of efficacy for acute agitation is primarily based on the Positive and Negative Symptoms Scale-Agitation Item (PEC). The PEC consists of five agitation-related items (poor impulse control, tension, hostility, uncooperativeness, and excitement), each scored from 1 (minimum score) to 7 (maximum score). Thus, the PEC (the sum of these five subscales) ranges from 5 to 35.

[0429] Overall agitation and sedation were assessed using the Agitation-Sedation Scale (ACES), where 1 indicated marked agitation, 2 indicated moderate agitation, 3 indicated mild agitation, 4 indicated normal behavior, 5 indicated mild sedation, 6 indicated moderate sedation, 7 indicated marked sedation, 8 indicated deep sleep, and 9 indicated inability to awaken.

[0430] Global clinical improvement in agitation in response to treatment is also measured by the Clinical Global Impression-Improvement (CGI-I). CGI-I scores range from 1 to 7: 0 = not assessed (missing), 1 = very improved, 2 = much improved, 3 = slightly improved, 4 = no change, 5 = slightly worse, 6 = much worse, and 7 = very worse.

[0431] Clinical improvement in overall agitation in response to treatment will also be measured with the mCGI-S scale administered by the investigator, with mCGI-S scores ranging from 0 to 3: 0 = no agitation, 1 = mild agitation, 2 = moderate agitation, and 3 = severe agitation.

[0432] Safety and Tolerability Assessments: AEs, clinical tests, ECG, percent oxygen saturation measured by pulse oximetry, and vital signs (including under orthostatic stress) will be monitored for tolerability and safety assessments. All observed and self-reported AEs will be recorded. The investigator will grade the AE's relationship to study treatment as unrelated, unlikely / unlikely related, possibly related, probably related, or definitely related. Vital signs, including systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate, will be monitored at rest and under orthostatic stress. The application site will be examined for any signs of local irritation. Clinical laboratory analytes will be tested and urinalysis will be performed.

[0433] Additional assessments: demographic characteristics, medical and psychiatric history, smoking history, previous and concomitant medications, physical examination, pregnancy.

[0434] Pharmacokinetics: Sparse PK sampling of plasma concentrations at specified time points will be reported. Population PK / PD analysis of plasma concentrations versus clinical response will be investigated using a separate Statistical Analysis Plan (SAP) and reported separately. Graphical assessment of PK versus vital signs and other potential PD parameters may also be investigated.

[0435] Part 2: Safety and Tolerability Assessments: AEs, clinical laboratory values, ECG, pulse oximetry, and vital signs will be monitored for tolerability assessments during clinic visits. Informants will collect AEs 8 hours after study treatment or 8 hours after rescue medication (if taken), whichever is later. All observed and self-reported AEs will be recorded by informants via the EMA application during this 8-hour period. In addition, investigators will assess and record additional AEs at all clinic visits. The investigator will grade AEs as unrelated, unlikely / unlikely related, possibly related, probably related, or definitely related to study treatment. Vital signs, including SBP, DBP, and heart rate at rest and under orthostatic stress, will be monitored during monthly clinic visits. ECGs will be obtained during these clinic visits. Blood for clinical laboratory assays will be drawn during clinic visits. Finally, the application site is examined during the clinic visit for any signs of local irritation.

[0436] Validity: The mCGI-S was rated by both informants and patients to assess validity in Part 2. Informant ratings were paramount. This modified scale is expected to have higher inter- and intrarater reliability than the modified scale, which is based on the psychiatric training required to conduct PEC assessments.

[0437] Additional assessments included: demographic characteristics, medical and psychiatric history, smoking history, previous and concomitant medications, physical examination, pregnancy, duration of agitation episodes, and emergency services intervention.

[0438] Statistical Planning: General: Generally, summary statistics (number, mean, standard deviation, median, minimum, and maximum for continuous variables, and number and percentage of subjects in each category for categorical variables) will be provided for each evaluation variable and by treatment group. Unless otherwise stated, all statistical tests and confidence intervals will be two-sided, with alpha (α) set at 0.05.

[0439] Efficacy Analysis: The primary efficacy endpoint for Part 1 is the absolute change from baseline in the PEC total score at 2 hours post-dose. The null and alternative hypotheses to be tested are expressed as H01: Δdexmedetomidine sublingual film_60 = ΔPBO and HA1: Δdexmedetomidine sublingual film_60 ≠ ΔPBO, where Δdexmedetomidine sublingual film_60 represents the change from baseline in PEC at 2 hours post-dose in the dexmedetomidine sublingual film 60 mcg group, and ΔPBO represents the change from baseline in PEC at 2 hours post-dose in the placebo group. This hypothesis will be tested using a mixed model repeated measures (MMRM) model.

[0440] Safety Analysis: Safety data analysis will be performed on all subjects who received at least one dose of study treatment. The number and percentage of subjects who experienced one or more AEs will be summarized by treatment, relationship to study drug, and severity. AEs will be coded using the Medical Dictionary for Regulatory Affairs (MedDRA). A list of subjects who experienced an AE, serious adverse event (SAE), and / or withdrawal due to death will be provided. Clinical laboratory parameters will be summarized by treatment using descriptive statistics and data listing of clinically significant abnormalities. Vital sign and ECG data will be summarized by change from baseline using descriptive statistics.

[0441] Sample size determination: The sample size for Part 1 was based on an assumed mean difference of 2.0 and a common standard deviation of 5.00 between the active dexmedetomidine sublingual film and placebo in PEC scores at 2 hours. With these assumptions, 200 patients assigned in a 1:1 ratio to drug and placebo would provide 80% power to detect a significant difference at α = 0.05.

[0442] A blinded re-estimate of sample size will be calculated after 40% of subjects (n = 80) complete Part 1 of the study. A pooled standard deviation for both the placebo and dexmedetomidine sublingual film treatment groups will be completed by an unblinded statistician with appropriate firewalls between any person or entity involved in the study. The sample size calculation again uses a treatment difference of 2.0 and the pooled standard deviation obtained from the 80 completed patients to find the sample size with 90% power at α = 0.05. However, the sample size will not increase beyond 266 patients, and the sample size will not decrease from 200.

[0443] The sample size for the home-based Part 2 study of 250 patients, 125 per treatment group (randomized 1:1 to dexmedetomidine sublingual film:placebo), was expected to provide enough patients to detect possible adverse drug reactions with home use without false positives. Any new adverse drug reactions would be considered in addition to those already identified and would be included in the dexmedetomidine sublingual film labeling.

[0444] [Table 1-1] [Table 1-2] [Table 1-3]

[0445] [Table 2-1] [Table 2-2] [Table 2-3]

[0446] [Table 3-1] [Table 3-2]

[0447] Example 2. Efficacy and safety of dexmedetomidine hydrochloride sublingual film evaluated for home use in a multicenter, double-blind, placebo-controlled study for agitation associated with schizophrenia and bipolar disorder.

[0448] the purpose Main purpose: Part 1: To determine whether a 60 microgram (mcg) dose of dexmedetomidine sublingual film effectively reduced symptoms of agitation, as assessed using the Positive and Negative Symptom Scale-Agitation Item (PEC) change from baseline, compared with the change from baseline for placebo.

[0449] Part 2: To evaluate the safety of dexmedetomidine sublingual film when used in the home setting based on treatment-emergent adverse events (TEAEs) and serious TSAEs collected by both informants and clinical investigators.

[0450] Secondary Goals Part 1: 1. To determine the overall clinical improvement after administration of study treatment as measured by the Clinical Global Impression-Improvement scale (CGI-I). 2. To determine the overall clinical improvement after drug administration as measured by the modified Clinical Global Impression-Severity Scale (mCGI-S). 3. Describe the duration of sedation as measured by the Agitation-Sedation Scale (ACES). 4. To determine the safety profile of dexmedetomidine sublingual film as assessed by TEAEs, serious TEAEs, vital sign measurements, electrocardiogram (ECG), and clinical laboratory results. 5. Describe overall tolerability with respect to TEAEs

[0451] Part 2: 1. To assess the reduction in signs and symptoms of agitation based on the CGI-C and mCGI-S scales 2 hours after administration of the study treatment. 2. To describe the duration of sedation as measured by the Agitation-Sedation Scale (ACES). 3. To evaluate the continuing effectiveness of dexmedetomidine sublingual film in treating agitated episodes as measured by the Clinical Global Impression-Change (CGI-C) and mCGI-S scales and the frequency of agitated episodes. 4. To determine the number of interactions with emergency services resulting from agitation episodes (specifically, hospitalizations, emergency room visits, urgent care visits, and law enforcement interventions).

[0452] exploratory purpose Part 1: 1. To describe patient opinions regarding taste, acceptability, and preference of dexmedetomidine sublingual film. 2. To evaluate patient satisfaction with dexmedetomidine sublingual film in the treatment of agitation episodes. The Treatment Satisfaction Questionnaire for Medication (TSQM) will be administered for this purpose at the end of the treatment period. 3. To determine overall clinical improvement after medication administration as measured by rescue medication use. 4. To evaluate the agreement between PEC scores and mCGI-S assessments

[0453] Part 2: 1. To assess the reduction of signs and symptoms of agitation based on the Agitation Behavior Scale, the Karolinska Sleepiness Scale (KSS), and item 9 of the Beck Depression Inventory II (BDI-II). 2. To evaluate patient satisfaction with dexmedetomidine sublingual film in the treatment of agitation episodes. TSQM will be performed at the end of treatment for this purpose. 3. To determine overall clinical improvement after medication administration as measured by rescue medication use. 4. To assess the agreement between informant and patient ratings of the mCGI-S and CGI-C scales.

[0454] Primary endpoint Part 1: Change in PEC score from baseline compared to placebo at 2 hours after drug administration.

[0455] Part 2: Comparison of serious adverse events (SAEs) and TEAEs compared to placebo.

[0456] Secondary endpoints Part 1: 1. Number of PEC responders (patients who achieved a 40% or greater reduction from baseline in PEC total score) at or before 2 hours after drug administration. 2. Change in PEC score from baseline compared to placebo over time measured 30 minutes to 8 hours after drug administration. 3. CGI score 2 hours after drug administration. 4. Number of CGI-I responders (patients achieving a CGI-I score of 1 or 2) at 2 hours after drug administration. 5. Change in mCGI-S score from baseline assessed 2 hours after drug administration. 6. Number of mCGI-S responders (patients who achieved a CGI-S score of 0 or 1) 2 hours after drug administration. 7. Change in ACES score from baseline at 2, 4, and 8 hours after drug administration. 8. The safety profile of dexmedetomidine sublingual film will be measured by the frequency of adverse events (AEs), vital sign measurements, ECG, and clinical laboratory results. 9. Overall tolerability of the oral film will be measured by the frequency of TEAE reports and the incidence of local (oral / sublingual) tolerability.

[0457] Part 2: 1. Change in informant mCGI-S score from before administration of the first treatment episode to 2 hours after drug administration (mCGI-S-INF). 2. Number of mCGI-S-INF responders (patients who achieved an mCGI-S-INF score of 0 or 1) 2 hours after drug administration in the first treatment episode. 3. Change in ACES score (measured by informant) from baseline at 2 hours after drug administration in the first treatment episode. 4. CGI-C-INF score 2 hours after drug administration in the first treatment episode. 5. Number of CGI-C-INF responders (patients achieving a CGI-C-INF score of 1 or 2) 2 hours after drug administration in the first treatment episode. 6. Change in mCGI-S-INF score from pre-dose to 2 hours post-drug administration of the last treatment episode (to measure continued efficacy). 7. Number of mCGI-S-INF responders 2 hours after drug administration of the last treatment episode (measures continued efficacy). 8. CGI-C-INF score 2 hours after drug administration of the last treatment episode (measures continued efficacy). 9. Number of mCGI-C-INF responders 2 hours after drug administration of the last treatment episode (measuring continued efficacy). 10. Proportion of all treated agitation episodes meeting the definition of mCGI-S-INF responders (patients achieving an mCGI-S-INF score of 0 or 1) at 2 hours (measures sustained efficacy) Proportion of all treated agitation episodes meeting the definition of CGI-C-INF responders (patients achieving a CGI-C score of 1 or 2 as determined by an informant) at 11.2 hours (measures sustained efficacy) 12. Number and frequency of agitation episodes (to measure continued effectiveness) 13. Number of interactions with emergency services related to agitation episodes reported by the informant.

[0458] Exploratory endpoints Part 1: 1. Patient opinions regarding taste, acceptability, and liking of the study treatment will be assessed using a preference questionnaire. 2. To assess patient satisfaction with dexmedetomidine sublingual film in the treatment of agitation episodes using the TSQM. 3. Time to administration of rescue medication during the 8-hour post-procedure assessment in subjects receiving dexmedetomidine sublingual film compared to placebo. 4. Proportion of subjects per treatment group who received rescue medication during the 8-hour post-treatment assessment in subjects who received dexmedetomidine sublingual film compared to placebo. 5. Correlation between PEC and mCGI-S at baseline and 2 hours.

[0459] Part 2: 1. Changes in the Agitation Behavior Scale, KSS, and item 9 of the BDI-II from pre-dose to 2 hours after drug administration. 2. To assess patient satisfaction with dexmedetomidine sublingual film in the treatment of agitation episodes using the TSQM. 3. Time to administer rescue medication in subjects receiving dexmedetomidine sublingual film compared to placebo. 4. Proportion of subjects per treatment group who received rescue medication in subjects who received dexmedetomidine sublingual film compared to placebo. 5. Correlations between informant and patient ratings of the mCGI-S and CGI-C scales at baseline and 2 hours.

[0460] Study Design: This was a Phase III, randomized, double-blind, placebo-controlled, two-part study evaluating the efficacy, safety, and tolerability of dexmedetomidine sublingual film in adult (18-75 years) men and women with acute agitation associated with bipolar I disorder, bipolar II disorder, schizophrenia, schizoaffective disorder, or schizophreniform disorder.

[0461] Parts 1 and 2 were enrolled simultaneously. All patients enrolled in Part 1 were individuals who had not previously received dexmedetomidine sublingual film or been prescribed IGALMI™. Patients in Part 2 of the study were not treated with prescribed IGALMI™ and may have participated in Part 1 of the study or other dexmedetomidine sublingual film studies.

[0462] Part 1: Clinic Period The first part of the study consisted of an 8-hour clinic treatment period for patients experiencing an acute episode of agitation, followed by a post-treatment observation period. During the clinic period, patients were randomized 1:1 to receive either 60 mcg of dexmedetomidine sublingual film or a matching placebo. Eligible patients (those with any type of dementia) were identified through SNIFF, mental health, psychiatric, or medical emergency services (including medical / psychiatric observation facilities), or as patients newly admitted to a hospital setting due to acute agitation, or patients already hospitalized due to a chronic condition. Subjects were either settled in the clinical trial setting or admitted to remain under medical supervision during screening procedures to assess eligibility and throughout study participation.

[0463] Randomization was not formally stratified, but the randomization scheme was designed so that no more than 70% of patients in each arm of the study had a primary diagnosis of bipolar disorder (bipolar I or bipolar II) or schizophrenia (including schizoaffective disorder and schizophreniform disorder).

[0464] Once eligibility was confirmed, patients were randomized to receive either 60 mcg of dexmedetomidine sublingual film or a matching dose of placebo. At the time of administration, patients were instructed on how to administer the study medication sublingually and that they should hold the medication in the sublingual cavity until it dissolved. Patients self-administered the medication under the supervision of a trained staff member. If a patient was unable to self-administer, the event was recorded and the patient's participation in the study was terminated. Such patients were replaced.

[0465] Participants were also evaluated for local irritation around the area where the film was placed. Efficacy and safety assessments were performed periodically before and after administration. Every effort was made to have patients complete all assessments according to the clinical trial protocol.

[0466] Rescue medication was administered if warranted by the patient's condition (determined by the investigator), which could be either a benzodiazepine (lorazepam up to 4 mg or oxazepam up to 60 mg) or any antipsychotic except clozapine, pimozide, or prochlorperazine (maximum dose approximately equivalent to 300 mg of chlorpromazine as specified by BioXcel and selected by the investigator).

[0467] Patients are required to remain in the clinic for a minimum of 8 hours of observation after administration of study treatment. If rescue medication is administered, patients must remain in the clinic for a minimum of 8 hours after administration.

[0468] Efficacy, safety, tolerability, and pharmacokinetics (PK) were assessed at various time points throughout the treatment period (see Table 4: Schedule of Events Part 1 for details).

[0469] Part 2: Implementation in the social (home) environment The second part of the study was a 12-week trial to evaluate the safety of dexmedetomidine sublingual film when used as needed for agitation episodes at home. During the at-home study period, patients were randomized 1:1 to receive either dexmedetomidine sublingual film or a matching dose of placebo film 60 mcg when agitation episodes occurred at home. Eligible patients were individuals who experienced regular agitation episodes. Additionally, patients were required to have a reliable informant who participated in the study administration and accompanied them to monthly clinic visits when agitation episodes were treated with the study medication.

[0470] Randomization was not formally stratified, but the randomization scheme was designed so that no more than 70% of patients in each arm of the study had a primary diagnosis of bipolar disorder (bipolar I or bipolar II) or schizophrenia (including schizoaffective disorder and schizophreniform disorder).

[0471] Patients and informants were trained at screening regarding their responsibilities during the study, including how to grade agitation severity using the mCGI-S and how to use the Ecological Momentary Assessment (EMA) application. At the baseline visit, patients and informants were trained regarding the circumstances under which informants could recommend that patients self-administer a dose of study treatment or rescue medication. Patients were further trained regarding when, based on their own perception, they could take study treatment or rescue medication. Patients and informants were also instructed on how patients should administer the study treatment sublingually and that they should hold the study treatment in the sublingual cavity until dissolved. Furthermore, patient-informant dyads were trained regarding risk assessment in the event of an agitation episode and appropriate responses if risk increased. Study reference cards were provided to patients and informants, providing guidance regarding administration of study treatment or rescue medication, safety precautions, and management of risks during agitation episodes and self-harm, suicide, or violence.

[0472] At home, when an agitation episode occurred, patients self-administered the study treatment under the supervision of an informant. If the patient was unable to self-administer during the first agitation episode in which treatment was attempted, the event was recorded and the patient's participation was terminated. Such patients were replaced.

[0473] If an informant was not present when a patient felt the need to treat their agitation, they used the EMA application to rate the severity of their agitation and, if they chose, took the study treatment at that time. If a patient recorded an agitation episode independently, an informant was notified via the EMA application to follow up and record the episode data, if readily available.

[0474] Patients and informants were also responsible for entering information into the EMA application installed on the device. Certain information was entered when an agitation episode occurred. On days when no agitation episode occurred, other information was collected via the EMA application (the application prompted patients and informants to enter this information).

[0475] In addition, patients and informants returned to the clinic for follow-up visits 1 and 2 months after the baseline visit (days 28 and 56), and a final study visit at the end of the study at 3 months (day 84) (see Table 5: Part 2 Event Schedule).

[0476] At the time of randomization at the baseline visit, patients will be dispensed four packages, each containing one 60 mcg strip of dexmedetomidine sublingual film or matching placebo. If all packages are used before the next scheduled clinic visit, the patient or informant will be required to return the used packages and return to the clinic to obtain four additional doses of study treatment.

[0477] Patients were allowed up to two doses of study medication within an 8-hour period. At the baseline visit, the investigator provided patients with a prescription for a rescue medication of the investigator's choice. If persistent agitation occurred, patients could choose to have the study medication repeated (re-administered) after at least 30 minutes had elapsed since the initial dose. If a re-administration occurred, patients could take the rescue medication after another 30 minutes had elapsed. Patients were initially directed to administer the study medication for the agitated episode. However, patients could choose to use rescue medication to treat the agitated episode at any time after the study medication. If rescue medication was taken, the study medication could not be used to treat that agitated episode. Rescue medication could be either a benzodiazepine (lorazepam maximum dose 4 mg or oxazepam maximum dose 60 mg) or any antipsychotic except clozapine, pimozide, or prochlorperazine (maximum dose approximately equivalent to 300 mg of chlorpromazine as specified by BioXcel and selected by the investigator).

[0478] Target population Selection of study population All patients enrolled in Part 1 were individuals who had not previously received dexmedetomidine sublingual film or been prescribed IGALMI™. Patients in Part 2 of the study had to have not been treated with prescribed IGALMI™ and may have participated in Part 1 of the study or other dexmedetomidine sublingual film studies.

[0479] Part 1 Approximately 200 patients were initially planned to be enrolled in Part 1 of the study at up to 20 study sites in the United States. Once 40% of the 200 patients (80 patients) had completed Part 1 of the study, a blinded analysis of the sum of the standard deviations of change in both treatment groups was obtained to calculate the final sample size. The sample size could be increased to a maximum of 266 patients.

[0480] Part 2: Part 2 enrolled approximately 250 patients at up to 30 study sites in the U.S. Parts 1 and 2 were expected to enroll simultaneously.

[0481] Inclusion criteria Patients were eligible for inclusion in the study if they met all of the following criteria:

[0482] Inclusion Criteria (Part 1 and Part 2) 1. Male and female patients aged 18 to 75 years. 2. Patients who were able to read, understand, and provide written informed consent. 3. Patients who meet Diagnostic and Statistical Manual of Mental Disorders, v5, Text Revision (DSM-5 / 5-TR) criteria for a primary diagnosis of bipolar I or bipolar II disorder, schizophrenia, schizoaffective disorder, or schizophreniform disorder. 4. Patients in good general health prior to study entry as determined by a detailed medical history, physical examination, 12-lead ECG with rhythm strips, blood chemistry profile, hematology, and urinalysis, in the opinion of the investigator. 5. Female participants (if of childbearing potential and sexually active) and male participants (if sexually active with a partner of childbearing potential) who agree to use medically acceptable, effective contraception throughout the study and for one week after completion. Medically acceptable contraception methods that participants and their partners may use include abstinence, the birth control pill or patch, spermicide-containing diaphragms, intrauterine devices (IUDs), foam or spermicide-containing condoms, spermicide vaginal suppositories, surgical sterilization, and progestin implants or progestin injections. Prohibited methods included rhythm methods, withdrawal, condoms only, or diaphragms only.

[0483] Additional inclusion criteria for patients enrolled in Part 1: 6. Patients who are clinically determined to be agitated at screening and baseline, with a total score of 14 or greater on the five items that make up the PEC (poor impulse control, tension, hostility, uncooperativeness, and agitation). 7. Patients with a score of 4 or higher on at least one of the five PEC items at baseline.

[0484] Additional inclusion criteria for patients enrolled in Part 2: 8. Based on medical history, within the past 2 months, the patient must have had at least one clinical episode of agitation requiring intervention (e.g., receipt of as-needed (PRN) medication for the episode, clinic visit, emergency room visit, emergency medical services intervention, law enforcement intervention). 9. Patient was able to understand and comply with study procedures, including completing the EMA application assessment. 10. Patients had an informant who was able to read, understand, and provide written informed consent, and who was able to understand and follow study procedures, including the evaluation of the EMA application and completing other EMA application required procedures during the study. Finally, the informant must accompany the participant to monthly clinic visits and be interviewed by the investigator to assess the mean mCGI-S score for the period since the investigator's previous mCGI-S assessment.

[0485] Exclusion criteria Subjects were excluded from the study if they met any of the following criteria:

[0486] Exclusion Criteria (Part 1 and Part 2) 1. Patients with serious or unstable medical diseases, including ongoing liver disease (moderate to severe liver impairment), renal disease, gastrointestinal disease, respiratory disease, cardiovascular disease (including ischemic heart disease and congestive heart failure), endocrine disease, or blood disease. 2. Comorbid psychiatric disorders were generally allowed. However, substance use disorders (within the past two years) were excluded if the substance involved was other than nicotine or caffeine. Note that marijuana / cannabis use, even with a positive UDS or admitted subject use, was not excluded if the use met the following criteria: a) marijuana is prescribed for medical use (medical marijuana), b) marijuana is not the sole focus of treatment, c) the severity of cannabis-related SUD is mild or less (as defined by DSM-5 substance use disorder criteria), and 4) illicit or recreational use has not escalated to the point of recovery from the effects of cannabis or withdrawal symptoms (even agitation) associated with its use. 3. The investigator believed the patient had a history of agitated episodes attributable to substance use. 4. A diagnosis of antisocial personality disorder, unstable personality disorder, or narcissistic personality disorder that preceded the diagnosis of schizophrenia or bipolar disorder or, in the opinion of the investigator, was independent of the signs and symptoms of schizophrenia or bipolar disorder. 5. Suicidal ideation as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS). Ideational functioning scores of 4 or greater in the past year will exclude patients. Clinically significant risk of suicide based on the investigator's clinical opinion or a history of actual suicide attempt in the past year will also exclude patients. 6. Active self-injurious behavior. 7. Female patients who had a positive pregnancy test at screening or baseline or were breastfeeding. 8. Patients currently receiving treatment with alpha-1 noradrenergic blockers (terazosin, doxazosin, tamsulosin, alfuzosin, or prazosin), alpha-2 adrenergic agonists, or other prohibited drugs. 9. Patients have hydrocephalus, a seizure disorder, or a history of significant head trauma, cerebral infarction, transient ischemic attack, subarachnoid hemorrhage, brain tumor, encephalopathy, meningitis, Parkinson's disease, or focal neurological findings. 10. History of syncope or other syncopal episodes, hypovolemia, signs of orthostatic hypotension, a decrease in systolic blood pressure (SBP) of 20 millimeters of mercury (mmHg) or more or a decrease in diastolic blood pressure (DBP) of 10 mmHg or more at 1 or 3 minutes after standing after 5 minutes of supine rest, a heart rate less than 55 beats per minute at screening and baseline, or an SBP less than 100 mmHg or a DBP less than 60 mmHg. 11. Patients with laboratory or ECG abnormalities deemed clinically significant by the investigator or qualified designee that were clinically relevant to the patient's participation in the study (such as a diagnosis of high-degree atrioventricular block [≥2nd degree atrioventricular block without a pacemaker], sick sinus syndrome). 12. Patients with a known personal or family history of hereditary long QT syndrome. 13. Patients who received an investigational drug within 30 days prior to the start of the study (30 days prior to the first dose in Part 1, 30 days prior to Day 0 in Part 2). 14. Patients have previously received dexmedetomidine sublingual film (trade name IGALMI™) via prescription. 15. Patients who are deemed by the investigator to be inappropriate candidates for dexmedetomidine administration (e.g., have a history of allergic reaction to dexmedetomidine) or who are deemed unsuitable for participation in the study for any reason.

[0487] Additional exclusion criteria for patients enrolled in Part 1: 16. Patients with agitation caused by acute intoxication, including confirmation of alcohol by breath analyzer or confirmation of drugs of abuse (excluding THC) during urine screening. 17. Use of benzodiazepines or other hypnotics or antipsychotics within 4 hours prior to study treatment. 18. Patients who have previously received dexmedetomidine sublingual film in a clinical trial.

[0488] Informant inclusion criteria: Informants who meet the following criteria are eligible for the second part of the study: 1. Be aged 18 years or older at the time of screening 2. Spouse, partner, family member, friend, or home care aide or residential caregiver of an adult patient who was determined to be eligible for the study according to the patient inclusion / exclusion criteria. 3.Knew the patient for at least 12 months. 4. Currently living with the patient or in regular contact with the patient at least 5 days a week. 5. There were no plans to discontinue patient consultation or care during the study period. 6. Willing and able to provide written informed consent. 7. Willing and able to follow study procedures during the study, including the evaluation of EMA applications and completing other EMA application required procedures. 8. Willing and able to accompany the patient, remain on the clinic premises during the clinic visit, and be interviewed by the investigator.

[0489] Test Procedures Methods for assigning patients to treatment groups After confirmation of eligibility, patients were randomized as follows:

[0490] Part 1: Patients were randomized 1:1 to receive 60 mcg of dexmedetomidine sublingual film or a matching dose of placebo.

[0491] Part 2: Patients were randomized 1:1 to receive 60 mcg of dexmedetomidine sublingual film or a matching dose of placebo.

[0492] Study randomization was computer-generated.

[0493] Test product, dosage, and administration method product: The product, dexmedetomidine hydrochloride, was a thin-film formulation of dexmedetomidine for sublingual (SL) or buccal (BL) administration. Each dose delivered 60 micrograms of dexmedetomidine. The product was a small, solid-dose film formulation, approximately 286 mm2 in area and 0.7 mm thick, designed to completely dissolve in the sublingual cavity within 1 to 3 minutes. Patients received one film strip to place under the tongue in the oral cavity.

[0494] (a) Administration of study treatment Patients were instructed on how to administer the study treatment sublingually and that it should be held in the sublingual cavity until it dissolved. Although the study treatment could be administered sublingually or bucally, all patients in this study received the study treatment sublingually only. Patients self-administered dexmedetomidine sublingual film. If patients were unable to self-administer during the first agitation episode in Part 1 or during the first agitation episode in which treatment was attempted in Part 2, the event was recorded and the patient's participation in the study was terminated. If patients were found to be unable to consistently self-administer during subsequent agitation episodes in Part 2, the investigator must determine whether the patient could remain in the study.

[0495] Patients are required to refrain from eating or drinking water for 15 minutes after taking the study treatment.

[0496] In Part 1, patients were evaluated for local irritation around the area where the study treatment was placed.

[0497] Patients and informants were advised to avoid activities requiring alertness, such as driving or operating machinery, for at least 8 hours after administration of the study drug.

[0498] Home patient and informant assessment When the informant identified the onset of an agitation episode based on the patient's excessive verbal or physical activity and the informant's direct experience with the patient's agitation episode, the informant rated the severity of the agitation at that time using the mCGI-S-INF. The patient also rated the severity of the agitation at that time using the mCGI-S-PAT. Patients and informants entered their ratings into their own EMA applications.

[0499] If the patient rated the severity of their agitation as 2 (moderate) or 3 (severe), a notification was sent to the informant. Patients could also tell their informant that they were beginning to experience an agitation episode. When this occurred, the patient and informant rated the severity of their agitation at that time and entered those ratings into their respective EMA applications.

[0500] If the informant is not present when the patient feels the need to treat their agitation, the patient will be required to rate the severity of their agitation using the EMA application and, if they choose, can take the study treatment at that time. If the patient records an agitation episode independently, the informant will be notified via the EMA application to follow up and record the episode data, if readily available.

[0501] If the informant rated the severity of agitation as 2 (moderate) or 3 (severe), the informant could recommend that the patient take the study treatment. The patient may refuse to take the study treatment if the informant recommended it. If they refused, this information was entered into the EMA application by the informant along with the reason for the refusal. If the patient took the study treatment at a later time, this information was entered into the EMA application by the informant. The patient could decide that they needed the study treatment and take it regardless of their mCGI-S score or the informant's recommendation.

[0502] If the patient was unable to self-administer during the first agitation episode in which treatment was attempted, the event was recorded. The investigator must determine whether the patient can continue participating in the study. If the patient was unable to self-administer during a subsequent episode, the investigator must determine whether the patient can continue participating in the study.

[0503] Informants were also asked to answer a series of questions via the EMA application, some of which were assessed only when an agitation episode occurred, while others were administered daily (see Table 6).

[0504] Patient and informant assessments performed when an agitation episode occurred When an agitation episode occurred, the EMA application was used by informants and patients to record the duration of the agitation episode, use of study or rescue medications, efficacy and safety assessments, side effects, and other medications (if possible). The time at which each question or assessment was completed was recorded in the EMA application. Any agitation episode outcomes, including any interactions with emergency services (specifically, hospitalization, emergency room visit, urgent care visit, intervention by other emergency services such as ambulance services, and intervention by law enforcement), were also recorded via the EMA application.

[0505] Daily patient and informant assessments Informants were asked to provide the following information daily via the EMA application when prompted by the application twice daily (see Table 6: Home Patient and Informant Assessments). The application prompted informants to enter the following information: i.mCGI-S (informant and patient) scores were asked twice a day (once in the morning and once in the evening) ii. Question as to whether the patient experienced any previously unreported agitation episodes that day (once daily, evenings only) iii. Questioning of any intervention with emergency services (once a day, in the evening only, and only if an unreported agitation episode occurs)

[0506] At the same time each day, patients were prompted to enter their mCGI-S scores via the EMA application. Patients and informants were asked not to share their ratings with each other.

[0507] Exam evaluation Effectiveness The efficacy of the study treatment was assessed in Part 1 using the validated instruments listed below. Efficacy assessments were conducted in Part 2 using the informant-rated mCGI-S (primary) during each observed agitation episode, the patient-rated mCGI-S (secondary) during each observed agitation episode, and the investigator-rated mCGI-S at each study clinic visit over an overall 1-month period based on patient and informant interviews. i. Positive and Negative Symptoms Scale Excitement Item (PEC) ii. Agitation Sedation Scale (ACES) iii. Karolinska Sleepiness Scale (KSS) - The Karolinska Sleepiness Scale is a single-item scale that subjectively measures sleepiness at a given time (Akerstedt and Gillberg, 1990). Responses are as follows: 1 - very awake, 2 - very awake, 3 - awake, 4 - somewhat awake, 5 - neutral, 6 - signs of sleepiness, 7 - sleepy but no effort to stay awake, 8 - sleepy, some effort to stay awake, 9 - very sleepy, great effort to stay awake, fighting sleepiness, and 10 - very sleepy, unable to stay awake. Patients rated their sleepiness with the EMA app. iv. Clinical Global Impression-Improvement Scale (CGI-I)

[0508] Clinical Global Impression-Change Scale (CGI-C): The CGI-C is a scale administered by informants (CGI-C-INF) and patients (CGI-C-PAT) that measures the overall change in the patient's agitation state after study drug administration. CGI-C scores range from 1 to 5. 0 = Not rated (not found) 1=much ​​better, 2 = somewhat good; 3 = no change; 4 = slightly worse; 5=Much worse

[0509] The CGI-C focused on the severity of agitation rather than the overall illness severity of bipolar disorder or schizophrenia and related disorders. v. Modified Clinical Global Impression-Severity Scale (mCGI-S) vi.Agitated Behavior Scale

[0510] Pharmacokinetics Blood samples (4 milliliters (mL) each) for PK analysis were collected in Part 1 at 2, 4, 6, and 8 hours post-dose according to the event schedule (Table 4).

[0511] Efficacy analysis Primary endpoint The primary efficacy endpoint in Part 1 was the absolute change from baseline in the PEC total score at 2 hours post-dose.

[0512] Secondary endpoints Secondary efficacy endpoints in Part 1 were: 1. Number of PEC responders (patients who achieved a 40% or greater reduction from baseline in PEC total score) at or before 2 hours after drug administration. 2. Change in PEC score from baseline compared to placebo over time measured 30 minutes to 8 hours after drug administration. 3. Change in CGI-I score from baseline at 2 hours after drug administration. 4. Number of CGI-I responders (patients achieving a CGI-I score of 1 or 2) at 2 hours after drug administration. 5. Change in mCGI-S score from baseline assessed 2 hours after drug administration. 6. Number of mCGI-S responders (patients who achieved a CGI-S score of 0 or 1) 2 hours after drug administration. 7. Change in ACES score from baseline at 2, 4, and 8 hours after drug administration.

[0513] Secondary efficacy endpoints in Part 2 were: 1. Change in informant mCGI-S score from before administration of the first treatment episode to 2 hours after drug administration (mCGI-S-INF). 2. Number of mCGI-S-INF responders (patients who achieved an mCGI-S-INF score of 0 or 1) 2 hours after drug administration in the first treatment episode. 3. Change in ACES score (measured by informant) from baseline at 2 hours after drug administration in the first treatment episode. 4. CGI-C-INF score 2 hours after drug administration in the first treatment episode. 5. Number of CGI-C-INF responders (patients achieving a CGI-C-INF score of 1 or 2) 2 hours after drug administration in the first treatment episode. 6. Change in mCGI-S-INF score from pre-dose to 2 hours post-drug administration of the last treatment episode (to measure continued efficacy). 7. Number of mCGI-S-INF responders 2 hours after drug administration of the last treatment episode (measures continued efficacy). 8. CGI-C-INF score 2 hours after drug administration of the last treatment episode (measures continued efficacy). 9. Number of mCGI-C-INF responders 2 hours after drug administration of the last treatment episode (measuring continued efficacy). 10. Proportion of all treated agitation episodes meeting the definition of mCGI-S-INF responders (patients achieving an mCGI-S-INF score of 0 or 1) at 2 hours (measures sustained efficacy) Proportion of all treated agitation episodes meeting the definition of CGI-C-INF responders (patients achieving a CGI-C score of 1 or 2 as determined by an informant) at 11.2 hours (measures sustained efficacy) 12. Number and frequency of agitation episodes (to measure continued effectiveness)

[0514] Part 1: Secondary efficacy endpoints in Part 1, including change in agitation in response to treatment as measured by the PEC, CGI-I, and mCGI-S scales, and change from baseline in ACES scores, were analyzed using MMRM models. The MMRM models for PEC, mCGI-S, and ACES scores included change from baseline to 2 hours post-dose as the outcome, and baseline values ​​for the outcome and treatment group as covariates. The model for CGI-I scores included scores from 30 minutes to 2 hours post-dose as the outcome, and baseline mCGI-S scores and treatment group as covariates. The number of PEC responders (patients who achieved a 40% or greater reduction from baseline in the PEC total score at or before 2 hours post-dose), CGI-I responders (patients who achieved an mCGI-S score of 0 or 1 after drug administration), and mCGI-S responders (patients who achieved an mCGI-S score of 0 or 1 at 2 hours post-dose) were analyzed using chi-square tests.

[0515] All values ​​collected after rescue medication use and withdrawal from the study were set to missing.

[0516] Part 2: The secondary efficacy endpoints in Part 2, change in agitation in response to treatment as measured by the CGI-C-INF and mCGI-S-INF scales, and change from pre-dose in ACES scores, were analyzed using the MMRM model described above for the analysis of secondary efficacy endpoints in Part 1. The number of CGI-C-INF responders (patients who achieved a CGI-C-INF score of 1 or 2) at 2 hours post-drug administration and the number of mCGI-S-INF responders (patients who achieved a mCGI-S-INF score of 0 or 1) at 2 hours post-drug administration were analyzed using chi-square tests.

[0517] All values ​​collected after rescue medication use and withdrawal from the study were set to missing.

[0518] The frequency of treated agitation episodes was assessed with a Poisson model including treatment group as a covariate. This was a single outcome defined as the number of treated agitation episodes for each subject. Results were summarized as incidence rate ratios, and significance levels for tests of the null hypothesis of no difference between active dose and placebo were derived from the significance levels for tests of each dose level versus placebo.

[0519] The proportion of all treated agitation episodes meeting the definition of mCGI-S-INF responders was analyzed using an ANCOVA model, with the proportion of episodes meeting the definition of mCGI-S-INF responders as covariates for outcome and treatment group. The proportion of all treated agitation episodes meeting the definition of CGI-S-INF responders was analyzed similarly.

[0520] Other secondary and exploratory endpoints for both Parts 1 and 2 were analyzed using a variety of methods depending on the outcome, including two-sample t-tests, Fisher's exact tests, Kaplan-Meier curves of time to event, and descriptive methods such as box plots, frequency distributions, and shift tables. All significance levels are reported as nominal levels. Details of these analyses were provided in the SAP.

[0521] Safety analysis All safety analyses were performed using the safety population. All patients who received at least one dose of study treatment were included in the safety analysis population.

[0522] Adverse events were characterized by type, severity, seriousness, and relationship to treatment. Adverse events were coded by preferred term and system organ class using the latest version of MedDRA.

[0523] [Table 4-1] [Table 4-2] [Table 4-3]

[0524] [Table 5-1] [Table 5-2] [Table 5-3]

[0525] [Table 6-1] [Table 6-2]

[0526] [Table 7]

[0527] Results and Discussion: The results of the study are provided in Tables 8-21 below.

[0528] PEC data were collected at 0.5, 1, 2, 4, 6, and 8 hours after administration of the dexmedetomidine or placebo sublingual film. As shown in Figure 1 and Table 10, a decrease in PEC scores was observed within both the treatment and placebo cohorts, but significant separation was maintained at each time point. Notably, at 2 hours post-dose, the least squares mean PEC scores decreased by 4.8 in the treatment cohort and 3.8 in the placebo cohort, with a P value of 0.077. Similarly, at 4 hours post-dose, the least squares mean PEC scores decreased by 5.4 in the treatment cohort and 4.3 in the placebo cohort, with a P value of 0.049 (see Table 10).

[0529] An alternative metric for quantifying drug efficacy is the responder rate, defined as the proportion of patients who showed a 40% reduction in PEC score. In this study, the responder rates at 2 hours post-dose were 50% and 33% in the treatment and placebo cohorts, respectively. Similarly, the responder rates at 4 hours post-dose were 51% and 39% in the treatment and placebo cohorts, respectively (see Table 10 and Figure 2).

[0530] In this study, the secondary endpoint was the reduction in score assessed by the Clinical Global Impression-Improvement scale (CGI-I). At 2 hours post-dose, the CGI-I scores for the treatment and placebo groups were 2.8 and 3.1, respectively, with a P value of 0.059 (see Table 13 and Figure 3). Similarly, the responder rates for the treatment and placebo groups were 38.6% and 26.0%, respectively, with a P value of 0.039 (see Table 13 and Figure 4).

[0531] The 60 mcg dose was safe and well tolerated at all time points. The 120 mcg and 180 mcg dexmedetomidine sublingual films were approved by the FDA based on previously reported clinical trials, in which the safety profiles of both doses were deemed acceptable by the FDA. Compared to the previously approved dose, the 60 mcg dose demonstrated an enhanced safety profile across all adverse event (AE) categories monitored in this clinical trial (see Table 21). For example, 13% of patients experienced somnolence (defined as a feeling of drowsiness, sleepiness, fatigue, or listlessness) compared with 7% in the placebo group. In comparison, the incidence of somnolence was 23% and 22% with the 120 mcg and 180 mcg doses, respectively. Only one event (1%) of orthostatic hypotension occurred in the 60 mcg treatment group (none in the placebo group), while incidences were reported in 3% and 5% of the earlier 120 mcg and 180 mcg dose groups, respectively (see Table 21).

[0532] Subgroup analysis of the data showed that efficacy in the schizophrenia group was superior to efficacy in the bipolar group when the results were assessed by underlying disease diagnosis. As shown in Tables 11 and 12 and Figures 5A and 5B, the reduction in PEC scores at 2 hours post-dose for the schizophrenia group was 4.9 and 3.3 for the dexmedetomidine sublingual film cohort and placebo, respectively, with a P value of 0.013. In contrast, the simultaneous reduction in PEC scores in the bipolar group was 4.8 and 4.3 for the dexmedetomidine sublingual film cohort and placebo, respectively, with a P value of 0.663. An increased placebo response was observed in the bipolar group, with a PEC score change of approximately 4.5 compared to 3.2 in the schizophrenia group (Tables 11 and 12).

[0533] [Table 8]

[0534] [Table 9-1] [Table 9-2] [Table 9-3]

[0535] [Table 10-1] [Table 10-2] [Table 10-3]

[0536] [Table 11-1] [Table 11-2]

[0537]

Table 12-1

Table 12-2

[0538]

Table 13-1

Table 13-2

[0539]

Table 14-1

Table 14-2

[0540]

Table 15-1

Table 15-2

[0541] Table 16

[0542] Table 17

[0543]

Table 18-1

Table 18-2

[0544] [Table 19]

[0545] [Table 20]

[0546] [Table 21]

[0547] Example 3. Efficacy and safety of dexmedetomidine hydrochloride sublingual film evaluated for home use in a multicenter, double-blind, placebo-controlled study for agitation associated with schizophrenia and bipolar disorder.

[0548] the purpose: Main purpose: Part 1: To determine whether a 60 microgram (mcg) dose of dexmedetomidine sublingual film effectively reduced symptoms of agitation, as assessed using the Positive and Negative Symptom Scale-Agitation Item (PEC) change, compared with change from baseline with placebo.

[0549] Part 2: To evaluate the safety of 80 mcg dexmedetomidine sublingual film when used in the home setting based on serious adverse events (SAEs) and treatment-emergent adverse events (TEAEs).

[0550] Secondary Objectives: Part 1: 1. To determine the overall clinical improvement after administration of study treatment as measured by the Clinical Global Impression-Improvement scale (CGI-I). 2. To determine the overall clinical improvement after drug administration as measured by the modified Clinical Global Impression-Severity Scale (mCGI-S). 3. To describe the duration of sedation as measured by the Agitation-Sedation Scale (ACES). 4. To determine the safety profile of dexmedetomidine sublingual film as assessed by TEAEs, serious TEAEs, vital sign measurements, electrocardiogram (ECG), and clinical laboratory results. 5. To describe overall tolerability with respect to TEAEs.

[0551] Part 2: 1.To assess the impact of dexmedetomidine sublingual film on medical and emergency service resource use due to agitation episodes. To assess the safety and tolerability profile of 2.80 mcg dexmedetomidine sublingual film. 3. To evaluate the effect of 80mcg dexmedetomidine sublingual film on signs and symptoms of agitation following study drug administration in patients with schizophrenia and bipolar disorder. 6. To evaluate the ongoing effectiveness of dexmedetomidine sublingual film in treating agitation episodes. 7. To assess the effect of dexmedetomidine sublingual film on patient-specific goals regarding the management of agitated behavior. 8. To determine overall clinical improvement after medication administration as measured by rescue medication use.

[0552] Exploratory purpose: Part 1: 1. To describe patient opinions regarding taste, acceptability, and preference of dexmedetomidine sublingual film. 2. To evaluate patient satisfaction with dexmedetomidine sublingual film in the treatment of agitation episodes. The Treatment Satisfaction Questionnaire for Medication (TSQM) will be administered for this purpose at the end of the treatment period. 3. To determine overall clinical improvement after medication administration as measured by rescue medication use. 4. To evaluate the agreement between PEC scores and mCGI-S ratings.

[0553] Part 2: 1.To assess patient satisfaction with dexmedetomidine sublingual film in the treatment of agitation episodes. 2. To assess the agreement between informant and patient ratings of the mCGI-S and Clinical Global Impression-Corrected (CGI-C) scales.

[0554] Evaluation items: Primary endpoint: Part 1: Change in PEC score from baseline compared to placebo at 2 hours after drug administration.

[0555] Part 2: Incidence of SAEs and TEAEs compared with placebo.

[0556] Secondary endpoints: Part 1: 1. Number of PEC responders (patients who achieved a 40% or greater reduction from baseline in PEC total score) at or before 2 hours after drug administration. 2. Change in PEC score from baseline compared to placebo over time measured 30 minutes to 8 hours after drug administration. 3. Change in CGI-I score from baseline at 2 hours after drug administration. 4. Number of CGI-I responders (patients who achieved a CGI-I score of 1 or 2) 2 hours after drug administration 5. Change in mCGI-S score from baseline assessed 2 hours after drug administration. 6. Number of mCGI-S responders (patients who achieved a CGI-S score of 0 or 1) 2 hours after drug administration. 7. Change in ACES score from baseline at 2, 4, and 8 hours after drug administration. 8. The safety profile of dexmedetomidine sublingual film will be measured by the frequency of TEAEs, vital sign measurements, ECG, and clinical laboratory results. 9. Overall tolerability of the oral film will be measured by the frequency of TEAE reports and the incidence of local (oral / sublingual) tolerability.

[0557] Part 2: 1. Incidence of agitation-related emergency services interventions. 2. The incidence of overall adverse events and AEs leading to discontinuation. 3. Percentage of patients who reported somnolence (informant-reported ACES score ≥ 8) before and after treatment. 4. Percentage of patients reporting somnolence from pre-dose to post-dose (patient-reported Karolinska Sleepiness Scale [KSS] score ≥ 7). 5. Percentage of patients reporting improvement in agitation after administration in the first treatment episode compared to placebo (Yes / No). 6. Percentage of mCGI-S responders (patients achieving an mCGI-S score of 0 or 1) after drug administration in the first treatment episode. 7. The proportion of patients reporting a 1-point improvement in mCGI-S score after drug administration in the first treatment episode. 8. Percentage of CGI-C responders (patients achieving a CGI-C score of 1 or 2) after drug administration in the first treatment episode. 9. Change in mCGI-S score from pre- to post-administration of the first treatment episode. 10. CGI-C score after drug administration in the first treatment episode. 11. Time from administration of first treatment episode to end of agitation episode. 12. Proportion of patients reporting improvement in agitation after administration across all treatment episodes compared to placebo (Yes / No). 13. Percentage of mCGI-S responders after drug administration for the last treatment episode and all treatment episodes. 14. Proportion of patients reporting a 1-point improvement in mCGI-S score after drug administration for the last treatment episode and all treatment episodes. 15. Percentage of CGI-C responders after drug administration for the last treatment episode and all treatment episodes. 16. Change in mCGI-S score from pre- to post-drug administration for the last treatment episode and all treatment episodes. 17. CGI-C score after drug administration for the last treatment episode and all treatment episodes. 18. Frequency of treated agitation episodes compared with placebo. 19. Time from administration to the end of the agitation episode for the last treatment episode and across all treatment episodes. 20. Changes in agitation behavior scales after drug administration. 21. Change in Goal Attainment Scale (GAS) from baseline to end of study. 22. Proportion of patients receiving rescue medication compared with placebo. 23. Time to rescue medication use in patients receiving dexmedetomidine sublingual film compared to placebo.

[0558] Exploratory endpoints: Part 1: 1. Patient opinions regarding taste, acceptability, and liking of the study treatment will be assessed using a preference questionnaire. 2. To assess patient satisfaction with dexmedetomidine sublingual film in the treatment of agitation episodes using the TSQM. 3. Time to administration of rescue medication during the 8-hour post-procedure assessment in subjects receiving dexmedetomidine sublingual film compared to placebo. 4. Proportion of subjects per treatment group who received rescue medication during the 8-hour post-treatment assessment in subjects who received dexmedetomidine sublingual film compared to placebo. 5. Correlation between PEC and mCGI-S at baseline and 2 hours.

[0559] Part 2: 1. Evaluate patient satisfaction with treatment of agitation episodes using the TSQM. 2. Correlations between informant and patient ratings of the mCGI-S and CGI-C scales before and after drug administration.

[0560] Study Design: This is a Phase 3, randomized, double-blind, placebo-controlled, two-part study evaluating the efficacy, safety, and tolerability of 60 mcg or 80 mcg doses of dexmedetomidine sublingual film in adult (18-75 years) men and women with acute agitation associated with a primary diagnosis of bipolar I disorder, bipolar II disorder, schizophrenia, schizoaffective disorder, or schizophreniform disorder. The first part of the study consisted of an 8-hour office treatment period for patients experiencing an acute episode of agitation, followed by a post-treatment observation period. The second part of the study was a 12-week study to evaluate the safety and efficacy of 80 mcg dexmedetomidine sublingual film when used in a home setting to treat patients' episodes of agitation.

[0561] All patients enrolled in Part 1 were individuals who had not previously received dexmedetomidine sublingual film or been prescribed IGALMI™. Patients in Part 2 of the study had to have not been treated with prescribed IGALMI™ and may have participated in Part 1 of the study or other double-blind dexmedetomidine sublingual film studies.

[0562] Part 1: Implementation in a clinic setting: During the clinic study period, patients will be randomized 1:1 to receive 60 mcg dexmedetomidine sublingual film or a matching placebo. Eligible patients may be identified in outpatient clinics, mental health centers, psychiatric or emergency medical services (including medical / psychiatric observation units), or as newly admitted patients for acute agitation or patients already hospitalized for an underlying major psychiatric disorder. Patients will reside or be admitted to the clinical research facility where they will be under medical observation while undergoing screening procedures to assess eligibility, during treatment, and for at least an 8-hour post-treatment observation period.

[0563] Randomization will not be formally stratified, but the randomization scheme will be designed so that no more than 70% of patients in this portion of the trial will have a primary diagnosis of bipolar disorder (bipolar I or bipolar II) or schizophrenia (including schizoaffective disorder and schizophreniform disorder).

[0564] Once eligibility is confirmed, patients will be randomized to receive either a 60 mcg dexmedetomidine sublingual film or a matching dose of placebo. During administration, patients will be instructed on how to administer the study treatment sublingually and that it must be held in the sublingual cavity until dissolved. Patients will self-administer under the supervision of a trained clinic staff member. If the patient is unable to self-administer, the event will be recorded and the patient's participation in the study will be terminated. Patients will also be assessed for local irritation in the area where the film is placed. Efficacy and safety assessments will be conducted periodically before and after administration. Every effort must be made to have patients complete all protocol-defined assessments.

[0565] Rescue medications may be administered if warranted by the patient's condition (as determined by the investigator). Rescue medications may be either benzodiazepines (lorazepam, maximum dose 4 milligrams [mg] or oxazepam, maximum dose 60 mg) or any antipsychotic except clozapine, pimozide, or prochlorperazine (maximum dose approximately equivalent to 300 mg of chlorpromazine, as specified by BioXcel and selected by the investigator).

[0566] Patients are required to remain in the clinic for a minimum of 8 hours of observation after administration of study treatment.

[0567] Efficacy, safety, tolerability, and pharmacokinetics (PK) will be assessed at various time points throughout the treatment period (see Table 22: Schedule of Events Part 1 for details).

[0568] Part 2: Implementation in the social (home) environment Part 2 is a 12-week, phase 3, randomized, double-blind, placebo-controlled study in a home community setting to evaluate the safety and efficacy of an 80 mcg dose of dexmedetomidine sublingual film.

[0569] Eligible patients were individuals who had received stable treatment for their underlying primary diagnosis for at least three months and experienced periodic agitation episodes. Eligible patients could be enrolled individually or with a reliable informant who could participate in study administration if agitation episodes were treated with the study medication and accompany them to monthly clinic visits. Individually enrolled patients must have a contact who can assist with patient outreach and follow-up if site staff are unable to contact the patient for more than one week. After confirmation of eligibility, patients or patient / informant dyads were randomized 1:1 to receive either 80 mcg of dexmedetomidine sublingual film or a matching dose of placebo film when an agitation episode occurred at home.

[0570] At the baseline visit, patients or patient / informant dyads will be trained on their responsibilities during the study, including how to recognize signs and symptoms of agitation using the Agitation Behavior Scale and Goal Attainment Scale, managing agitation episodes through non-pharmacological methods (if appropriate), when to administer study treatment or rescue medication, how to take study medication, how to complete an agitation diary, and when to contact site staff. A study reference guide will be provided to patients or patient / informant dyads along with these instructions. If an agitation episode occurs, patients or patient / informant dyads will be required to complete an agitation episode diary for each episode and contact site staff as soon as possible (maximum 48 hours after the episode occurs). Note that agitation episodes in the home setting pose a higher risk of harm to the patient than those managed in a clinical setting. Additionally, 50% of patients will receive placebo as the study treatment. Patients or patient / informant dyads will be trained on safety measures, assessing risk in the event of an agitation episode, and when to call emergency services.

[0571] After randomization at the baseline visit, patients or patient / informant dyads will be dispensed three packages, each containing one 80 mcg strip of dexmedetomidine sublingual film or matching placebo. If all packages are used before the next scheduled clinic visit, the patient or informant (part of the patient / informant dyad) will be required to return the used packages and return to the clinic for three additional doses of study treatment. In this case, the investigator should carefully consider the appropriateness of the patient's antipsychotic and / or mood-stabilizing treatment and review the patient's adherence to that treatment. Additional packages may be dispensed at Visits 1 and 2, if needed, but patients should not have more than three packages of study medication total at any time.

[0572] The patient or patient / informant dyad will also be instructed on how the patient should administer the study treatment sublingually and how to hold the study treatment in the sublingual cavity until it dissolves.

[0573] At the baseline visit, the investigator will provide the patient or patient / informant dyad with a prescription for the investigator's choice of rescue medication. Patients will be instructed to administer the study medication first for the agitation episode. Ideally, patients should not take the rescue medication until 2 hours after the study procedure. If rescue medication is taken to treat the agitation episode, the study medication cannot be used to treat the agitation episode thereafter. If symptoms persist or worsen, the patient or patient / informant should be advised to contact site staff and / or seek medical care.

[0574] Training for patients or patient / informant dyads includes how to identify signs and symptoms of agitation in patients using an agitation behavior scale and a goal attainment scale. Patients are trained on when they can take study medication or rescue medication based on their own perceptions and on circumstances under which the informant can recommend that the patient self-administer a dose of study medication or rescue medication. Patients should be advised to administer study medication at home and whenever possible throughout the study. In patient / informant dyads, the informant should be present when the patient is initiating study medication and whenever possible throughout the study. This is important for collecting study data. Once the patient is familiar with the administration and subsequent effects of the study medication, the patient can administer it without the informant's presence, but it is always preferable for the informant to be present with the patient. If the patient independently records an agitation episode, follow-up is required by contacting the informant (as soon as possible) and the facility (within 48 hours).

[0575] If the patient fails to self-administer the study medication during the first agitation episode in which treatment is attempted, the event will be recorded as a missed agitation episode, along with the reason. The investigator must determine whether the patient can continue participating in the study. If, in Part 2, the patient is found to be unable to consistently self-administer during subsequent agitation episodes, the investigator must determine whether the patient can continue participating in the study. Such patients may be replaced.

[0576] Study site staff will contact patients or patient / informant dyads twice weekly from Day 0 through Day 84 or early discontinuation (ET) to inquire about any agitation episodes since the last contact. If an agitation episode has occurred, the site will request answers to all questions in the agitation episode diary based on the patient interview. For patient / informant dyads, information from the patient and informant should be recorded separately during the interview. During subsequent clinic visits, site staff should review and adjust the agitation episode diary completed by the patient or patient / informant dyad and update the corresponding electronic case report form (eCRF) as needed. If an agitation episode treated with study medication occurs, an assessment of suicidal ideation behavior should be conducted during a telephone interview using the Columbia-Suicide Severity Rating Scale (C-SSRS).

[0577] In addition, patients or patient / informant dyads will return to the clinic for follow-up visits 1 and 2 months (Days 28 and 56) after the baseline visit, and a final study visit at the end of the study at 3 months (Day 84) (see Table 23: Part 2 Event Schedule).

[0578] Independent Data Monitoring Committee: Part 2 of the study will be monitored under the oversight of a Data Monitoring Committee (DMC) independent of the sponsor.

[0579] Planned Number of Subjects: In Part 1 of the study, approximately 200 patients will be enrolled at up to approximately 20 study sites in the United States (US). In Part 2, approximately 250 patient-informant pairs will be enrolled at up to 30 study sites in the US. The same site may participate in Parts 1 and 2. Patients in Part 1 of the study must not have previously been treated with dexmedetomidine sublingual film or prescribed IGALMI™. Patients in Part 2 of the study must not have been treated with prescribed IGALMI™ and may have participated in Part 1 of the study or other double-blind dexmedetomidine sublingual film studies.

[0580] Eligibility Diagnosis and Main Criteria: Patient Inclusion Criteria (Part 1 and Part 2) 1. Male and female patients aged 18 to 75 years. 2. Patients who are able to read, understand, and provide written informed consent. 3. Patients who meet Diagnostic and Statistical Manual of Mental Disorders, v5, Text Revision (DSM-5 / 5-TR) criteria for a primary diagnosis of bipolar I or bipolar II disorder, schizophrenia, schizoaffective disorder, or schizophreniform disorder. 4. Patients who, in the opinion of the investigator, are in good general health prior to study entry based on a detailed medical history, physical examination, 12-lead ECG, blood chemistry profile, hematology, and urinalysis. 5. Female participants (if of childbearing potential and sexually active) and male participants (if sexually active with a partner of childbearing potential) who agree to use medically acceptable, effective contraception throughout the study and for one month after completion of the study. Medically acceptable contraception methods used by participants and / or their partners include abstinence, birth control pills or patches, spermicide-impregnated diaphragms, intrauterine devices (IUDs), foam or spermicide-impregnated condoms, spermicide vaginal suppositories, surgical sterilization, and progestin implants or injections. Prohibited methods include rhythm methods, withdrawal, condoms only, or diaphragms only.

[0581] Additional inclusion criteria for patients enrolled in Part 1: 1.Patients who are clinically determined to be agitated at screening and baseline, with a total score of 14 or more on the five items (poor impulse control, tension, hostility, uncooperativeness, and agitation) that make up the PANSS Agitation Item (PEC). 2. Patients with a score of 4 or higher on at least one of the five PEC items at baseline.

[0582] Additional inclusion criteria for patients enrolled in Part 2: Patients may be enrolled on their own or with an informant as part of a patient / informant dyad (see Informant Inclusion Criteria). 1. Based on medical history, within the past 2 months, the patient had at least one clinical episode of agitation requiring intervention (e.g., receipt of as-needed [PRN] medication for the episode, clinic visit, emergency room visit, emergency medical services intervention, law enforcement intervention). 2. Patients receiving stable treatment for the past 3 months for the underlying primary diagnosis. 3. Patients are able to understand and comply with study procedures, including completing an agitation episode diary.

[0583] Patient Exclusion Criteria (Part 1 and Part 2) 1. Patients with serious or unstable medical illnesses, including ongoing liver disease (moderate to severe liver impairment), renal disease, gastrointestinal disease, respiratory disease, cardiovascular disease (including ischemic heart disease and congestive heart failure), endocrine disease, or blood disease. 2. Comorbid psychiatric disorders are generally allowed. However, substance use disorders (SUDs) (within the past two years) are excluded if the substance involved is other than nicotine or caffeine. Please note that marijuana / cannabis use is not an exclusion when there is a positive urine drug screen (UDS) or the patient is admitted to use if the use meets the following criteria: a) marijuana is prescribed for medical use (medical marijuana), b) marijuana is not the sole focus of treatment, c) the severity of the cannabis-related SUD is mild or less (as defined by DSM-5 substance use disorder criteria), and 4) the illicit or recreational use has not escalated to the point of recovery from the effects of cannabis or the withdrawal symptoms (even agitation) associated with its use. 3. The investigator believes that the patient has a history of agitated episodes attributable to substance use. 4. A diagnosis of antisocial personality disorder, unstable personality disorder, or narcissistic personality disorder that precedes the diagnosis of schizophrenia or bipolar disorder or, in the opinion of the investigator, is independent of the signs and symptoms of schizophrenia or bipolar disorder. 5. Suicidal ideation as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS). Ideational functioning scores of 4 or greater in the past year will exclude patients. Clinically significant risk of suicide based on the investigator's clinical opinion or a history of actual suicide attempt in the past year will also exclude patients. 6. Active self-injurious behavior. 7.Female patients who have a positive pregnancy test at screening or baseline or are breastfeeding. 8. Patients currently receiving treatment with alpha-1 noradrenergic blockers (terazosin, doxazosin, tamsulosin, alfuzosin, or prazosin), alpha-2 adrenergic agonists, or other prohibited drugs. 9. Patients have hydrocephalus, a seizure disorder, or a history of significant head trauma, cerebral infarction, transient ischemic attack, subarachnoid hemorrhage, brain tumor, encephalopathy, meningitis, Parkinson's disease, or focal neurological findings. 10. History of syncope or other syncopal episodes, hypovolemia, signs of orthostatic hypotension, a decrease in systolic blood pressure (SBP) of 20 millimeters of mercury (mmHg) or more or a decrease in diastolic blood pressure (DBP) of 10 mmHg or more at 1 or 3 minutes after standing after 5 minutes of supine rest, a heart rate less than 55 beats per minute at screening and baseline, or an SBP less than 100 mmHg or a DBP less than 60 mmHg. 11. Patients with laboratory or ECG abnormalities deemed clinically significant by the investigator or qualified designee that were clinically relevant to the patient's participation in the study (such as a diagnosis of high-degree atrioventricular block [≥2nd degree atrioventricular block without a pacemaker], sick sinus syndrome). 12. Patients with a known personal or family history of hereditary long QT syndrome. 13. Patients who received an investigational drug within 30 days prior to the start of the study (30 days prior to the first dose in Part 1, 30 days prior to Day 0 in Part 2). 14. Patients who have previously received dexmedetomidine sublingual film via prescription (under the brand name IGALMI™) or in an open-label clinical trial. 15. Patients who are deemed by the investigator to be inappropriate candidates for dexmedetomidine administration (e.g., have a history of allergic reaction to dexmedetomidine) or who are deemed unsuitable for participation in the study for any reason.

[0584] Additional exclusion criteria for patients enrolled in Part 1: 16. Patients with agitation caused by acute intoxication, including confirmation of alcohol by breath analyzer or confirmation of drugs of abuse (excluding THC) during urine screening. 17. Use of benzodiazepines or other hypnotics or antipsychotics within 4 hours prior to study treatment. 18. Patients who have previously received dexmedetomidine sublingual film in a clinical trial.

[0585] Informant inclusion criteria (Part 2 only) 1.Age 18 years or older at the time of screening. 2. Spouse, partner, family member, friend, home manager, or home care aide of an adult patient who is determined to be eligible for the study according to the patient inclusion / exclusion criteria. 3. Known the patient for at least 12 months cumulatively. 4. Currently living with the patient or in regular contact with the patient at least 5 days a week. 5. There are no plans to discontinue patient consultation or care during the study period. 6. Willing and able to provide written informed consent. 7. Willing and able to comply with study procedures, including completing an agitation episode diary and other study procedures during the study. 8. Willing and able to accompany the patient, remain on the clinic premises during the clinic visit, and be interviewed by the investigator.

[0586] Test Procedures Randomization After confirmation of eligibility, patients will be randomized as follows:

[0587] Part 1: Patients were randomized 1:1 to receive 60 mcg of dexmedetomidine sublingual film or a matching dose of placebo.

[0588] Part 2: Patients were randomized 1:1 to receive 80 mcg of dexmedetomidine sublingual film or a matching dose of placebo.

[0589] Study randomization will be computer generated.

[0590] Test product, dosage form and route of administration: The product, dexmedetomidine hydrochloride, is a thin film formulation of dexmedetomidine for sublingual or buccal administration. The administration delivers 60 mcg of dexmedetomidine in the first portion and 80 mcg of dexmedetomidine in the second portion. The product is a thin film with an area of ​​approximately 286 square millimeters (mm ) designed to completely dissolve in the sublingual cavity within 1 to 3 minutes. 2 ) and a small solid dose film formulation 0.7 millimeters (mm) thick. Patients receive one film strip to place under the tongue in the oral cavity.

[0591] Control treatment, dose, and mode of administration: A matching dose of placebo film will be taken sublingually as above.

[0592] Treatment duration: Part 1: 8 hours, Part 2: 12 weeks.

[0593] Treatment medication administration: Patients will be instructed on how to administer the study treatment sublingually and that it should be held in the sublingual cavity until it dissolves. Although the study treatment can be administered sublingually or bucally, all patients in this study will administer the study treatment sublingually only. Patients will self-administer the dexmedetomidine sublingual film. If a patient is unable to self-administer in Part 1, an event will be recorded and the patient's participation will be terminated.

[0594] In Part 2, if the patient is unable to self-administer during the first agitation episode in which treatment is attempted, the event will be recorded and the investigator will be required to determine whether the patient can continue participating in the study.If in Part 2, the patient is found to be unable to consistently self-administer during subsequent agitation episodes, the investigator will be required to determine whether the patient can continue participating in the study.

[0595] Patients are required to refrain from eating or drinking water for 15 minutes after taking the study treatment.

[0596] In Part 1, patients are evaluated for local irritation around the area where the study treatment was placed.

[0597] Patients and informants are advised to avoid activities requiring alertness, such as driving or operating machinery, for at least 8 hours after administration of the study drug.

[0598] Exam assessment: Effectiveness The efficacy of the study treatment will be assessed in Part 1 using the validated instruments listed below: In Part 2, efficacy assessments will be conducted using the mCGI-S, CGI-C, GAS, and Agitated Behavior Scale. i. Positive and Negative Symptoms Scale Excitement Item (PEC) ii. Clinical Global Impression-Improvement Scale (CGI-I) iii. Clinical Global Impression-Change Scale (CGI-C): The CGI-C is a scale administered by informants (CGI-C-INF) and patients (CGI-C-PAT) that measures the overall change in the patient's agitation state after study drug administration. CGI-C scores range from 1 to 5. 0 = Not rated (not found) 1 = Much better, 2=A little better, 3 = no change; 4=A little worse 5=It's gotten a lot worse The CGI-C focuses on the severity of agitation rather than the overall illness severity of bipolar disorder or schizophrenia and related disorders. iv. Modified Clinical Global Impression-Severity Scale (mCGI-S): Part 1 is assessed by the investigator, and Part 2 is assessed by both the informant (mCGI-S-INF) and the patient (mCGI-S-PAT). The mCGI-S is used as an efficacy assessment in Part 2. The Handbook of Psychiatric Measures, Second Edition (Rash et al., 2008) describes an 8-point CGI-S, with a score of 0 being used if the CGI-S was not assessed, and scores of 1 to 7 indicating an increase in the severity of the psychiatric disorder or symptom being assessed. In this study, the CGI-S was modified to a 4-point scale (mCGI-S), where 0 indicates no agitation and scores of 1 to 3 indicate an increase in the severity of agitation (mild, moderate, severe). The mCGI-S is dichotomized as a score of 1 or less or 2 or greater. The mCGI-S focuses on the severity of agitation rather than the overall illness severity of bipolar disorder or schizophrenia and related disorders. v. Agitation Behavior Scale: The Agitation Behavior Scale consists of 14 observable agitated behaviors identified through a literature review of patients experiencing agitation associated with bipolar disorder and qualitative interviews with caregivers. The Agitation Behavior Scale items are individually rated by informants using a 5-point ordinal scale (0 = none, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe) according to the current level of agitation severity they have observed in the patient. These 14 items are: repetitive or compulsive behaviors; impulsive and lacking self-control; speaking quickly and yelling; resisting treatment, uncooperative, stubborn; irritable and short-tempered; self-injurious behaviors (non-suicidal) such as skin picking, hair pulling, self-cutting, and head-banging; crying and tearfulness; verbal abuse and screaming; non-verbal anger (gestures or body language); destroying, breaking, throwing, hitting, or hitting objects; physical aggression (pushing, throwing, kicking); restlessness, fidgeting, inability to sit quietly; pacing or wandering and difficulty communicating clearly. vi. Goal Attainment Scaling: Goal attainment scaling is a patient-centered method for scoring a patient's individual goals (individualized endpoints) from an intervention (Kiresuk and Sherman 1968). At baseline, the patient or patient / informant dyad and the investigator identify a pre-specified number of personal goals (maximum of three goals) related to the management of each agitation episode. The level of goal attainment (successful outcome) is defined for each goal on a 5-point scale and scored at each clinic visit.

[0599] Pharmacokinetics: Blood samples (4 milliliters [mL] each) for PK analysis will be collected in Part 1 (Table 22) at 2, 4, 6, and 8 hours post-dose according to the event schedule (Table 4).

[0600] [Table 22-1] [Table 22-2] [Table 22-3]

[0601] [Table 23-1] [Table 23-2]

Table 23-3

Claims

1. 1. A method for treating agitation in a patient having schizophrenia or bipolar disorder, comprising oromucosally administering to the patient a dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the patient is in a non-clinical setting.

2. The method of claim 1 , wherein the patient has schizophrenia.

3. 10. The method of claim 1, wherein the patient has bipolar disorder.

4. 4. The method of claim 3, wherein the patient has bipolar I disorder.

5. 4. The method of claim 3, wherein the patient has bipolar II disorder.

6. 10. The method of claim 1, wherein the non-clinical setting is a home, a group home, an assisted living facility, a correctional facility, a hospice, or a long-term care facility.

7. 3. The method of claim 1 or 2, wherein the patient is in a state of mild to moderate agitation.

8. 4. The method of any one of claims 1 to 3, wherein the patient has no more than two episodes of agitation per week.

9. The method of any one of claims 1 to 4, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered to the patient via a caregiver.

10. The method of any one of claims 1 to 4, wherein the dexmedetomidine is self-administered by the patient.

11. 7. The method of any one of claims 1 to 6, comprising administering to the patient a second dose of dexmedetomidine at least about 2 hours after the first dose if the PEC score does not improve by 2 or more points.

12. 12. The method of claim 11, wherein the second dose is about 60 micrograms, about 70 micrograms, about 80 micrograms, about 90 micrograms, about 100 micrograms, about 110 micrograms, about 120 micrograms, or about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.

13. 9. The method of any one of claims 1 to 8, wherein administration of dexmedetomidine or a pharmaceutically acceptable salt thereof provides an anti-agitation effect within about 30 minutes of administration without causing significant sedation.

14. 10. The method of any one of claims 1 to 9, wherein administration of dexmedetomidine or a pharmaceutically acceptable salt thereof provides an anti-agitation effect within about 120 minutes of administration without causing significant sedation.

15. 11. The method of any one of claims 1 to 10, comprising alerting a caregiver or informant of an impending episode of agitation via an Ecological Momentary Assessment (EMA) device or other remotely enabled device.

16. 12. The method of any one of claims 1 to 11, comprising assessing the reduction in agitation using the modified CGI-Severity (CGI-S) 4-point (0-3) scale.

17. 12. The method of any one of claims 1 to 11, comprising assessing reduction in agitation using change from baseline in the Positive and Negative Syndrome Scale-Agitation item (PEC) compared to placebo.

18. 14. The method of any one of claims 1 to 13, comprising alerting a caregiver to the reduction in agitation via an Ecological Momentary Assessment (EMA) device or other remotely enabled device.

19. 15. The method of any one of claims 1 to 14, comprising assessing the severity of agitation via a wearable device or sensor in contact with the patient's body.

20. 17. The method of any one of claims 1 to 16, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof to the patient buccally, sublingually, or gingivally.

21. The method of any one of claims 1 to 16, wherein the composition is a film, a tablet, a film, a spray, a gel, or a drop.

22. The method of any one of claims 1 to 17, wherein the patient is 18 years of age or older.

23. 10. The method of claim 1, wherein the patient has had at least one episode of agitation within the past month.

Images