IGALMI

1 INDICATIONS AND USAGE IGALMI is indicated for the acute treatment of agitation associated with schizophrenia or bipolar I or II disorder in adults. IGALMI is an alpha-2 adrenergic receptor agonist indicated in adults for the acute treatment of agitation associated with schizophrenia or bipolar I or II disorder. ( 1 ) Limitations of Use : The safety and effectiveness of IGALMI has not been established beyond 24 hours from the first dose. ( 1 , 5.4 , 5.5 ) Limitations of Use The safety and effectiveness of IGALMI have not been established beyond 24 hours from the first dose [see Warnings and Precautions (5.4 , 5.5) ] .

2 DOSAGE AND ADMINISTRATION IGALMI should be administered under the supervision of a healthcare provider. A healthcare provider should monitor vital signs and alertness after IGALMI administration to prevent falls and syncope. ( 2.1 ) Administer sublingually or buccally. Do not chew or swallow. ( 2.1 ) Recommended dosage ( 2.2 ): Patient Population Agitation Severity Initial Dose See Full Prescribing Information for recommendations on administering up to two additional doses and maximum recommended dosages. Adults Mild or Moderate 120 mcg Severe 180 mcg Mild or Moderate Hepatic Impairment Mild or Moderate 90 mcg Severe 120 mcg Severe Hepatic Impairment Mild or Moderate 60 mcg Severe 90 mcg Geriatric Patients (≥ 65 years old) Mild, Moderate, or Severe 120 mcg IGALMI 120 mcg and 180 mcg dosage strengths may be cut in half to obtain the 60 mcg and 90 mcg doses, respectively. See Full Prescribing Information for preparation and administration instructions. ( 2.3 ) 2.1 Important Recommendations Prior to Initiating IGALMI and During Therapy IGALMI should be administered under the supervision of a healthcare provider. A healthcare provider should monitor vital signs and alertness after IGALMI administration to prevent falls and syncope [see Warnings and Precautions (5.5) ] . IGALMI is for sublingual or buccal administration. Do not chew or swallow IGALMI. Do not eat or drink for at least 15 minutes after sublingual administration, or at least one hour after buccal administration. 2.2 Recommended Dosage Table 1 includes dosage recommendations for IGALMI based on agitation severity for adults, patients with hepatic impairment, and geriatric patients. Lower dosages are recommended for patients with hepatic impairment and geriatric patients [see Warnings and Precautions (5.1) and Use in Specific Populations (8.5 , 8.6) ]. If agitation persists after the initial dose, up to two additional doses may be administered at least two hours apart. The dosage recommendations for additional doses vary depending upon the patient population and agitation severity (see Table 1 ). Assess vital signs including orthostatic measurements prior to the administration of any subsequent doses. Due to risk of hypotension, additional half-doses are not recommended in patients with systolic blood pressure (SBP) less than 90 mmHg, diastolic blood pressure (DBP) less than 60 mmHg, heart rate (HR) less than 60 beats per minute, or postural decrease in SBP ≥ 20 mmHg or in DBP ≥ 10 mmHg. Table 1: Dosage Recommendations for IGALMI in Adults, Adult Patients with Hepatic Impairment, and Geriatric Patients with Agitation Associated with Schizophrenia or Bipolar I or II Disorder Patient Population Agitation Severity Initial Dose IGALMI 120 mcg and 180 mcg dosage strengths may be cut in half to obtain the 60 mcg and 90 mcg doses, respectively [see Dosage and Administration (2.3) ] . Optional 2 nd /3 rd Doses Maximum Recommended Total Daily Dosage Adults Mild or Moderate 120 mcg 60 mcg 240 mcg Severe 180 mcg 90 mcg 360 mcg Patients with Mild or Moderate Hepatic Impairment Hepatic impairment: Mild (Child-Pugh Class A); Moderate (Child-Pugh Class B); Severe (Child-Pugh Class C) Mild or Moderate 90 mcg 60 mcg 210 mcg Severe 120 mcg 60 mcg 240 mcg Patients with Severe Hepatic Impairment Mild or Moderate 60 mcg 60 mcg 180 mcg Severe 90 mcg 60 mcg 210 mcg Geriatric Patients (≥ 65 years old) Mild, Moderate, or Severe 120 mcg 60 mcg 240 mcg 2.3 Preparation and Administration Instructions Keep IGALMI in the foil pouch until ready to administer. IGALMI should be immediately administered once the pouch is opened and the dose prepared. Prepare and administer IGALMI under the supervision of a healthcare provider as follows: Healthcare Professional: Prepare IGALMI Dose for Patient 1 Open the sealed foil pouch by tearing straight across at the notch. Perform Steps 2a, 2b, 2c and 2d only if a 60 mcg or 90 mcg dose (half of a film) is needed, then proceed to Step 3. If administering a full dose (1 film), proceed directly to Step 3. 2a Remove the film from the pouch with clean dry hands. 2b Cut the film in half between the dots with clean, dry scissors. 2c Discard unused half in waste container. 2d Place the half film for administration to the patient back into the pouch. 3 Immediately give the pouch to the patient. 4 Instruct patient to remove the film from the pouch with clean dry hands. 5 For sublingual administration: Instruct patient to place film under the tongue. The film will stick in place. Note: Patient may not eat or drink for 15 minutes after sublingual administration. For buccal administration: Instruct patient to place film behind lower lip. The film will stick in place. Note: Patient may not eat or drink for one hour after buccal administration. 6 Instruct patient to: Close their mouth. Allow the film to dissolve. Do not chew or swallow the film. Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure

4 CONTRAINDICATIONS None. None. ( 4 )

5 WARNINGS AND PRECAUTIONS Hypotension, Orthostatic Hypotension, and Bradycardia: Avoid use of IGALMI in patients with hypotension, orthostatic hypotension, advanced heart block, severe ventricular dysfunction, or history of syncope. Ensure that patients are alert and not experiencing orthostatic or symptomatic hypotension prior to resuming ambulation. ( 5.1 ) QT Interval Prolongation: IGALMI prolongs the QT interval; avoid use in patients with risk factors for prolonged QT interval. ( 5.2 ) Somnolence: Patients should not perform activities requiring mental alertness, such as operating a motor vehicle or operating hazardous machinery for at least eight hours after taking IGALMI. ( 5.3 ) 5.1 Hypotension, Orthostatic Hypotension, and Bradycardia IGALMI causes dose-dependent hypotension, orthostatic hypotension, and bradycardia . In clinical studies, 18%, 16%, and 9% of patients treated with 180 mcg of IGALMI, 120 mcg of IGALMI, and placebo, respectively, experienced orthostatic hypotension (defined as SBP decrease ≥ 20 mmHg or DBP decrease ≥ 10 mmHg after 1, 3, or 5 minutes of standing) at 2 hours post-dose. In those studies, 7%, 6%, and 1% of patients treated with 180 mcg of IGALMI, 120 mcg of IGALMI, and placebo, respectively, experienced HR ≤ 50 beats per minute within 2 hours of dosing [see Adverse Reactions (6.1) ]. In clinical studies with IGALMI, patients were excluded if they had treatment with alpha-1 noradrenergic blockers, benzodiazepines, other hypnotics or antipsychotic drugs four hours prior to study drug administration; had a history of syncope or syncopal attacks; SBP < 110 mmHg; DBP < 70 mmHg; HR < 55 beats per minute; or had evidence of hypovolemia or orthostatic hypotension. Reports of hypotension and bradycardia, including some resulting in fatalities, have been associated with the use of another dexmedetomidine product given intravenously (IGALMI is for sublingual or buccal use and is not approved for intravenous use). Clinically significant episodes of bradycardia and sinus arrest have been reported after administration of this other dexmedetomidine product to young, healthy adult volunteers with high vagal tone and when this product was given by rapid intravenous or bolus administration. Because IGALMI decreases sympathetic nervous system activity, hypotension and/or bradycardia may be more pronounced in patients with hypovolemia, diabetes mellitus, or chronic hypertension, and in geriatric patients [see Dosage and Administration (2.2) and Use in Specific Populations (8.5) ]. Avoid use of IGALMI in patients with hypotension, orthostatic hypotension, advanced heart block, severe ventricular dysfunction, or history of syncope. After IGALMI administration, patients should be adequately hydrated and should sit or lie down until vital signs are within normal range. If a patient is unable to remain seated or lying down, precautions should be taken to reduce the risk of falls. Ensure that a patient is alert and not experiencing orthostatic hypotension or symptomatic hypotension prior to allowing them to resume ambulation [see Dosage and Administration (2.1) ]. 5.2 QT Interval Prolongation IGALMI prolongs the QT interval. Avoid use of IGALMI in patients at risk of torsades de pointes or sudden death including those with known QT prolongation, a history of other arrhythmias, symptomatic bradycardia, hypokalemia or hypomagnesemia, and in patients receiving other drugs known to prolong the QT interval [see Drug Interactions (7.1) and Clinical Pharmacology (12.2) ]. 5.3 Somnolence IGALMI can cause somnolence. In placebo-controlled clinical studies in adults with agitation associated with schizophrenia or bipolar I or II disorder, somnolence (including fatigue and sluggishness) was reported in 23% and 22% of patients treated with IGALMI 180 mcg and 120 mcg, respectively, compared to 6% of placebo-treated patients. Patients should not perform activities requiring mental alertness, such as operating a motor vehicle or operating hazardous machinery, for at least eight hours after taking IGALMI [see Adverse Reactions (6.1) ] . 5.4 Risk of Withdrawal Reactions Symptoms of withdrawal have been observed after treatment with another dexmedetomidine product administered as a continuous IV infusion in the ICU for another indication. In this study, 12 (5%) adult patients who received intravenous dexmedetomidine up to 7 days (regardless of dose) experienced at least 1 event related to withdrawal within the first 24 hours after discontinuing dexmedetomidine and 7 (3%) adult patients who received intravenous dexmedetomidine experienced at least 1 event related with withdrawal 24 to 48 hours after discontinuing dexmedetomidine. The most common withdrawal reactions were nausea, vomiting, and agitation. In these subjects, tachycardia and hypertension requiring intervention occurred at a frequency of <5% in the 48 hours following intravenous dexmedetomidine discontinuation. Withdrawal symptoms have been reported in pediatric patients who received another dexmedetomidine product intravenously for another indication. IGALMI is not approved for pediatric use. Withdrawal symptoms reported in published literature include cardiovascular symptoms, such as hypertension, tachycardia, arrhythmias, and in severe cases, hypertensive crisis; neurological symptoms, such as agitation, anxiety, tremors, seizures, and altered mental status; and autonomic symptoms such as diaphoresis, nausea, vomiting, hyperthermia, and mydriasis. In a randomized, double-blind, placebo-controlled, multiple ascending dose study assessing IGALMI at doses up to 120 mcg per day administered over 7 days in healthy volunteers, elevated heart rate and systolic blood pressure and vomiting occurred at a higher frequency upon abrupt discontinuation of 120-mcg doses of IGALMI as compared to placebo. There may be a risk of physical dependence and a withdrawal syndrome if IGALMI is used in a manner other than indicated [see Dosage and Administration (2.2) and Drug Abuse and Dependence (9.3) ] . 5.5 Tolerance and Tachyphylaxis Use of another dexmedetomidine product administered intravenously beyond 24 hours has been associated with tolerance and tachyphylaxis and a dose-related increase in adverse reactions. The effectiveness of IGALMI beyond 24 hours after the first dose has not been established. There may be a risk of tolerance and tachyphylaxis if IGALMI is administered at higher doses or for a longer duration than were evaluated, or in a manner other than indicated [see Dosage and Administration (2.2) and Drug Abuse and Dependence (9.3) ] .

7 DRUG INTERACTIONS Drugs that Prolong the QT interval: Avoid use. ( 7.1 ) Anesthetics, Sedatives, Hypnotics, Opioids: Concomitant use may cause enhanced CNS depressant effects. Reduction in dosage of IGALMI or the concomitant medication may be required. ( 7.2 ) 7.1 Drugs that Prolong the QT Interval Concomitant use of drugs that prolong the QT interval may add to the QT-prolonging effects of IGALMI and increase the risk of cardiac arrhythmia. Avoid the use of IGALMI in combination with other drugs known to prolong the QT interval [see Warnings and Precautions (5.2) ] . 7.2 Anesthetics, Sedatives, Hypnotics, and Opioids Concomitant use of IGALMI with anesthetics, sedatives, hypnotics, or opioids is likely to lead to enhanced CNS depressant effects. Specific studies with another dexmedetomidine product given intravenously have confirmed these effects with sevoflurane, isoflurane, propofol, alfentanil, and midazolam. Due to possible enhanced CNS effects when given concomitantly with IGALMI, consider a reduction in dosage of IGALMI or the concomitant anesthetic, sedative, hypnotic, or opioid.

6 ADVERSE REACTIONS The following adverse reactions are discussed in detail in other sections of the labeling: Hypotension, Orthostatic Hypotension, and Bradycardia [see Warnings and Precautions (5.1) ] QT Interval Prolongation [see Warnings and Precautions (5.2) ] Somnolence [see Warnings and Precautions (5.3) ] Risk of Withdrawal Reactions [see Warnings and Precautions (5.4) ] Tolerance and Tachyphylaxis [see Warnings and Precautions (5.5) ] The most common adverse reactions (incidence ≥5% and at least twice the rate of placebo) are somnolence, oral paresthesia or oral hypoesthesia, dizziness, dry mouth, hypotension, and orthostatic hypotension. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact BioXcel Therapeutics, Inc. at 1-833-201-1088 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. The safety of IGALMI was evaluated in 507 adult patients with agitation associated with schizophrenia (N=255) or bipolar I or II disorder (N=252) in two randomized, placebo-controlled studies (Studies 1 and 2) [see Clinical Studies (14) ] . In both studies, patients were admitted to a clinical research unit or a hospital and remained under medical supervision for at least 24 hours following treatment. Patients were 18 to 71 years of age (mean age was 46 years old); 45% were female and 55% were male; 66% were Black, 31% were White, 2% were multiracial, and 1% were other. In these studies, patients received an initial dose of IGALMI 180 mcg (N=252), IGALMI 120 mcg (N=255), or placebo (N=252). Patients who were hemodynamically stable (i.e., those with systolic blood pressure (SBP) > 90 mmHg, diastolic blood pressure (DBP) > 60 mmHg, and heart rate (HR) > 60 beats per minute) and without orthostatic hypotension (i.e., reduction in SBP < 20 mmHg or DBP < 10 mmHg upon standing) were eligible for an additional dose after 2 hours. An additional half dose (90 mcg, 60 mcg, or placebo) was given to 7.1% (18/252), 22.7% (58/255) and 44.0% (111/252) of patients in the IGALMI 180 mcg, IGALMI 120 mcg or placebo arms, respectively. After at least an additional 2 hours, an additional second half dose (total IGALMI dose of 360 mcg, total IGALMI dose of 240 mcg, or placebo, respectively) was given to 3.2% (8/252), 9.4% (24/255), and 21.0% (53/252) of patients in the IGALMI 180 mcg, IGALMI 120 mcg or placebo arms, respectively. In these studies, one patient discontinued treatment due to an adverse reaction of oropharyngeal pain. The most common adverse reactions (incidence ≥ 5% and at least twice the rate of placebo) were: somnolence, oral paresthesia or oral hypoesthesia, dizziness, dry mouth, hypotension, and orthostatic hypotension. Table 2 presents the adverse reactions that occurred in IGALMI-treated patients at a rate of at least 2% and at a higher rate than in placebo-treated patients in Studies 1 and 2. Table 2: Adverse Reactions Reported in ≥2% of IGALMI-Treated Patients and Greater than Placebo in Two Placebo-Controlled Studies of Agitated Adult Patients with Schizophrenia or Bipolar I or II Disorder (Studies 1 and 2) Adverse Reaction IGALMI 180 mcg N=252 % IGALMI 120 mcg N=255 % Placebo N=252 % Somnolence Somnolence includes the terms fatigue and sluggishness 23 22 6 Paresthesia oral or hypoesthesia oral 7 6 1 Dizziness 6 4 1 Hypotension 5 5 0 Orthostatic hypotension 5 3 <1 Dry mouth 4 7 1 Nausea 3 2 2 Bradycardia 2 2 0 Abdominal discomfort Abdominal discomfort includes dyspepsia, gastroesophageal reflux disease 2 0 1 Hypotension, Orthostatic Hypotension, and Bradycardia in Two Placebo-Controlled Studies In clinical studies, patients were excluded if they were treated with alpha-1 noradrenergic blockers, benzodiazepines, antipsychotic drugs, or other hypnotics four hours prior to study drug administration; had a history of syncope or syncopal attacks; their SBP was less than 110 mmHg; their DBP was less than 70 mmHg; their HR was less than 55 beats per minute; or they had evidence of hypovolemia or orthostatic hypotension. In these studies, vital signs were monitored (at 30 minutes, 1-, 2-, 4-, 6-, and 8-hours post-dose), including orthostatic vital signs at 2-, 4-, and 8-hours post-dose. Maximum positional decreases in SBP and DBP after standing were observed at two hours post-dose. Maximal reductions on BP and HR were observed two hours post-dose. Table 3 presents the mean BP and HR decrease across all patients from both studies at 2 hours post dose. Table 3: Mean Blood Pressure and Heart Rate Decrease At 2 Hours Post-Dose IGALMI 180 mcg N=252 IGALMI 120 mcg N=255 Placebo N=252 Mean SBP Decrease (mmHg) 15 13 1 Mean DBP Decrease (mmHg) 8 7 <1 Mean Heart Rate Decrease (bpm) 9 7 3 In the clinical studies: 13%, 8%, and < 1% of patients in the single dose 180 mcg IGALMI, 120 mcg IGALMI, and placebo groups, respectively, experienced SBP ≤ 90 mmHg and a decrease ≥ 20 mmHg of SBP within 24 hours of dosing. 19%, 17%, and 2% of the patients in the 180 mcg IGALMI, 120 mcg IGALMI, and placebo groups, respectively, had a DBP ≤ 60 mmHg and a DBP decrease ≥ 10 mmHg within 24 hours of dosing. 4%, 3%, and 0% of patients in the 180 mcg IGALMI, 120 mcg IGALMI, and placebo groups, respectively, had a HR ≤ 50 beats per minute and a HR decrease ≥ 20 beats per minute within 24 hours of dosing. At 8 hours post-dose, 2% of patients in the IGALMI 180 mcg group experienced a SBP ≤ 90 mmHg and decrease ≥ 20 mmHg compared with one patient (<1%) in the IGALMI 120 mcg group and none in the placebo group. At 24 hours, none of the patients in the IGALMI 180 mcg group experienced a SBP ≤90 mmHg and decrease ≥ 20 mmHg compared with one patient (<1%) in the IGALMI 120 mcg group and none in the placebo group. At 8 hours post-dose, none of the patients in the IGALMI 180 mcg group had a HR ≤ 50 beats per minute and a HR decrease ≥ 20 beats per minute compared with one patient in the 120 mcg group (<1%) and none in the placebo group. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of another dexmedetomidine product given intravenously (IGALMI is not approved for intravenous use). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders : Anemia Cardiac Disorders : Arrhythmia, atrial fibrillation, atrioventricular block, bradycardia, cardiac arrest, cardiac disorder, extrasystoles, myocardial infarction, supraventricular tachycardia, tachycardia, ventricular arrhythmia, ventricular tachycardia Eye Disorders : Photopsia, visual impairment Gastrointestinal Disorders : Abdominal pain, diarrhea, nausea, vomiting General Disorders and Administration Site Conditions : Chills, hyperpyrexia, pain, pyrexia, thirst Hepatobiliary Disorders : Hepatic function abnormal, hyperbilirubinemia Investigations : Alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, blood urea increased, electrocardiogram T wave inversion, gammaglutamyltransferase increased, electrocardiogram QT prolonged Metabolism and Nutrition Disorders : Acidosis, hyperkalemia, hypoglycemia, hypovolemia, hypernatremia Nervous System Disorders : Convulsion, dizziness, headache, neuralgia, neuritis, speech disorder Psychiatric Disorders : Agitation, confusional state, delirium, hallucination, illusion Renal and Urinary Disorders : Oliguria, polyuria Respiratory, Thoracic and Mediastinal Disorders : Apnea, bronchospasm, dyspnea, hypercapnia, hypoventilation, hypoxia, pulmonary congestion, respiratory acidosis Skin and Subcutaneous Tissue Disorders : Hyperhidrosis, pruritus, rash, urticaria Surgical and Medical Procedures : Light anesthesia Vascular Disorders : Blood pressure fluctuation, hemorrhage, hypertension, hypotension

8.1 Pregnancy Risk Summary There are no available data on IGALMI use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal effects. Available data from published randomized controlled trials and case reports over several decades of use with intravenously administered dexmedetomidine during pregnancy have not identified a drug-associated risk of major birth defects or miscarriage; however, the reported exposures occurred after the first trimester. Most of the available data are based on studies with exposures that occurred at the time of cesarean-section delivery, and these studies have not identified an adverse effect on maternal outcomes or infant Apgar scores. Available data indicate that dexmedetomidine crosses the placenta. In animal reproductive studies fetal toxicity occurred in the presence of maternal toxicity with subcutaneous administration of dexmedetomidine to pregnant rats during organogenesis at doses 5 times the maximum recommended human dose [MRHD] of 360 mcg/day based on mg/m 2 body surface area. Adverse developmental effects, including early implantation loss and decreased viability of second generation offspring, occurred when pregnant rats were subcutaneously administered doses less than or equal to the MRHD based on mg/m 2 from late pregnancy through lactation and weaning (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Increased post-implantation losses and reduced live pups in the presence of maternal toxicity (decreased body weight) occurred in a rat embryo-fetal development study in which pregnant dams were administered subcutaneous doses of dexmedetomidine of 200 mcg/kg/day (equivalent to 5 times the MRHD of 360 mcg/day based on mg/m 2 ) during the period of organogenesis (Gestation Day (GD) 5 to 16). No embryo-fetal toxicity was observed at 20 mcg/kg/day (less than the MRHD of 360 mcg/day based on mg/m 2 ). No malformations were reported at any dose level. No malformation or embryo-fetal toxicity were observed in a rabbit embryo-fetal developmental study in which pregnant dams were administered dexmedetomidine intravenously at doses up to 96 mcg/kg/day (equivalent to 5 times the MRHD of 360 mcg/day based on mg/m 2 ) during the period of organogenesis (GD 6 to 18). Reduced pup and adult offspring weights and grip strength were reported in a rat developmental toxicology study in which pregnant females were administered dexmedetomidine subcutaneously at 8 mcg/kg/day (less than the MRHD of 360 mcg/day based on mg/m 2 ) during late pregnancy through lactation and weaning (GD 16 to postnatal day [PND] 25). Decreased viability of second generation offspring and an increase in early implantation loss along with delayed motor development occurred at 32 mcg/kg/day (equivalent to the MRHD of 360 mcg/day based on mg/m 2 ) when first generation offspring were mated. This study limited dosing to hard palate closure (GD 15-18) through weaning instead of standard dosing from implantation (GD 6-7) to weaning (PND 21).