IGALMI SIDE EFFECTS

SIDE EFFECTS

The following adverse reactions are discussed in detail in other sections of the labeling:

• Hypotension, Orthostatic Hypotension, and Bradycardia.
• QT Interval Prolongation.
• Somnolence.
• Risk of Withdrawal Reactions.
• Tolerance and Tachyphylaxis.

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). 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, paresthesia or oral hypoesthesia, dizziness, dry mouth, hypotension, and orthostatic hypotension.

Table 1 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 1: 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)

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 2 presents the mean BP and HR decrease across all patients from both studies at 2 hours post dose.

Table 2: Mean Blood Pressure and Heart Rate Decrease At 2 Hours Post-Dose

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.

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