The following adverse reactions are discussed in more detail in Precautions: Increased Mortality in Elderly Patients with Dementia-Related Psychosis; Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-related Psychosis; Neuroleptic Malignant Syndrome; Tardive Dyskinesia; Metabolic Changes (Hyperglycemia and Diabetes Mellitus, Dyslipidemia, and Weight Gain); Hyperprolactinemia; Leukopenia, Neutropenia, and Agranulocytosis; Orthostatic Hypotension and Syncope; Seizures; Potential for Cognitive and Motor Impairment; Body Temperature Dysregulation; Suicide; Dysphagia; Neurological Adverse Reactions in Patients with Parkinson's Disease or Dementia with Lewy Bodies.
Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
The information as follows is derived from an integrated clinical study database for LATUDA consisting of 2905 patients exposed to one or more doses of LATUDA for the treatment of schizophrenia in placebo-controlled studies. This experience corresponds with a total experience of 985.3 patient-years. A total of 769 LATUDA-treated patients had at least 24 weeks and 371 LATUDA-treated patients had at least 52 weeks of exposure.
Adverse events during exposure to study treatment were obtained by general inquiry and voluntarily reported adverse experiences, as well as results from physical examinations, vital signs, ECGs, weights and laboratory investigations. Adverse experiences were recorded by clinical investigators using their own terminology. In order to provide a meaningful estimate of the proportion of individuals experiencing adverse events, events were grouped in standardized categories using MedDRA terminology.
Schizophrenia: Short-term Studies: The following findings are based on the short-term, placebo-controlled studies for schizophrenia in which LATUDA was administered at daily doses ranging from 20 to 160 mg (n=1508).
Commonly Observed Adverse Reactions: The most common adverse reactions (incidence ≥ 5% and at least twice the rate of placebo) in patients treated with LATUDA were somnolence, akathisia, extrapyramidal symptoms, and nausea.
Adverse Reactions Associated with Discontinuation of Treatment: A total of 9.5% (143/1508) LATUDA-treated patients and 9.3% (66/708) of placebo-treated patients discontinued due to adverse reactions. There were no adverse reactions associated with discontinuation in subjects treated with LATUDA that were at least 2% and at least twice the placebo rate.
Adverse Reactions Occurring at an Incidence of 2% or More in LATUDA-Treated Patients: Adverse reactions associated with the use of LATUDA (incidence of 2% or greater, rounded to the nearest percent and LATUDA incidence greater than placebo) that occurred during acute therapy (up to 6 weeks in patients with schizophrenia) are shown in Table 7.
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Dose-Related Adverse Reactions in the Schizophrenia Studies: Akathisia and extrapyramidal symptoms were dose-related. The frequency of akathisia increased with dose up to 120 mg/day (5.6% for LATUDA 20 mg, 10.7% for LATUDA 40 mg, 12.3% for LATUDA 80 mg, and 22.0% for LATUDA 120 mg). Akathisia was reported by 7.4% (9/121) of patients receiving 160 mg/day. Akathisia occurred in 3.0% of subjects receiving placebo. The frequency of extrapyramidal symptoms increased with dose up to 120 mg/day (5.6% for LATUDA 20 mg, 11.5 % for LATUDA 40 mg, 11.9% for LATUDA 80 mg, and 22.0% for LATUDA 120 mg).
Extrapyramidal Symptoms: Schizophrenia: In the short-term, placebo-controlled schizophrenia studies, for LATUDA-treated patients, the incidence of reported events related to extrapyramidal symptoms (EPS), excluding akathisia and restlessness, was 13.5% versus 5.8% for placebo-treated patients. The incidence of akathisia for LATUDA-treated patients was 12.9% versus 3.0% for placebo-treated patients. Incidence of EPS by dose is provided in Table 8.
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In the short-term, placebo-controlled schizophrenia studies, data was objectively collected on the Simpson Angus Rating Scale (SAS) for extrapyramidal symptoms (EPS), the Barnes Akathisia Scale (BAS) for akathisia and the Abnormal Involuntary Movement Scale (AIMS) for dyskinesias.
Schizophrenia: The mean change from baseline for LATUDA-treated patients was comparable to placebo-treated patients, with the exception of the Barnes Akathisia Scale global score (LATUDA, 0.1; placebo, 0.0). The percentage of patients who shifted from normal to abnormal was greater in LATUDA-treated patients versus placebo for the BAS (LATUDA, 14.4%; placebo, 7.1%) and the SAS (LATUDA, 5.0%; placebo, 2.3%) and the AIMS (LATUDA, 7.4%; placebo, 5.8%).
Dystonia: Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first-generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.
Schizophrenia: In the short-term, placebo-controlled schizophrenia clinical studies, dystonia occurred in 4.2% of LATUDA-treated subjects (0.0% LATUDA 20 mg, 3.5% LATUDA 40 mg, 4.5% LATUDA 80 mg, 6.5% LATUDA 120 mg and 2.5% LATUDA 160 mg) compared to 0.8% of subjects receiving placebo. Seven subjects (0.5%, 7/1508) discontinued clinical trials due to dystonic events - four were receiving LATUDA 80 mg/day and three were receiving LATUDA 120 mg/day.
Other Adverse Reactions Observed During the Premarketing Evaluation of LATUDA: Following is a list of adverse reactions reported by patients treated with LATUDA at multiple doses of ≥20 mg once daily within the premarketing database of 2905 patients with schizophrenia. The reactions listed are those that could be of clinical importance, as well as reactions that are plausibly drug-related on pharmacologic or other grounds. Reactions listed in Table 7 or those that appear elsewhere in the LATUDA label are not included. Although the reactions reported occurred during treatment with LATUDA, they were not necessarily caused by it.
Reactions are further categorized by organ class and listed in order of decreasing frequency according to the following definitions: those occurring in at least 1/100 patients (frequent) (only those not already listed in the tabulated results from placebo-controlled studies appear in this listing); those occurring in 1/100 to 1/1000 patients (infrequent); and those occurring in fewer than 1/1000 patients (rare).
Blood and Lymphatic System Disorders: Infrequent: anemia.
Cardiac Disorders: Frequent: tachycardia; Infrequent: AV block 1st degree, angina pectoris, bradycardia.
Ear and Labyrinth Disorders: Infrequent: vertigo.
Eye Disorders: Frequent: blurred vision.
Gastrointestinal Disorders: Frequent: abdominal pain, diarrhea; Infrequent: gastritis.
General Disorders and Administrative Site Conditions: Rare: sudden death.
Investigations: Frequent: CPK increased.
Metabolism and Nutritional System Disorders: Frequent: decreased appetite.
Musculoskeletal and Connective Tissue Disorders: Rare: rhabdomyolysis.
Nervous System Disorders: Infrequent: cerebrovascular accident, dysarthria.
Psychiatric Disorders: Infrequent: abnormal dreams, panic attack, sleep disorder.
Renal and Urinary Disorders: Infrequent: dysuria; Rare: renal failure.
Reproductive System and Breast Disorders: Infrequent: amenorrhea, dysmenorrhea; Rare: breast enlargement, breast pain, galactorrhea, erectile dysfunction.
Skin and Subcutaneous Tissue Disorders: Frequent: rash, pruritus; Rare: angioedema.
Vascular Disorders: Frequent: hypertension.
Clinical Laboratory Changes: Schizophrenia: Serum Creatinine: In short-term, placebo-controlled trials, the mean change from Baseline in serum creatinine was +0.05 mg/dL for LATUDA-treated patients compared to +0.02 mg/dL for placebo-treated patients. A creatinine shift from normal to high occurred in 3.0% (43/1453) of LATUDA-treated patients and 1.6% (11/681) on placebo. The threshold for high creatinine value varied from >0.79 to >1.3 mg/dL based on the centralized laboratory definition for each study (see Table 9).
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