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adverse reactions
6 ADVERSE REACTIONS The following are discussed in more detail in previous sections of the labeling: Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see Boxed Warning and Warnings and Precautions ( 5.1 )] Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis [see Warnings and Precautions ( 5.2 )] Neuroleptic Malignant Syndrome (NMS) [see Warnings and Precautions ( 5.3 )] Tardive Dyskinesia [see Warnings and Precautions ( 5.4 )] Metabolic Changes [see Warnings and Precautions ( 5.5 )] Hyperprolactinemia [see Warnings and Precautions ( 5.6 )] Orthostatic Hypotension and Syncope [see Warnings and Precautions ( 5.7 )] Falls [see Warnings and Precautions ( 5.8 )] Leukopenia, Neutropenia and Agranulocytosis [see Warnings and Precautions ( 5.9 )] Potential for Cognitive and Motor Impairment [see Warnings and Precautions ( 5.10 )] Seizures [see Warnings and Precautions ( 5.11 )] Dysphagia [see Warnings and Precautions ( 5.12 )] Priapism [see Warnings and Precautions ( 5.13 )] Body Temperature Regulation [see Warnings and Precautions ( 5.14 )] The most common adverse reactions in clinical trials (≥ 5% and greater than twice placebo) were increased weight, sedation/somnolence, and musculoskeletal pain. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Indivior Inc. at 1-877-782-6966 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the 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 practice. The safety of PERSERIS was evaluated in a total of 837 adult patients with schizophrenia who received at least 1 dose of PERSERIS during the clinical development program. A total of 322 patients were exposed to PERSERIS for at least 6 months, of which 234 patients were exposed to PERSERIS for at least 12 months; 281 and 176 of these, respectively, received the 120 mg dose. Adverse drug reactions in adult patients with schizophrenia (≥ 5% in any PERSERIS-treated group and greater than placebo) during the 8-week double-blind, placebo-controlled study) were weight increased, constipation, sedation/somnolence, pain in extremity, back pain, akathisia, anxiety, and musculoskeletal pain. In addition, the frequency of reported injection site reactions was similar across treatment groups with both PERSERIS and placebo; the most common (≥ 5%) of which were injection site pain, and erythema. The systemic safety profile for PERSERIS was consistent with the known safety profile of oral risperidone. Commonly-Observed Adverse Drug Reactions in Double-Blind, Placebo-Controlled Clinical Studies – Schizophrenia Adverse Reactions with an incidence of 2% or more and greater than placebo are shown in Table 4 . Table 4 Adverse Drug Reactions in 2% or More of PERSERIS-Treated Patients (and Greater than Placebo) in an 8-Week Double-Blind, Placebo-Controlled Study * Sedation includes sedation and somnolence System Organ Class Preferred Term PERSERIS 90 mg (n = 115) PERSERIS 120 mg (n = 117) Placebo (n = 118) Percentage of Patients Reporting ADR Gastrointestinal disorders Constipation 7.0 7.7 5.1 Abdominal discomfort 2.6 2.6 1.7 Dry mouth 1.7 2.6 1.7 Investigations Weight increased 13.0 12.8 3.4 Metabolism and nutrition disorders Increased appetite 1.7 3.4 1.7 Musculoskeletal and connective tissue disorders Back pain 3.5 6.8 4.2 Pain in extremity 0.9 7.7 5.1 Musculoskeletal pain 5.2 5.1 2.5 Musculoskeletal stiffness 2.6 0.9 1.7 Muscle spasms 0 2.6 0 Nervous system disorders Sedation* 7.0 7.7 0 Akathisia 2.6 6.8 4.2 Extrapyramidal disorder 4.3 1.7 0.8 Psychiatric disorders Anxiety 2.6 6.8 5.1 Other Adverse Drug Reactions Observed During the Clinical Trial Evaluation of PERSERIS The following list does not include reactions: 1) already listed in previous tables or elsewhere in labeling, 2) which are part of the disease state, 3) for which a drug cause was remote, 4) which were so general as to be uninformative, or 5) which were not considered to have significant clinical implications. Blood and Lymphatic System Disorders: neutropenia Ear and Labyrinth Disorders: vertigo Endocrine Disorders: hyperprolactinemia Eye Disorders: blepharospasm Gastrointestinal Disorders: nausea, dyspepsia, vomiting, diarrhea, abdominal pain upper, salivary hypersecretion, hypoesthesia oral, tongue movement disturbance General Disorders and Administration Site Conditions: injection site reaction (including injection site pain, induration, pruritus, bruising, erythema, inflammation, swelling and irritation) fatigue, edema peripheral, asthenia, chest discomfort Investigations: blood prolactin increased, blood glucose increased, glycosylated hemoglobin increased, electrocardiogram abnormal, electrocardiogram QT prolonged, blood creatine phosphokinase increased Metabolism and Nutrition Disorders: diabetes mellitus, decreased appetite Musculoskeletal, Connective Tissue, and Bone Disorders: arthralgia, muscle twitching, joint stiffness, trismus Nervous System Disorders: headache, dizziness, tremor, drooling, dyskinesia, lethargy, dystonia, hypoesthesia, oromandibular dystonia, tardive dyskinesia, cogwheel rigidity, dysarthria, balance disorder, parkinsonian rest tremor, parkinsonism, slow speech Psychiatric Disorders: insomnia, libido decreased, bruxism, restlessness, anorgasmia, loss of libido Reproductive System and Breast Disorders: erectile dysfunction, galactorrhea, breast tenderness, breast pain, amenorrhea, breast engorgement, ejaculation delayed, ejaculation disorder, gynecomastia, hypomenorrhea, breast discharge, breast enlargement, ejaculation failure, menstruation delayed, menstruation irregular, polymenorrhea Skin and Subcutaneous Tissue Disorders: night sweats Vascular Disorders: hypertension, hypotension, orthostatic hypotension Other Adverse Reactions Observed During the Clinical Trial Evaluations of Oral Risperidone The following is a list of additional ADRs that have been reported during the clinical trial evaluation of oral risperidone, regardless of frequency of occurrence: Blood and Lymphatic System Disorders: anemia, granulocytopenia Cardiac Disorders: tachycardia, sinus bradycardia, sinus tachycardia, atrioventricular block first degree, bundle branch block left, bundle branch block right, atrioventricular block Ear and Labyrinth Disorders: ear pain, tinnitus Eye Disorders: vision blurred, oculogyration, ocular hyperemia, eye discharge, conjunctivitis, eye rolling, eyelid edema, eye swelling, eyelid margin crusting, dry eye, lacrimation increased, photophobia, glaucoma, visual acuity reduced Gastrointestinal Disorders: dysphagia, fecaloma, fecal incontinence, gastritis, lip swelling, cheilitis, aptyalism General Disorders: thirst, gait disturbance, chest pain, influenza-like illness, pitting edema, edema, chills, sluggishness, malaise, face edema, discomfort, generalized edema, drug withdrawal syndrome, peripheral coldness, feeling abnormal Immune System Disorders: drug hypersensitivity Infections and Infestations: nasopharyngitis, upper respiratory tract infection, sinusitis, urinary tract infection, pneumonia, influenza, ear infection, viral infection, pharyngitis, tonsillitis, bronchitis, eye infection, localized infection, cystitis, cellulitis, otitis media, onychomycosis, acarodermatitis, bronchopneumonia, respiratory tract infection, tracheobronchitis, otitis media chronic Investigations: body temperature increased, alanine aminotransferase increased, heart rate increased, eosinophil count increased, white blood cell count decreased, hemoglobin decreased, blood creatine phosphokinase increased, hematocrit decreased, body temperature decreased, blood pressure decreased, transaminases increased Metabolism and Nutrition Disorders: polydipsia, anorexia Musculoskeletal, Connective Tissue, and Bone Disorders: joint swelling, musculoskeletal chest pain, posture abnormal, myalgia, neck pain, muscular weakness, muscle rigidity, muscle contracture, rhabdomyolysis Nervous System Disorders: dizziness postural, disturbance in attention, unresponsive to stimuli, depressed level of consciousness, movement disorder, hypokinesia, bradykinesia, transient ischemic attack, coordination abnormal, cerebrovascular accident, masked facies, speech disorder, syncope, loss of consciousness, muscle contractions involuntary, Parkinson's disease, tongue paralysis, akinesia, cerebral ischemia, cerebrovascular disorder, neuroleptic malignant syndrome, diabetic coma, head titubation Psychiatric Disorders: agitation, blunted affect, confusional state, middle insomnia, nervousness, sleep disorder, listlessness Renal and Urinary Disorders: enuresis, dysuria, pollakiuria, urinary incontinence Reproductive System and Breast Disorders: vaginal discharge, menstrual disorder, retrograde ejaculation, sexual dysfunction Respiratory, Thoracic, and Mediastinal Disorders: nasal congestion, dyspnea, epistaxis, wheezing, pneumonia aspiration, sinus congestion, dysphonia, productive cough, pulmonary congestion, respiratory tract congestion, rales, respiratory disorder, hyperventilation, nasal edema Skin and Subcutaneous Tissue Disorders: rash, dry skin, erythema, skin discoloration, skin lesion, pruritus, skin disorder, rash erythematous, rash papular, acne, hyperkeratosis, seborrheic dermatitis, rash generalized, rash maculopapular Vascular Disorders: flushing Discontinuations Due to Adverse Drug Reactions (ADRs) There was no single adverse reaction leading to discontinuation that occurred at a rate of ≥ 2% in PERSERIS-treated patients and greater than placebo. Dose Dependency of Adverse Drug Reactions in Clinical Trials Changes in Body Weight Data from the double-blind placebo-controlled study indicated there was a dose-dependent increase in mean changes in weight from baseline to postdose assessments in the PERSERIS 90 mg and 120 mg groups compared with the placebo group [see Warnings and Precautions ( 5.5 ), Adverse Reactions (6.1, Table 4 )] . Increased Prolactin In the 8-week double-blind, placebo-controlled study, there was a typical increase in mean prolactin levels in fasting blood samples from baseline to the EOS assessments in both the PERSERIS 90 mg and 120 mg groups, while mean prolactin for the placebo group remained stable during the study. Changes in mean prolactin were dose-dependent and more pronounced in female patients than male patients. Extrapyramidal Symptoms (EPS) Several methods were used to measure EPS, including: (1) the Barnes Akathisia Rating Scale (BARS) global clinical rating score which evaluates akathisia, (2) the Abnormal Involuntary Movement Scale (AIMS) scores which evaluates dyskinesia, (3) the Simpson-Angus Scale (SAS) global score which broadly evaluates parkinsonism, and (4) the incidence of spontaneous reports of EPS-related adverse reactions. In the 8-week double-blind, placebo-controlled study, the mean changes from baseline in BARS, AIMS, and SAS total scores were comparable between PERSERIS- and placebo-treated patients. At all postbaseline assessments, mean changes from baseline were between -0.1 and 0.2 (inclusive) for the BARS, between 0 and 0.2 (inclusive) for the AIMS and between -0.1 and 0.2 (inclusive) for the SAS. The rates of ADRs associated with EPS were similar across treatment groups, including placebo. There was a higher incidence of akathisia in the PERSERIS 120 mg (6.8%) group compared with the PERSERIS 90 mg (2.6%) and placebo group (4.2%); reports of extrapyramidal disorders were higher in the PERSERIS 90 mg group (4.3%) compared with the PERSERIS 120 mg (1.7%) and placebo group (0.8%). In contrast, there was a higher incidence of dystonia in the placebo group (2.5%) compared with the PERSERIS groups (0 and 0.9%, respectively). Dystonia 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. Although 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 has been observed in males and younger age groups. Changes in ECG In the 8-week double-blind, placebo-controlled study, there were no clinically relevant differences in mean changes from baseline to EOS in ECG parameters, including QT c F (Fridericia's corrected QT interval), QRS and PR intervals, and heart rate, in patients in either PERSERIS treatment group (90 mg and 120 mg) compared with placebo. Similarly, in the 12-month, long-term safety study, there were no clinically relevant changes in mean ECG interval values from baseline to postdose assessments. Pain Assessment and Local Injection Site Reactions Local injection site pain was assessed using patient-reported VAS scales (0 = no pain to 100 = unbearably painful). In the 8-week, double-blind placebo-controlled study, the mean patient-reported injection site pain VAS scores were similar for all treatment groups following both injections. Pain scores decreased from a mean of 27 (VAS score) 1 minute after the first dose to a range of 3 to 7 (VAS score) 30 to 60 minutes postdose. In the 12-month, long-term safety study, the 1-minute postdose injection site pain VAS scores were highest on Day 1 (mean of 25) and decreased over time with subsequent injections (14 to 16 following last injection). The local injection site was assessed by appropriately trained personnel. Throughout the clinical development program, the maximum reported intensity at any time point for each injection site assessment (pain, tenderness, inflammation/swelling and erythema) was none or mild for most patients receiving PERSERIS. Most patients (≥ 79%) reported no tenderness and most who had tenderness reported mild severity. Less than 1% of patients had moderate tenderness at any time point and 1 patient at Injections 1, 2, and 5 had severe tenderness. At each time point, most patients (≥ 75%) reported no pain on injection. Of patients who did have pain on injection, almost all of these were mild at each time point; only 1 or 2 patients at Injections 1, 2, 7, and 12 had moderate pain on injection. At least 92% of patients reported no erythema on each injection. All reports of erythema were of mild severity except for 2 cases of moderate erythema on Injection 1. Inflammation/swelling had a similar profile, with at least 88% of patients reporting no inflammation/swelling and only mild symptoms except for 1 case of moderate severity on Injection 1. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of oral risperidone. 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. These adverse reactions include: alopecia, anaphylactic reaction, angioedema, atrial fibrillation, cardiopulmonary arrest, catatonia, diabetic ketoacidosis in patients with impaired glucose metabolism, dysgeusia, hypoglycemia, hypothermia, ileus, inappropriate antidiuretic hormone secretion, intestinal obstruction, jaundice, mania, pancreatitis, pituitary adenoma, precocious puberty, pulmonary embolism, QT prolongation, sleep apnea syndrome, somnambulism, Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), sudden death, thrombocytopenia, thrombotic thrombocytopenic purpura, urinary retention, and water intoxication. Postmarketing cases of extrapyramidal symptoms (dystonia and dyskinesia) have been reported in patients concomitantly taking methylphenidate and risperidone when there was an increase or decrease in dosage, initiation, or discontinuation of either or both medications.