Paliperidoneside effects

The following are discussed in more detail in other sections of the labeling: Increased mortality in elderly patients with dementia-related psychosis Cerebrovascular adverse reactions, including stroke, in elderly patients with dementia-related psychosis Neuroleptic malignant syndrome QT prolongation Tardive dyskinesia Metabolic changes Orthostatic hypotension and syncope Falls Leukopenia, neutropenia, and agranulocytosis Hyperprolactinemia Potential for cognitive and motor impairment Seizures Dysphagia Priapism Disruption of body temperature regulation The most common adverse reactions were upper respiratory tract infection, injection site reaction, weight increased, headache, and parkinsonism. To report SUSPECTED ADVERSE REACTIONS, contact Janssen Pharmaceuticals, Inc. at 1-800-526-7736 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 clinical practice. Patient Exposure The data described in this section is derived from the randomized double-blind active controlled non-inferiority study of INVEGA HAFYERA and 3-month paliperidone palmitate extended-release injectable suspension. During the double-blind phase, 478 patients were randomized to receive 2 injection cycles of INVEGA HAFYERA over a 12-month duration. The mean (SD) duration of exposure was 329.8 days in the INVEGA HAFYERA group and 336.4 days in the PP3M group during the double-blind phase: Adverse Reactions in the Double-Blind, Active-Controlled Clinical Trial Commonly Observed Adverse Reactions: The most common adverse reactions (incidence at least 5% in the double-blind Phase) of the INVEGA HAFYERA clinical trial were, upper respiratory tract infection, injection site reaction, weight increased, headache and parkinsonism. Discontinuation of Treatment Due to Adverse Reactions: In the double-blind phase of the INVEGA HAFYERA clinical trial 1.3% of subjects in the INVEGA HAFYERA group and 0.4% of subjects in the 3-month paliperidone palmitate extended-release injectable suspension group discontinued due to adverse reactions. Adverse Reactions Occurring at an Incidence of 2% or More in INVEGA HAFYERA-Treated Patients: Table 7 lists the adverse reactions reported in the INVEGA HAFYERA clinical trial. Table 7. Incidences of Adverse Reactions 2% or More of INVEGA HAFYERA-Treated Patients for the Double-Blind Phase of the Randomized Double-blind Active Controlled Trial in Patients with Schizophrenia Double Blind System Organ Class PP3M PP3M – Every-three-month paliperidone palmitate extended-release injectable suspension (N=224) % INVEGA HAFYERA (N=478) % Adverse Reaction Gastrointestinal disorders Diarrhea The following terms were combined: Diarrhea includes: Diarrhea, Diarrhea infectious.

Injection site reaction: includes Injection site reaction, Injection site discomfort, Injection site erythema, Injection site hemorrhage, Injection site induration, Injection site nodule, Injection site oedema, Injection site pain, Injection site swelling.

Weight increased includes: Weight increased, Body mass index increased, Obesity, Waist circumference increased. Upper respiratory tract infection includes: Upper respiratory tract infection, Nasopharyngitis, Pharyngitis, Rhinitis, Viral pharyngitis, Viral upper respiratory tract infection.

Back pain includes: Back pain, Neck pain, Spinal pain.

Musculoskeletal pain includes: Musculoskeletal pain, Musculoskeletal chest pain, Myalgia, Pain in extremity.

Akathisia includes: Akathisia, Restless legs syndrome, Restlessness.

Extrapyramidal symptoms includes: blepharospasms, bradykinesia, drooling, dyskinesia, dystonia, hypokinesia, musculoskeletal stiffness, muscle rigidity, muscle spasms, oculogyric crisis, Parkinsonism, Parkinsonism rest tremor, reduced facial expression, tardive dyskinesia.

Insomnia includes: Insomnia, Initial insomnia, Middle insomnia.

Psychosis includes: acute psychosis, delusion, delusion of reference, hallucination (auditory), psychotic disorder, psychotic symptom, and schizophrenia. 1 2 General disorders and administration site conditions Injection site reaction 5 11 Infections and infestations Upper respiratory tract infection 13 12 Urinary tract infection 1 3 Metabolism and nutrition disorders Weight increased 8 9 Musculoskeletal and connective tissue disorders Back pain 1 3 Musculoskeletal pain 1 3 Nervous system disorders Akathisia 4 4 Headache 5 7 Extrapyramidal symptoms 5 7 Psychiatric disorders Psychosis 3 3 Anxiety 0 3 Insomnia 2 3 Demographic Differences An examination of population subgroups in the INVEGA HAFYERA trial did not reveal any evidence of differences in safety on the basis of age, gender, or race alone. Extrapyramidal Symptoms (EPS) Data from the randomized double-blind active controlled study provided information regarding EPS. Several methods were used to measure EPS: the Simpson-Angus Rating Scale Global Score which broadly evaluates parkinsonism, the Barnes Akathisia Rating Scale Global Clinical Rating Score which evaluates akathisia, the Abnormal Involuntary Movement Scale scores which evaluates dyskinesia, and use of anticholinergic medications to treat EPS (Table 8) and incidence of spontaneous reports of EPS (Table 9). Table 8. Extrapyramidal Symptoms (EPS) Assessed by Rating Scales Incidence and Use of Anticholinergic Medication During the Double-blind Phase PP3M PP3M - Every-three-month paliperidone palmitate extended-release injectable suspension (N=224) % INVEGA HAFYERA (N=478) % Note: Percentages are calculated based on number of subjects in the DB Safety analysis set per treatment group. Use of Anticholinergic Medication Use of Anti-EPS Medication During the Double-blind Phase 13 15 Parkinsonism Percent of subjects with Simpson-Angus Scale Global Score >0.3(Global Score defined as total sum of items score divided by the number of items). 6 7 Akathisia Percent of subjects with Barnes Akathisia Rating Scale Global Clinical Rating Score ≥2 3 3 Dyskinesia Percent of subjects with a score ≥3 on any of the first seven items or a score ≥2 on two or more of any of the first seven items of the Abnormal Involuntary Movement Scale 1 1 Table 9. Extrapyramidal Symptoms (EPS)-Related Events by MedDRA Preferred Term Double-blind Phase EPS Group PP3M PP3M – Every-three-month paliperidone palmitate extended-release injectable suspension Parkinsonism group includes: Bradykinesia, drooling, hypokinesia, muscle rigidity, musculoskeletal stiffness, parkinsonism, parkinsonian rest tremor, reduced facial expression Hyperkinesia group includes: Akathisia, restlessness, restless legs syndrome Dyskinesia group includes: Dyskinesia, muscle twitching, tardive dyskinesia Dystonia group includes: Blepharospasm, dystonia, muscle spasms, oculogyric crisis (N=224) % INVEGA HAFYERA (N=478) % Overall percentage of subjects with EPS-related adverse events 9 10 Parkinsonism 4 5 Hyperkinesia 4 4 Tremor 0 <1 Dyskinesia 1 2 Dystonia 1 1 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. 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. Pain Assessment and Local Injection Site Reactions Investigator ratings of injection site. Induration, redness and swelling were observed in 13% in the INVEGA HAFYERA group and 9% in the PP3M group during the double-blind Phase. Investigator evaluation of tenderness was higher for subjects in the INVEGA HAFYERA group versus the 3-month paliperidone palmitate extended-release injectable suspension group (31% vs. 19%) during the double-blind Phase. Active INVEGA HAFYERA medication was given at double-blind baseline and Month 6, while placebo medication was given at the other injection times. Subject ratings of injection site pain. The average score for the subject's evaluation of injection pain on a scale of 0 to 100 was approximately 16 at the open-label Phase end point and approximately 5 in both groups at the double-blind Phase end point. Other Adverse Reactions Observed During the Clinical Trial Evaluation of INVEGA HAFYERA The following additional adverse reactions were identified in the randomized double-blind active controlled study. The following list does not include reactions: 1) already listed in previous tables or elsewhere in labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, 4) which were not considered to have significant clinical implications. Blood and lymphatic system disorders: anemia Cardiac disorders: bradycardia, tachycardia Ear and labyrinth disorders: vertigo Gastrointestinal disorders: constipation, nausea, vomiting General disorders and administration site conditions: fatigue Hepatobiliary disorders: transaminases increased Infections and infestations: cystitis, respiratory tract infection, tonsillitis Metabolism and nutritional disorders: decreased appetite, increased appetite, weight decreased Psychiatric disorders: depression Reproductive system and breast disorders: breast pain, menstrual disorder Skin and subcutaneous tissue disorders: rash Vascular disorders: hypertension Additional Adverse Reactions Reported in Clinical Trials with the 1-Month and 3-Month Paliperidone Palmitate Extended-Release Injectable Suspension The following is a list of additional adverse reactions that have been reported in clinical trials with the 1-month and 3-month paliperidone palmitate extended-release injectable suspensions that are not listed elsewhere: Cardiac disorders: atrioventricular block first degree, bundle branch block, palpitations, postural orthostatic tachycardia syndrome Eye disorders: eye movement disorder, eye rolling, oculogyric crisis, vision blurred Gastrointestinal disorders: abdominal discomfort/abdominal pain upper, diarrhea, dry mouth, toothache General disorders and administration site conditions: asthenia, chest discomfort Immune system disorders: hypersensitivity Investigations: electrocardiogram abnormal Metabolism and nutrition disorders: hyperinsulinemia Musculoskeletal and connective tissue disorders: myalgia, pain in extremity, joint stiffness, muscle spasms, muscle twitching, nuchal rigidity Nervous system disorders: bradykinesia, cerebrovascular accident, convulsion, dizziness, dizziness postural, dysarthria, hypertonia, lethargy, oromandibular dystonia, psychomotor hyperactivity, syncope Psychiatric disorders: agitation, nightmare Reproductive system and breast disorders: breast discharge, erectile dysfunction, gynecomastia, sexual dysfunction Respiratory, thoracic and mediastinal disorders: cough Skin and subcutaneous tissue disorders: drug eruption, eczema, pruritus, pruritus generalized, urticaria Vascular disorders: hypotension, orthostatic hypotension Additional Adverse Reactions Reported in Clinical Trials with Oral Paliperidone The following is a list of additional adverse reactions that have been reported in clinical trials with oral paliperidone: Cardiac disorders: bundle branch block left, sinus arrhythmia Gastrointestinal disorders: abdominal pain, constipation, flatulence, small intestinal obstruction General disorders and administration site conditions: edema, edema peripheral Immune system disorders: anaphylactic reaction Musculoskeletal and connective tissue disorders: arthralgia, torticollis, trismus Nervous system disorders: grand mal convulsion, parkinsonian gait, transient ischemic attack Psychiatric disorders: sleep disorder Reproductive system and breast disorders: breast engorgement, breast tenderness, retrograde ejaculation Respiratory, thoracic and mediastinal disorders: nasal congestion, pharyngolaryngeal pain, pneumonia aspiration Skin and subcutaneous tissue disorders: rash papular Vascular disorders: ischemia

6.2 Postmarketing

Experience The following adverse reactions have been identified during post-approval use of paliperidone; because these reactions were 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: angioedema, catatonia, ileus, somnambulism, swollen tongue, thrombotic thrombocytopenic purpura, urinary incontinence, and urinary retention. Cases of anaphylactic reaction after injection with the 1-month paliperidone palmitate extended-release suspension have been reported during postmarketing experience in patients who have previously tolerated oral risperidone or oral paliperidone. Paliperidone is the major active metabolite of risperidone. Adverse reactions reported with oral risperidone and risperidone long-acting injection can be found in the Adverse Reactions section of the Prescribing Information for those products.