Adverse reactions : תופעות לוואי

6 ADVERSE REACTIONS
The following are discussed in more detail in other sections of the labeling: 
•   Increased mortality in elderly patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.1)]
•   Cerebrovascular adverse events, including stroke, in elderly patients with dementia-related psychosis [see Warnings and Precautions (5.2)]
•   Neuroleptic malignant syndrome [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 [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)]
•   Disruption of body temperature regulation [see Warnings and Precautions (5.14)] •   Avoidance of inadvertent injection into a blood vessel [see Warnings and Precautions (5.15)]
•   Osteodystrophy and tumors in animals [see Warnings and Precautions (5.16)] The most common adverse reactions in clinical trials in patients with schizophrenia (≥ 5%) were: headache, parkinsonism, dizziness, akathisia, fatigue, constipation, dyspepsia, sedation, weight increased, pain in extremity, and dry mouth. The most common adverse reactions in the double- blind, placebo-controlled periods of the bipolar disorder trials were weight increased (5% in the monotherapy trial) and tremor and parkinsonism (≥ 10% in the adjunctive treatment trial).

The most common adverse reactions that were associated with discontinuation from the 12-week double-blind, placebo-controlled trial in patients with schizophrenia (causing discontinuation in ≥1% of patients) were agitation, depression, anxiety, and akathisia. Adverse reactions that were associated with discontinuation from the double-blind, placebo-controlled periods of the bipolar disorder trials were hyperglycemia (one patient in the monotherapy trial) and hypokinesia and tardive dyskinesia (one patient each in the adjunctive treatment trial).

The data described in this section are derived from a clinical trial database consisting of 2392 patients exposed to one or more doses of RISPERDAL CONSTA® for the treatment of schizophrenia. Of these 2392 patients, 332 were patients who received RISPERDAL CONSTA® while participating in a 12-week double-blind, placebo-controlled trial. Two hundred two (202) of the 332 were schizophrenia patients who received 25 mg or 50 mg RISPERDAL CONSTA®. The conditions and duration of treatment with RISPERDAL CONSTA® in the other clinical trials varied greatly and included (in overlapping categories) double-blind, fixed- and flexible-dose, placebo- or active-controlled studies and open-label phases of studies, inpatients and outpatients, and short-term (up to 12 weeks) and longer-term (up to 4 years) exposures. Safety was assessed by collecting adverse events and performing physical examinations, vital signs, body weights, laboratory analyses, and ECGs.

In addition to the studies in patients with schizophrenia, safety data are presented from a trial assessing the efficacy and safety of RISPERDAL CONSTA® when administered as monotherapy for maintenance treatment in patients with bipolar I disorder. The subjects in this multi-center, double-blind, placebo-controlled study were adult patients who met DSM-IV criteria for Bipolar Disorder Type I and who were stable on risperidone (oral or long-acting injection), were stable on other antipsychotics or mood stabilizers, or were experiencing an acute episode. After a 3-week period of treatment with open-label oral risperidone (N=440), subjects who demonstrated an initial response to oral risperidone in this period and those who were stable on risperidone (oral or long- acting injection) at study entry entered into a 26-week stabilization period of open-label RISPERDAL CONSTA® (N=501). Subjects who demonstrated a maintained response during this period were then randomized into a 24-month double-blind, placebo-controlled period in which they received RISPERDAL® CONSTA® (N=154) or placebo (N=149) as monotherapy. Subjects who relapsed or who completed the double-blind period could choose to enter an 8-week open- label RISPERDAL CONSTA® extension period (N=160).

Safety data are also presented from a trial assessing the efficacy and safety of RISPERDAL CONSTA® when administered as adjunctive maintenance treatment in patients with bipolar disorder. The subjects in this multi-center, double-blind, placebo-controlled study were adult patients who met DSM-IV criteria for Bipolar Disorder Type I or Type II and who experienced at least 4 episodes of mood disorder requiring psychiatric/clinical intervention in the previous 12 months, including at least 2 episodes in the 6 months prior to the start of the study. At the start of this study, all patients (N=275) entered into a 16-week open-label treatment phase in which they received RISPERDAL CONSTA® in addition to continuing their treatment as usual, which consisted of various mood stabilizers (primarily lithium and valproate), antidepressants, and/or anxiolytics. Patients who reached remission at the end of this 16-week open-label treatment phase (N=139) were then randomized into a 52-week double-blind, placebo-controlled phase in which they received RISPERDAL CONSTA® (N=72) or placebo (n=67) as adjunctive treatment in addition to continuing their treatment as usual. Patients who did not reach remission at the end of the 16-week open-label treatment phase could choose to continue to receive RISPERDAL CONSTA® as adjunctive therapy in an open-label manner, in addition to continuing their treatment as usual, for up to an additional 36 weeks as clinically indicated for a total period of up to 52 weeks; these patients (N=70) were also included in the evaluation of safety.

Adverse events during exposure to study treatment were obtained by general inquiry and recorded by clinical investigators using their own terminology. Consequently, to provide a meaningful estimate of the proportion of individuals experiencing adverse events, events were grouped in standardized categories using MedDRA terminology.

Throughout this section, adverse reactions are reported. Adverse reactions are adverse events that were considered to be reasonably associated with the use of RISPERDAL CONSTA® (adverse drug reactions) based on the comprehensive assessment of the available adverse event information.
A causal association for RISPERDAL CONSTA® often cannot be reliably established in individual cases. Further, 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.

The majority of all adverse reactions were mild to moderate in severity.

6.1    Clinical Trials Experience
Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials - Schizophrenia
Table 4 lists the adverse reactions reported in 2% or more of RISPERDAL CONSTA®-treated patients with schizophrenia in one 12-week double-blind, placebo-controlled trial.



Table 4.     Adverse Reactions in ≥2% of RISPERDAL CONSTA®-Treated Patients with Schizophrenia in a 12-Week Double-Blind, Placebo-Controlled Trial
Percentage of Patients Reporting Event
RISPERDAL CONSTA®                    Placebo
System/Organ Class                                       25 mg              50 mg Adverse Reaction                                        (N=99)             (N=103)             (N=98) Eye disorders
Vision blurred                                              2                  3                 0 
Gastrointestinal disorders
Constipation                                                     5                    7                    1 Dry mouth                                                        0                    7                    1 Dyspepsia                                                        6                    6                    0 Nausea                                                           3                    4                    5 Toothache                                                        1                    3                    0 Salivary hypersecretion                                          4                    1                    0 
General disorders and administration site conditions
Fatigue*                                                         3                    9                    0 Edema peripheral                                                 2                    3                    1 Pain                                                             4                    1                    0 Pyrexia                                                          2                    1                    0 
Infections and infestations
Upper respiratory tract infection                               2                    0                    1 
Investigations
Weight increased                                                5                    4                    2 Weight decreased                                                4                    1                    1 
Musculoskeletal and connective tissue disorders
Pain in extremity                                                6                    2                    1 
Nervous system disorders
Headache                                                         15                   21                  12 Parkinsonism*                                                    8                    15                  9 Dizziness                                                        7                    11                  6 Akathisia*                                                       4                    11                  6 Sedation*                                                        5                    6                   3 Tremor                                                           0                    3                   0 Syncope                                                          2                    1                   0 Hypoesthesia                                                     2                    0                   0 
Respiratory, thoracic and mediastinal disorders
Cough                                                            4                    2                    3 Sinus congestion                                                 2                    0                    0 
Skin and subcutaneous tissue disorders
Acne                                                              2                    2                    0 Dry skin                                                          2                    0                    0 * Fatigue includes fatigue and asthenia. Parkinsonism includes extrapyramidal disorder, musculoskeletal stiffness, muscle rigidity, and bradykinesia. Akathisia includes akathisia and restlessness. Sedation includes sedation and somnolence.


Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials – Bipolar Disorder
Table 5 lists the treatment-emergent adverse reactions reported in 2% or more of RISPERDAL CONSTA®-treated patients in the 24-month double-blind, placebo-controlled treatment period of the trial assessing the efficacy and safety of RISPERDAL CONSTA® when administered as monotherapy for maintenance treatment in patients with Bipolar I Disorder.


Table 5.    Adverse Reactions in ≥2% of Patients with Bipolar I Disorder Treated with RISPERDAL CONSTA® as Monotherapy in a 24-Month Double-Blind, Placebo-Controlled Trial Percentage of Patients Reporting Event
System/Organ Class                                    RISPERDALCONSTA®                    Placebo Adverse Reaction                                            (N=154)                       (N=149) Investigations
Weight increased                                               5                              1 Nervous system disorders
Dizziness                                                      3                              1 Vascular disorders
Hypertension                                                   3                              1 
Table 6 lists the treatment-emergent adverse reactions reported in 4% or more of patients in the 52-week double-blind, placebo-controlled treatment phase of a trial assessing the efficacy and safety of RISPERDAL CONSTA® when administered as adjunctive maintenance treatment in patients with bipolar disorder.



Table 6.     Adverse Reactions in ≥ 4% of Patients with Bipolar Disorder Treated with RISPERDAL CONSTA® as Adjunctive Therapy in a 52-Week Double-Blind, Placebo-Controlled Trial Percentage of Patients Reporting
Event
+
Placebo +
Treatment
Treatment as Usuala
System/Organ Class                                                                              as Usuala Adverse Reaction                                                               (N=72)           (N=67) General disorders and administration site conditions
Gait abnormal                                                                     4                  0 Infections and infestations
Upper respiratory tract infection                                                 6                  3 Investigations
Weight increased                                                                  7                  1 Metabolism and nutrition disorders
Decreased appetite                                                                6                  1 Increased appetite                                                                4                  0 Musculoskeletal and connective tissue disorders
Arthralgia                                                                        4                  3 Nervous system disorders
Tremor                                                                           24                 16 Parkinsonismb                                                                    15                  6 Dyskinesiab                                                                       6                  3 Sedationc                                                                         7                  1 Disturbance in attention                                                          4                  0 Reproductive system and breast disorders
Amenorrhea                                                                        4                  1 Respiratory, thoracic and mediastinal disorders
Cough                                                                             4                  1 a                                                         ®
Patients received double-blind RISPERDAL CONSTA or placebo in addition to continuing their treatment as usual, which included mood stabilizers, antidepressants, and/or anxiolytics.
b
Parkinsonism includes muscle rigidity, hypokinesia, cogwheel rigidity, and bradykinesia. Dyskinesia includes muscle twitching and dyskinesia.
c
Sedation includes sedation and somnolence.
Other Adverse Reactions Observed During the Clinical Trial Evaluation of Risperidone The following additional adverse reactions occurred in < 2% of the RISPERDAL CONSTA®- treated patients in the above schizophrenia double-blind, placebo-controlled trial dataset, in < 2% of the RISPERDAL CONSTA®-treated patients in the above double-blind, placebo-controlled period of the monotherapy bipolar disorder trial dataset, or in < 4% of the RISPERDAL CONSTA®-treated patients in the above double-blind, placebo-controlled period of the adjunctive treatment bipolar disorder trial dataset. The following also includes additional adverse reactions reported at any frequency in RISPERDAL CONSTA®-treated patients who participated in the open-label phases of the above bipolar disorder studies and in other studies, including double- blind, active controlled and open-label studies in schizophrenia and bipolar disorder.

Blood and lymphatic system disorders: anemia, neutropenia


Cardiac disorders: tachycardia, atrioventricular block first degree, palpitations, sinus bradycardia, bundle branch block left, bradycardia, sinus tachycardia, bundle branch block right 
Ear and labyrinth disorders: ear pain, vertigo

Endocrine disorders: hyperprolactinemia
Eye disorders: conjunctivitis, visual acuity reduced

Gastrointestinal disorders: diarrhea, vomiting, abdominal pain upper, abdominal pain, stomach discomfort, gastritis

General disorders and administration site conditions: injection site pain, chest discomfort, chest pain, influenza like illness, sluggishness, malaise, induration, injection site induration, injection site swelling, injection site reaction, face edema

Immune system disorders: hypersensitivity

Infections and infestations: nasopharyngitis, influenza, bronchitis, urinary tract infection, rhinitis, respiratory tract infection, ear infection, pneumonia, lower respiratory tract infection, pharyngitis, sinusitis, viral infection, infection, localized infection, cystitis, gastroenteritis, subcutaneous abscess

Injury and poisoning: fall, procedural pain

Investigations: blood prolactin increased, alanine aminotransferase increased, electrocardiogram abnormal, gamma-glutamyl transferase increased, blood glucose increased, hepatic enzyme increased, aspartate aminotransferase increased, electrocardiogram QT prolonged, glucose urine present

Metabolism and nutritional disorders: anorexia, hyperglycemia

Musculoskeletal, connective tissue and bone disorders: posture abnormal, myalgia, back pain, buttock pain, muscular weakness, neck pain, musculoskeletal chest pain 
Nervous system disorders: coordination abnormal, dystonia, tardive dyskinesia, drooling, paresthesia, dizziness postural, convulsion, akinesia, hypokinesia, dysarthria 
Psychiatric disorders: insomnia, agitation, anxiety, sleep disorder, depression, initial insomnia, libido decreased, nervousness

Renal and urinary disorders: urinary incontinence

Reproductive system and breast disorders: galactorrhea, oligomenorrhea, erectile dysfunction, sexual dysfunction, ejaculation disorder, gynecomastia, breast discomfort, menstruation irregular, menstruation delayed, menstrual disorder, ejaculation delayed

Respiratory, thoracic and mediastinal disorders: nasal congestion, pharyngolaryngeal pain, dyspnea, rhinorrhea

Skin and subcutaneous tissue disorders: rash, eczema, pruritus generalized, pruritus 
Vascular disorders: hypotension, orthostatic hypotension

Additional Adverse Reactions Reported with Oral RISPERDAL®
The following is a list of additional adverse reactions that have been reported during the clinical trial evaluation of oral RISPERDAL®, regardless of frequency of occurrence: 
Blood and Lymphatic Disorders: granulocytopenia

Cardiac Disorders: atrioventricular block
Ear and Labyrinth Disorders: tinnitus

Eye Disorders: ocular hyperemia, eye discharge, eye rolling, eyelid edema, eye swelling, eyelid margin crusting, dry eye, lacrimation increased, photophobia, glaucoma 
Gastrointestinal Disorders: abdominal pain upper, dysphagia, fecaloma, abdominal discomfort, fecal incontinence, lip swelling, cheilitis, aptyalism

General Disorders: thirst, feeling abnormal, gait disturbance, pitting edema, edema, chills, discomfort, generalized edema, drug withdrawal syndrome, peripheral coldness 
Immune System Disorders: drug hypersensitivity

Infections and Infestations: tonsillitis, eye infection, cellulitis, otitis media, onychomycosis, acarodermatitis, bronchopneumonia, respiratory tract infection, tracheobronchitis, otitis media chronic

Investigations: body temperature 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

Musculoskeletal, Connective Tissue, and Bone Disorders: joint swelling, joint stiffness, rhabdomyolysis, torticollis

Nervous System Disorders: hypertonia, balance disorder, dysarthria, unresponsive to stimuli, depressed level of consciousness, movement disorder, hypokinesia, parkinsonian rest tremor, transient ischemic attack, cerebrovascular accident, masked facies, speech disorder, loss of consciousness, muscle contractions involuntary, akinesia, cerebral ischemia, cerebrovascular disorder, neuroleptic malignant syndrome, diabetic coma, head titubation 
Psychiatric Disorders: blunted affect, confusional state, middle insomnia, listlessness, anorgasmia

Renal and Urinary Disorders: enuresis, dysuria, pollakiuria

Reproductive System and Breast Disorders: vaginal discharge, retrograde ejaculation, ejaculation disorder, ejaculation failure, breast enlargement

Respiratory, Thoracic, and Mediastinal Disorders: epistaxis, wheezing, pneumonia aspiration, dysphonia, productive cough, pulmonary congestion, respiratory tract congestion, rales, respiratory disorder, hyperventilation, nasal edema

Skin and Subcutaneous Tissue Disorders: erythema, skin discoloration, skin lesion, skin disorder, rash erythematous, rash papular, hyperkeratosis, dandruff, seborrheic dermatitis, rash generalized, rash maculopapular

Vascular Disorders: flushing

Discontinuations Due to Adverse Reactions
Schizophrenia
Approximately 11% (22/202) of RISPERDAL CONSTA®-treated patients in the 12-week double- blind, placebo-controlled schizophrenia trial discontinued treatment due to an adverse event, compared with 13% (13/98) who received placebo. The adverse reactions associated with discontinuation in two or more RISPERDAL CONSTA®-treated patients were: agitation (3%), depression (2%), anxiety (1%), and akathisia (1%).

Bipolar Disorder
In the 24-month double-blind, placebo-controlled treatment period of the trial assessing the efficacy and safety of RISPERDAL CONSTA® when administered as monotherapy for maintenance treatment in patients with bipolar I disorder, 1 (0.6%) of 154 RISPERDAL CONSTA®-treated patients discontinued due to an adverse reaction (hyperglycemia).


In the 52-week double-blind phase of the placebo-controlled trial in which RISPERDAL CONSTA® was administered as adjunctive therapy to patients with bipolar disorder in addition to continuing with their treatment as usual, approximately 4% (3/72) of RISPERDAL CONSTA®- treated patients discontinued treatment due to an adverse event, compared with 1.5% (1/67) of placebo-treated patients. Adverse reactions associated with discontinuation in RISPERDAL CONSTA®-treated patients were: hypokinesia (one patient) and tardive dyskinesia (one patient).

Dose Dependency of Adverse Reactions in Clinical Trials
Extrapyramidal Symptoms:
Two methods were used to measure extrapyramidal symptoms (EPS) in the 12-week double-blind, placebo-controlled trial comparing three doses of RISPERDAL CONSTA® (25 mg, 50 mg, and 75 mg) with placebo in patients with schizophrenia, including: (1) the incidence of spontaneous reports of EPS symptoms; and (2) the change from baseline to endpoint on the total score (sum of the subscale scores for parkinsonism, dystonia, and dyskinesia) of the Extrapyramidal Symptom Rating Scale (ESRS).

As shown in Table 1, the overall incidence of EPS-related adverse reactions (akathisia, dystonia, parkinsonism, and tremor) in patients treated with 25 mg RISPERDAL CONSTA® was comparable to that of patients treated with placebo; the incidence of EPS-related adverse reactions was higher in patients treated with 50 mg RISPERDAL CONSTA®.

The median change from baseline to endpoint in total ESRS score showed no worsening in patients treated with RISPERDAL CONSTA® compared with patients treated with placebo: 0 (placebo group); -1 (25-mg group, significantly less than the placebo group); and 0 (50-mg group).

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.

Changes in ECG
The electrocardiograms of 202 schizophrenic patients treated with 25 mg or 50 mg RISPERDAL CONSTA® and 98 schizophrenic patients treated with placebo in the 12-week double-blind, placebo-controlled trial were evaluated. Compared with placebo, there were no statistically 

significant differences in QTc intervals (using Fridericia’s and linear correction factors) during treatment with RISPERDAL CONSTA®.

The electrocardiograms of 227 patients with Bipolar I Disorder were evaluated in the 24-month double-blind, placebo-controlled period. There were no clinically relevant differences in QTc intervals (using Fridericia’s and linear correction factors) during treatment with RISPERDAL CONSTA® compared to placebo.

The electrocardiograms of 85 patients with bipolar disorder were evaluated in the 52-week double- blind, placebo-controlled trial. There were no statistically significant differences in QTc intervals (using Fridericia’s and linear correction factors) during treatment with RISPERDAL CONSTA® 25 mg, 37.5 mg, or 50 mg when administered as adjunctive treatment in addition to continuing treatment as usual compared to placebo.

Pain Assessment and Local Injection Site Reactions
The mean intensity of injection pain reported by patients with schizophrenia using a visual analog scale (0 = no pain to 100 = unbearably painful) decreased in all treatment groups from the first to the last injection (placebo: 16.7 to 12.6; 25 mg: 12.0 to 9.0; 50 mg: 18.2 to 11.8). After the sixth injection (Week 10), investigator ratings indicated that 1% of patients treated with 25 mg or 50 mg RISPERDAL CONSTA® experienced redness, swelling, or induration at the injection site.

In a separate study to observe local-site tolerability in which RISPERDAL CONSTA® was administered into the deltoid muscle every 2 weeks over a period of 8 weeks, no patient discontinued treatment due to local injection site pain or reaction. Clinician ratings indicated that only mild redness, swelling, or induration at the injection site was observed in subjects treated with 37.5 mg or 50 mg RISPERDAL CONSTA® at 2 hours after deltoid injection. All ratings returned to baseline at the predose assessment of the next injection 2 weeks later. No moderate or severe reactions were observed in any subject.

6.2    Postmarketing Experience
The following adverse reactions have been identified during postapproval use of risperidone; because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency: agranulocytosis, alopecia, anaphylactic reaction, angioedema, atrial fibrillation, blood cholesterol increased, blood triglycerides increased, catatonia, diabetes mellitus, diabetic ketoacidosis in patients with impaired glucose metabolism, drug withdrawal syndrome neonatal, dysgeusia, hypoglycemia, hypothermia, ileus, inappropriate antidiuretic hormone secretion, intestinal obstruction, jaundice, mania, pancreatitis, priapism, QT prolongation, sleep apnea syndrome, somnambulism, Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), thrombocytopenia, thrombotic thrombocytopenic purpura, urinary retention, and water intoxication. In addition, the following adverse reactions have been observed during postapproval use of RISPERDAL CONSTA®: cerebrovascular disorders, including cerebrovascular accidents, and diabetes mellitus aggravated.

Retinal artery occlusion after injection of RISPERDAL CONSTA® has been reported during postmarketing surveillance. This has been reported in the presence of abnormal arteriovenous anastomosis.

Serious injection site reactions including abscess, cellulitis, cyst, hematoma, necrosis, nodule, and ulcer have been reported with RISPERDAL CONSTA® during postmarketing surveillance.
Isolated cases required surgical intervention.

Very rarely, cases of anaphylactic reaction after injection with RISPERDAL CONSTA® have been reported during postmarketing experience in patients who have previously tolerated oral risperidone.

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.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important.
It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il