RISPERDAL CONSTA: Package Insert and Label Information (Page 4 of 8)

6.2 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 Adverse Reaction	RISPERDAL CONSTA® (N=154)	Placebo(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
System/Organ Class Adverse Reaction	RISPERDAL CONSTA® + Treatment as Usual *(N=72)	Placebo + Treatment as Usual *(N=67)
* Patients received double-blind RISPERDAL CONSTA® or placebo in addition to continuing their treatment as usual, which included mood stabilizers, antidepressants, and/or anxiolytics. † Parkinsonism includes muscle rigidity, hypokinesia, cogwheel rigidity, and bradykinesia. Dyskinesia includes muscle twitching and dyskinesia. ‡ Sedation includes sedation and somnolence.
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
Parkinsonism †	15	6
Dyskinesia †	6	3
Sedation ‡	7	1
Disturbance in attention	4	0
Reproductive system and breast disorders
Amenorrhea	4	1
Respiratory, thoracic and mediastinal disorders
Cough	4	1

6.3 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

6.4 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).

6.5 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.

6.6 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.

6.7 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.