RISPERIDONE (Page 5 of 12)

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.

Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials – Schizophrenia
Adult Patients with Schizophrenia Table 8 lists the adverse reactions reported in 2% or more of risperidone tablets-treated adult patients with schizophrenia in three 4- to 8-week, double-blind, placebo-controlled trials.

Table 8. Adverse Reactions in ≥2% of Risperidone Tablets-Treated Adult Patients (and greater than placebo) with Schizophrenia in Double-Blind, Placebo-Controlled Trials

* Parkinsonism includes extrapyramidal disorder, musculoskeletal stiffness, parkinsonism, cogwheel rigidity, akinesia, bradykinesia, hypokinesia, masked facies, muscle rigidity, and Parkinson’s disease. Akathisia includes akathisia and restlessness. Dystonia includes dystonia, muscle spasms, muscle contractions involuntary, muscle contracture, oculogyration, tongue paralysis. Tremor includes tremor and parkinsonian rest tremor.
System/Organ Class Adverse Reaction	Percentage of Patients Reporting Reaction
	Risperidone Tablets
	2–8 mg per day (N=366)	>8–16 mg per day (N=198)	Placebo (N=225)
Cardiac Disorders
Tachycardia	1	3	0
Eye Disorders
Vision blurred	3	1	1
Gastrointestinal Disorders
Nausea	9	4	4
Constipation	8	9	6
Dyspepsia	8	6	5
Dry mouth	4	0	1
Abdominal discomfort	3	1	1
Salivary hypersecretion	2	1	<1
Diarrhea	2	1	1
General Disorders
Fatigue	3	1	0
Chest pain	2	2	1
Asthenia	2	1	<1
Infections and Infestations
Nasopharyngitis	3	4	3
Upper respiratory tract infection	2	3	1
Sinusitis	1	2	1
Urinary tract infection	1	3	0
Investigations
Blood creatine phosphokinase increased	1	2	<1
Heart rate increased	<1	2	0
Musculoskeletal and Connective Tissue Disorders
Back pain	4	1	1
Arthralgia	2	3	<1
Pain in extremity	2	1	1
Nervous System Disorders
Parkinsonism *	14	17	8
Akathisia *	10	10	3
Sedation	10	5	2
Dizziness	7	4	2
Dystonia *	3	4	2
Tremor *	2	3	1
Dizziness postural	2	0	0
Psychiatric Disorders
Insomnia	32	25	27
Anxiety	16	11	11
Respiratory, Thoracic and Mediastinal Disorders
Nasal congestion	4	6	2
Dyspnea	1	2	0
Epistaxis	<1	2	0
Skin and Subcutaneous Tissue Disorders
Rash	1	4	1
Dry skin	1	3	0
Vascular Disorders
Orthostatic hypotension	2	1	0

Pediatric Patients with Schizophrenia

Table 9 lists the adverse reactions reported in 5% or more of risperidone tablets-treated pediatric patients with schizophrenia in a 6-week double-blind, placebo-controlled trial.

Table 9. Adverse Reactions in ≥5% of Risperidone Tablets-Treated Pediatric Patients (and greater than placebo) with Schizophrenia in a Double-Blind Trial

* Parkinsonism includes extrapyramidal disorder, muscle rigidity, musculoskeletal stiffness, and hypokinesia. Akathisia includes akathisia and restlessness. Dystonia includes dystonia and oculogyration.
System/Organ Class Adverse Reaction	Percentage of Patients Reporting Reaction
	Risperidone Tablets
	1–3 mg per day (N=55)	4–6 mg per day (N=51)	Placebo (N=54)
Gastrointestinal Disorders
Salivary hypersecretion	0	10	2
Nervous System Disorders
Sedation	24	12	4
Parkinsonism *	16	28	11
Tremor	11	10	6
Akathisia *	9	10	4
Dizziness	7	14	2
Dystonia *	2	6	0
Psychiatric Disorders
Anxiety	7	6	0

Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials – Bipolar Mania

Adult Patients with Bipolar Mania

Table 10 lists the adverse reactions reported in 2% or more of risperidone tablets-treated adult patients with bipolar mania in four 3-week, double-blind, placebo-controlled monotherapy trials.

Table 10. Adverse Reactions in ≥2% of Risperidone Tablets-Treated Adult Patients (and greater than placebo) with Bipolar Mania in Double-Blind, Placebo-Controlled Monotherapy Trials

* Parkinsonism includes extrapyramidal disorder, parkinsonism, musculoskeletal stiffness, hypokinesia, muscle rigidity, muscle tightness, bradykinesia, cogwheel rigidity. Akathisia includes akathisia and restlessness. Tremor includes tremor and parkinsonian rest tremor. Dystonia includes dystonia, muscle spasms, oculogyration, torticollis.
System/Organ Class Adverse Reaction	Percentage of Patients Reporting Reaction
	Risperidone Tablets 1–6 mg per day (N=448)	Placebo (N=424)
Eye Disorders
Vision blurred	2	1
Gastrointestinal Disorders
Nausea	5	2
Diarrhea	3	2
Salivary hypersecretion	3	1
Stomach discomfort	2	<1
General Disorders
Fatigue	2	1
Nervous System Disorders
Parkinsonism *	25	9
Sedation	11	4
Akathisia *	9	3
Tremor *	6	3
Dizziness	6	5
Dystonia *	5	1
Lethargy	2	1

Table 11 lists the adverse reactions reported in 2% or more of risperidone tablets-treated adult patients with bipolar mania in two 3-week, double-blind, placebo-controlled adjuvant therapy trials.

Table 11. Adverse Reactions in ≥2% of Risperidone Tablets-Treated Adult Patients (and greater than placebo) with Bipolar Mania in Double-Blind, Placebo-Controlled Adjunctive Therapy Trials

* Parkinsonism includes extrapyramidal disorder, hypokinesia and bradykinesia. Akathisia includes hyperkinesia and akathisia.
System/Organ Class Adverse Reaction	Percentage of Patients Reporting Reaction
	Risperidone Tablets + Mood Stabilizer (N=127)	Placebo + Mood Stabilizer (N=126)
Cardiac Disorders
Palpitations	2	0
Gastrointestinal Disorders
Dyspepsia	9	8
Nausea	6	4
Diarrhea	6	4
Salivary hypersecretion	2	0
General Disorders
Chest pain	2	1
Infections and Infestations
Urinary tract infection	2	1
Nervous System Disorders
Parkinsonism *	14	4
Sedation	9	4
Akathisia *	8	0
Dizziness	7	2
Tremor	6	2
Lethargy	2	1
Psychiatric Disorders
Anxiety	3	2
Respiratory, Thoracic and Mediastinal Disorders
Pharyngolaryngeal pain	5	2
Cough	2	0

Pediatric Patients with Bipolar Mania Table 12 lists the adverse reactions reported in 5% or more of risperidone tablets-treated pediatric patients with bipolar mania in a 3-week double-blind, placebo-controlled trial.

Table 12. Adverse Reactions in ≥5% of Risperidone Tablets-Treated Pediatric Patients (and greater than placebo) with Bipolar Mania in Double-Blind, Placebo-Controlled Trials

* Parkinsonism includes musculoskeletal stiffness, extrapyramidal disorder, bradykinesia, and nuchal rigidity. Dystonia includes dystonia, laryngospasm, and muscle spasms. Akathisia includes restlessness and akathisia.
System/Organ Class Adverse Reaction	Percentage of Patients Reporting Reaction
	Risperidone Tablets		Placebo (N=58)
	0.5–2.5 mg per day (N=50)	3–6 mg per day (N=61)
Eye Disorders
Vision blurred	4	7	0
Gastrointestinal Disorders
Abdominal pain upper	16	13	5
Nausea	16	13	7
Vomiting	10	10	5
Diarrhea	8	7	2
Dyspepsia	10	3	2
Stomach discomfort	6	0	2
General Disorders
Fatigue	18	30	3
Metabolism and Nutrition Disorders
Increased appetite	4	7	2
Nervous System Disorders
Sedation	42	56	19
Dizziness	16	13	5
Parkinsonism *	6	12	3
Dystonia *	6	5	0
Akathisia *	0	8	2
Psychiatric Disorders
Anxiety	0	8	3
Respiratory, Thoracic and Mediastinal Disorders
Pharyngolaryngeal pain	10	3	5
Skin and Subcutaneous Tissue Disorders
Rash	0	7	2

Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials — Autistic Disorder

Table 13 lists the adverse reactions reported in 5% or more of risperidone tablets-treated pediatric patients treated for irritability associated with autistic disorder in two 8-week, double-blind, placebo-controlled trials and one 6-week double-blind, placebo-controlled study.

Table 13. Adverse Reactions in ≥ 5% of Risperidone Tablets-Treated Pediatric Patients (and greater than placebo) Treated for Irritability Associated with Autistic Disorder in Double-Blind, Placebo-Controlled Trials

* Parkinsonism includes musculoskeletal stiffness, extrapyramidal disorder, muscle rigidity, cogwheel rigidity, and muscle tightness.
System/Organ Class Adverse Reaction	Percentage of Patients Reporting Reaction
	Risperidone Tablets 0.5–4.0 mg per day (N=107)	Placebo (N=115)
Gastrointestinal Disorders
Vomiting	20	17
Constipation	17	6
Dry mouth	10	4
Nausea	8	5
Salivary hypersecretion	7	1
General Disorders and Administration Site Conditions
Fatigue	31	9
Pyrexia	16	13
Thirst	7	4
Infections and Infestations
Nasopharyngitis	19	9
Rhinitis	9	7
Upper respiratory tract infection	8	3
Investigations
Weight increased	8	2
Metabolism and Nutrition Disorders
Increased appetite	44	15
Nervous System Disorders
Sedation	63	15
Drooling	12	4
Headache	12	10
Tremor	8	1
Dizziness	8	2
Parkinsonism *	8	1
Renal and Urinary Disorders
Enuresis	16	10
Respiratory, Thoracic and Mediastinal Disorders
Cough	17	12
Rhinorrhea	12	10
Nasal congestion	10	4
Skin and Subcutaneous Tissue Disorders
Rash	8	5

Other Adverse Reactions Observed During the Clinical Trial Evaluation of Risperidone

The following additional adverse reactions occurred across all placebo-controlled, active-controlled, and open-label studies of risperidone tablets in adults and pediatric patients.

Blood and Lymphatic System Disorders: anemia, granulocytopenia, neutropenia

Cardiac Disorders: 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

Endocrine Disorders: hyperprolactinemia

Eye Disorders: 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: edema peripheral, thirst, gait disturbance, influenza-like illness, pitting edema, edema, chills, sluggishness, malaise, chest discomfort, face edema, discomfort, generalized edema, drug withdrawal syndrome, peripheral coldness, feeling abnormal

Immune System Disorders: drug hypersensitivity

Infections and Infestations: 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, blood prolactin increased, alanine aminotransferase increased, electrocardiogram abnormal, eosinophil count increased, white blood cell count decreased, blood glucose increased, hemoglobin decreased, hematocrit decreased, body temperature decreased, blood pressure decreased, transaminases increased

Metabolism and Nutrition Disorders: decreased appetite, polydipsia, anorexia

Musculoskeletal and Connective Tissue Disorders: joint stiffness, joint swelling, musculoskeletal chest pain, posture abnormal, myalgia, neck pain, muscular weakness, rhabdomyolysis

Nervous System Disorders: balance disorder, disturbance in attention, dysarthria, unresponsive to stimuli, depressed level of consciousness, movement disorder, transient ischemic attack, coordination abnormal, cerebrovascular accident, speech disorder, syncope, loss of consciousness, hypoesthesia, tardive dyskinesia, dyskinesia, cerebral ischemia, cerebrovascular disorder, neuroleptic malignant syndrome, diabetic coma, head titubation

Psychiatric Disorders: agitation, blunted affect, confusional state, middle insomnia, nervousness, sleep disorder, listlessness, libido decreased, and anorgasmia

Renal and Urinary Disorders: enuresis, dysuria, pollakiuria, urinary incontinence

Reproductive System and Breast Disorders: menstruation irregular, amenorrhea, gynecomastia, galactorrhea, vaginal discharge, menstrual disorder, erectile dysfunction, retrograde ejaculation, ejaculation disorder, sexual dysfunction, breast enlargement

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

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

Vascular Disorders: hypotension, flushing

Discontinuations Due to Adverse Reactions Schizophrenia — Adults

Approximately 7% (39/564) of risperidone tablets-treated patients in double-blind, placebo-controlled trials discontinued treatment due to an adverse reaction, compared with 4% (10/225) who were receiving placebo. The adverse reactions associated with discontinuation in 2 or more risperidone tablets-treated patients were:

Table 14. Adverse Reactions Associated With Discontinuation in 2 or More Risperidone Tablets-Treated Adult Patients in Schizophrenia Trials

Adverse Reaction	Risperidone Tablets		Placebo (N=225 )
	2-8 mg/day (N=366)	>8-16 mg/day (N=198)
Dizziness	1.4%	1.0%	0%
Nausea	1.4%	0%	0%
Vomiting	0.8%	0%	0%
Parkinsonism	0.8%	0%	0%
Somnolence	0.8%	0%	0%
Dystonia	0.5%	0%	0%
Agitation	0.5%	0%	0%
Abdominal pain	0.5%	0%	0%
Orthostatic hypotension	0.3%	0.5%	0%
Akathisia	0.3%	2.0%	0%

Discontinuation for extrapyramidal symptoms (including Parkinsonism, akathisia, dystonia, and tardive dyskinesia) was 1% in placebo-treated patients, and 3.4% in active control-treated patients in a double-blind, placebo- and active-controlled trial.

Schizophrenia – Pediatrics
Approximately 7% (7/106), of risperidone tablets-treated patients discontinued treatment due to an adverse reaction in a double-blind, placebo-controlled trial, compared with 4% (2/54) placebo-treated patients. The adverse reactions associated with discontinuation for at least one risperidone tablets-treated patient were dizziness (2%), somnolence (1%), sedation (1%), lethargy (1%), anxiety (1%), balance disorder (1%), hypotension (1%), and palpitation (1%).

Bipolar Mania – Adults In double-blind, placebo-controlled trials with risperidone tablets as monotherapy, approximately 6% (25/448) of risperidone tablets-treated patients discontinued treatment due to an adverse event, compared with approximately 5% (19/424) of placebo-treated patients. The adverse reactions associated with discontinuation in risperidone tablets-treated patients were:

Table 15. Adverse Reactions Associated With Discontinuation in 2 or More Risperidone Tablets-Treated Adult Patients in Bipolar Mania Clinical Trials

Adverse Reaction	Risperidone Tablets 1-6 mg/day (N=448)	Placebo (N=448)
Parkinsonism	0.4%	0%
Lethargy	0.2%	0%
Dizziness	0.2%	0%
Alanine aminotransferase increased	0.2%	0.2%
Aspartate aminotransferase increased	0.2%	0.2%

Bipolar Mania – Pediatrics
In a double-blind, placebo-controlled trial 12% (13/111) of risperidone tablets-treated patients discontinued due to an adverse reaction, compared with 7% (4/58) of placebo-treated patients. The adverse reactions associated with discontinuation in more than one risperidone tablets-treated pediatric patient were nausea (3%), somnolence (2%), sedation (2%), and vomiting (2%).

Autistic Disorder – Pediatrics

In the two 8-week, placebo-controlled trials in pediatric patients treated for irritability associated with autistic disorder (n = 156), one risperidone tablets-treated patient discontinued due to an adverse reaction (Parkinsonism), and one placebo-treated patient discontinued due to an adverse event.

Dose Dependency of Adverse Reactions in Clinical Trials
Extrapyramidal Symptoms Data from two fixed-dose trials in adults with schizophrenia provided evidence of dose-relatedness for extrapyramidal symptoms associated with risperidone tablets treatment.

Two methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial comparing 4 fixed doses of risperidone tablets (2, 6, 10, and 16 mg/day), including (1) a Parkinsonism score (mean change from baseline) from the Extrapyramidal Symptom Rating Scale, and (2) incidence of spontaneous complaints of EPS:

Table 16.

Dose Groups	Placebo	Risperidone Tablets 2 mg	Risperidone Tablets 6 mg	Risperidone Tablets 10 mg	Risperidone Tablets 16 mg
Parkinsonism	1.2	0.9	1.8	2.4	2.6
EPS Incidence	13%	17%	21%	21%	35%

Similar methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial comparing 5 fixed doses of risperidone tablets (1, 4, 8, 12, and 16 mg/day):

Table 17.

Dose Groups	Risperidone Tablets 1 mg	Risperidone Tablets 4 mg	Risperidone Tablet s 8 mg	Risperidone Tablets 12 mg	Risperidone Tablets 16 mg
Parkinsonism	0.6	1.7	2.4	2.9	4.1
EPS Incidence	7%	12%	17%	18%	20%

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.

Other Adverse Reactions
Adverse event data elicited by a checklist for side effects from a large study comparing 5 fixed doses of risperidone tablets (1, 4, 8, 12, and 16 mg/day) were explored for dose-relatedness of adverse events. A Cochran-Armitage Test for trend in these data revealed a positive trend (p<0.05) for the following adverse reactions: somnolence, vision abnormal, dizziness, palpitations, weight increase, erectile dysfunction, ejaculation disorder, sexual function abnormal, fatigue, and skin discoloration.

Changes in Body Weight

Weight gain was observed in short-term, controlled trials and longer-term uncontrolled studies in adult and pediatric patients [see Warnings and Precautions (5.5), Adverse Reactions (6), and Use in Specific Populations (8.4)].

Changes in ECG Parameters Between-group comparisons for pooled placebo-controlled trials in adults revealed no statistically significant differences between risperidone and placebo in mean changes from baseline in ECG parameters, including QT, QTc, and PR intervals, and heart rate. When all risperidone tablets doses were pooled from randomized controlled trials in several indications, there was a mean increase in heart rate of 1 beat per minute compared to no change for placebo patients. In short-term schizophrenia trials, higher doses of risperidone (8-16 mg/day) were associated with a higher mean increase in heart rate compared to placebo (4-6 beats per minute). In pooled placebo-controlled acute mania trials in adults, there were small decreases in mean heart rate, similar among all treatment groups.

In the two placebo-controlled trials in children and adolescents with autistic disorder (aged 5 – 16 years) mean changes in heart rate were an increase of 8.4 beats per minute in the risperidone tablets groups and 6.5 beats per minute in the placebo group. There were no other notable ECG changes.

In a placebo-controlled acute mania trial in children and adolescents (aged 10 – 17 years), there were no significant changes in ECG parameters, other than the effect of risperidone tablets to transiently increase pulse rate (< 6 beats per minute). In two controlled schizophrenia trials in adolescents (aged 13 – 17 years), there were no clinically meaningful changes in ECG parameters including corrected QT intervals between treatment groups or within treatment groups over time.