Risperdal Side Effects Center

SIDE EFFECTS

The following are discussed in more detail in other sections of the labeling:

• Increased mortality in elderly patients with dementia-related psychosis [see BOX WARNING and WARNINGS AND PRECAUTIONS]
• Cerebrovascular adverse events, including stroke, in elderly patients with dementia-related psychosis [see WARNINGS AND PRECAUTIONS]
• Neuroleptic malignant syndrome [see WARNINGS AND PRECAUTIONS]
• Tardive dyskinesia [see WARNINGS AND PRECAUTIONS]
• Metabolic Changes (Hyperglycemia and diabetes mellitus, Dyslipidemia, and Weight Gain)[see WARNINGS AND PRECAUTIONS]
• Hyperprolactinemia [see WARNINGS AND PRECAUTIONS]
• Orthostatic hypotension [see WARNINGS AND PRECAUTIONS]
• Falls [see WARNINGS AND PRECAUTIONS]
• Leukopenia, neutropenia, and agranulocytosis [see WARNINGS AND PRECAUTIONS]
• Potential for cognitive and motor impairment [see WARNINGS AND PRECAUTIONS]
• Seizures [see WARNINGS AND PRECAUTIONS]
• Dysphagia [see WARNINGS AND PRECAUTIONS]
• Priapism [see WARNINGS AND PRECAUTIONS]
• Disruption of body temperature regulation [see WARNINGS AND PRECAUTIONS]
• Patients with Phenylketonuria [see WARNINGS AND PRECAUTIONS].

The most common adverse reactions in clinical trials (>5% and twice placebo) were parkinsonism, akathisia, dystonia, tremor, sedation, dizziness, anxiety, blurred vision, nausea, vomiting, upper abdominal pain, stomach discomfort, dyspepsia, diarrhea, salivary hypersecretion, constipation, dry mouth, increased appetite, increased weight, fatigue, rash, nasal congestion, upper respiratory tract infection, nasopharyngitis, and pharyngolaryngeal pain.

The most common adverse reactions that were associated with discontinuation from clinical trials (causing discontinuation in >1% of adults and/or >2% of pediatrics) were nausea, somnolence, sedation, vomiting, dizziness, and akathisia [see ADVERSE REACTIONS, Discontinuations Due To Adverse Reactions].

The data described in this section are derived from a clinical trial database consisting of 9803 adult and pediatric patients exposed to one or more doses of RISPERDAL^® for the treatment of schizophrenia, bipolar mania, autistic disorder, and other psychiatric disorders in pediatrics and elderly patients with dementia. Of these 9803 patients, 2687 were patients who received RISPERDAL^® while participating in double-blind, placebo-controlled trials. The conditions and duration of treatment with RISPERDAL^® 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 3 years) exposures. Safety was assessed by collecting adverse events and performing physical examinations, vital signs, body weights, laboratory analyses, and ECGs.

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 RISPERDAL^®-treated adult patients with schizophrenia in three 4-to 8-week, double-blind, placebo-controlled trials.

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

	Percentage of Patients Reporting Reaction
	RISPERDAL®
System/Organ Class   Adverse Reaction	2-8 mg per day (N=366)	>8-16 mg per day (N=198)	Placebo (N=225)
Cardiac Disorders   Tachycardia	1	3	0
Eye Disorder   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	2	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
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
* 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.

Pediatric Patients with Schizophrenia

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

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

	Percentage of Patients Reporting Reaction
	RISPERDAL®
System/Organ Class   Adverse Reaction	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
* Parkinsonism includes extrapyramidal disorder, muscle rigidity, musculoskeletal stiffness, and hypokinesia. Akathisia includes akathisia and restlessness. Dystonia includes dystonia and oculogyration.

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 RISPERDAL^®-treated adult patients with bipolar mania in four 3-week, double-blind, placebo-controlled monotherapy trials.

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

	Percentage of Patients Reporting Reaction
System/Organ Class   Adverse Reaction	RISPERDAL® 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
* 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.

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

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

	Percentage of Patients Reporting Reaction
System/Organ Class   Adverse Reaction	RISPERDAL®+ 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
* Parkinsonism includes extrapyramidal disorder, hypokinesia and bradykinesia. Akathisia includes hyperkinesia and akathisia.

Pediatric Patients with Bipolar Mania

Table 12 lists the adverse reactions reported in 5% or more of RISPERDAL^®-treated pediatric patients with bipolar mania in a 3-week double-blind, placebo-controlled trial.

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

System/Organ Class   Adverse Reaction	Percentage of Patients Reporting Reaction
	RISPERDAL®
	0.5-2.5 mg per day (N=50)	3-6 mg per day (N=61)	Placebo (N=58)
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
* Parkinsonism includes musculoskeletal stiffness, extrapyramidal disorder, bradykinesia, and nuchal rigidity. Dystonia includes dystonia, laryngospasm, and muscle spasms. Akathisia includes restlessness and akathisia.

 

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 RISPERDAL^®-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 RISPERDAL^®-Treated Pediatric Patients (and greater than placebo) Treated for Irritability
Associated with Autistic Disorder in Double-Blind, Placebo-Controlled Trials

System/Organ Class   Adverse Reaction	Percentage of Patients Reporting Reaction
	RISPERDAL®
	0.5-4.0 mg/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
* Parkinsonism includes musculoskeletal stiffness, extrapyramidal disorder, muscle rigidity, cogwheel rigidity, and muscle tightness.

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 RISPERDAL^® 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

Additional Adverse Reactions Reported With RISPERDAL CONSTA^®

The following is a list of additional adverse reactions that have been reported during the premarketing evaluation of RISPERDAL CONSTA^®, regardless of frequency of occurrence:

Cardiac Disorders: bradycardia

Ear and Labyrinth Disorders: vertigo

Eye Disorders: blepharospasm

Gastrointestinal Disorders: toothache, tongue spasm

General Disorders and Administration Site Conditions: pain

Infections and Infestations: lower respiratory tract infection, infection, gastroenteritis, subcutaneous abscess

Injury and Poisoning: fall

Investigations: weight decreased, gamma-glutamyltransferase increased, hepatic enzyme increased

Musculoskeletal, Connective Tissue, and Bone Disorders: buttock pain

Nervous System Disorders: convulsion, paresthesia

Psychiatric Disorders: depression

Skin and Subcutaneous Tissue Disorders: eczema

Vascular Disorders: hypertension

Additional Adverse Reactions Reported With RISPERDAL CONSTA^®

The following is a list of additional adverse reactions that have been reported during the premarketing evaluation of RISPERDAL CONSTA^®, regardless of frequency of occurrence:

Cardiac Disorders: bradycardia

Ear and Labyrinth Disorders: vertigo

Eye Disorders: blepharospasm

Gastrointestinal Disorders: toothache, tongue spasm

General Disorders and Administration Site Conditions: pain

Infections and Infestations: lower respiratory tract infection, infection, gastroenteritis, subcutaneous abscess

Injury and Poisoning: fall

Investigations: weight decreased, gamma-glutamyltransferase increased, hepatic enzyme increased

Musculoskeletal, Connective Tissue, and Bone Disorders: buttock pain

Nervous System Disorders: convulsion, paresthesia

Psychiatric Disorders: depression

Skin and Subcutaneous Tissue Disorders: eczema

Vascular Disorders: hypertension

Discontinuations Due To Adverse Reactions

Schizophrenia -Adults

Approximately 7% (39/564) of RISPERDAL^®-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 RISPERDAL^®-treated patients were:

Table 14. Adverse Reactions Associated With Discontinuation in 2 or More RISPERDAL^®-Treated Adult Patients in Schizophrenia Trials

Adverse Reaction	RISPERDAL®
	2-8 mg/day (N=366)	>8-16 mg/day (N=198)	Placebo (N=225)
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 RISPERDAL^®-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 RISPERDAL^®-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 RISPERDAL^® as monotherapy, approximately 6% (25/448) of RISPERDAL^®-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 RISPERDAL^®-treated patients were:

Table 15. Adverse Reactions Associated With Discontinuation in 2 or More RISPERDAL®Treated Adult Patients in Bipolar Mania Clinical Trials

Adverse Reaction	RISPERDAL®
	1-6 mg/day (N=448)	Placebo (N=424)
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 RISPERDAL^®-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 RISPERDAL^®-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 RISPERDAL^®-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 RISPERDAL^® treatment.

Two methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial comparing 4 fixed doses of RISPERDAL^® (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	RISPERDAL® 2 mg	RISPERDAL® 6 mg	RISPERDAL® 10 mg	RISPERDAL® 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 RISPERDAL^® (1, 4, 8, 12, and 16 mg/day):

Table 17.

Dose Groups	RISPERDAL® 1 mg	RISPERDAL® 4 mg	RISPERDAL® 8 mg	RISPERDAL® 12 mg	RISPERDAL® 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 RISPERDAL^® (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, ADVERSE REACTIONS, and Use In Specific Populations].

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 RISPERDAL^® 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 RISPERDAL^® 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 RISPERDAL^® 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.

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 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.

DRUG INTERACTIONS

Pharmacokinetic-Related Interactions

The dose of RISPERDAL^® should be adjusted when used in combination with CYP2D6 enzyme inhibitors (e.g., fluoxetine, and paroxetine) and enzyme inducers (e.g., carbamazepine) [see Table 18 and DOSAGE AND ADMINISTRATION]. Dose adjustment is not recommended for RISPERDAL^® when co-administered with ranitidine, cimetidine, amitriptyline, or erythromycin [see Table 18].

Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia

Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio*)		Risperidone Dose Recommendation
	Coadministered Drug	Risperidone	AUC	Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed
* Change relative to reference

Effect Of Risperidone On Other Drugs

Lithium

Repeated oral doses of RISPERDAL^® (3 mg twice daily) did not affect the exposure (AUC) or peak plasma concentrations (Cmax) of lithium (n=13). Dose adjustment for lithium is not recommended.

Valproate

Repeated oral doses of RISPERDAL^® (4 mg once daily) did not affect the pre-dose or average plasma concentrations and exposure (AUC) of valproate (1000 mg/day in three divided doses) compared to placebo (n=21). However, there was a 20% increase in valproate peak plasma concentration (Cmax) after concomitant administration of RISPERDAL^®. Dose adjustment for valproate is not recommended.

Digoxin

RISPERDAL^® (0.25 mg twice daily) did not show a clinically relevant effect on the pharmacokinetics of digoxin. Dose adjustment for digoxin is not recommended.

Pharmacodynamic-Related Interactions

Centrally Acting Drugs And Alcohol

Given the primary CNS effects of risperidone, caution should be used when RISPERDAL^® is taken in combination with other centrally acting drugs and alcohol.

Drugs With Hypotensive Effects

Because of its potential for inducing hypotension, RISPERDAL^® may enhance the hypotensive effects of other therapeutic agents with this potential.

Levodopa And Dopamine Agonists

RISPERDAL^® may antagonize the effects of levodopa and dopamine agonists.

Methylphenidate

Concomitant use with methylphenidate, when there is change in dosage of either medication, may increase the risk of extrapyramidal symptoms (EPS). Monitor for symptoms of EPS with concomitant use of RISPERDAL^® and methylphenidate [see ADVERSE REACTIONS].

Clozapine

Chronic administration of clozapine with RISPERDAL^® may decrease the clearance of risperidone.

Drug Abuse And Dependence

Controlled Substance

RISPERDAL^® (risperidone) is not a controlled substance.

Abuse

RISPERDAL^® has not been systematically studied in animals or humans for its potential for abuse. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of RISPERDAL^® misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior).

Dependence

RISPERDAL^® has not been systematically studied in animals or humans for its potential for tolerance or physical dependence.

Read the entire FDA prescribing information for Risperdal (Risperidone)