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These highlights do not include all the information needed to use risperidone safely and effectively. See full prescribing information for risperidone. Risperidone Tablets Initial U.S. Approval : 1993 | RISPERIDONE [WOCKHARDT LIMITED] | BioPortfolio

12:45 EST 27th January 2019 | BioPortfolio

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Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Risperidone is not approved for the treatment of patients with dementia-related psychosis. [See Warnings and Precautions (5.1)]

Table 1a. Change in Random Glucose from Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adult Subjects with Schizophrenia or Bipolar Mania
Risperidone
Placebo 1 to 8 mg/day >8 to 16 mg/day
Mean change from baseline (mg/dL)
n=555 n=748 n=164
Serum Glucose -1.4 0.8 0.6
Proportion of patients with shifts
Serum Glucose 0.6% 0.4% 0%
(<140 mg/dL to ≥220 mg/dL) (3/525) (3/702) (0/158)
Table 1b. Change in Fasting Glucose from Three Placebo-Controlled, 3- to 6-Week, Fixed-Dose Studies in Children and Adolescents with Schizophrenia (13 to 17 years of age), Bipolar Mania (10 to 17 years of age), or Autistic Disorder (5 to 17 years of age)
Risperidone
Placebo 0.5 to 6 mg/day
Mean change from baseline (mg/dL)
n=76 n=135
Serum Glucose -1.3 2.6
Proportion of patients with shifts
Serum Glucose 0% 0.8%
(<100 mg/dL to ≥126 mg/dL) (0/64) (1/120)
Table 2a. Change in Random Lipids From Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adult Subjects With Schizophrenia or Bipolar Mania
Risperidone
Placebo 1 to 8 mg/day >8 to 16 mg/day
Mean change from baseline (mg/dL)
Cholesterol n=559 n=742 n=156
Change from baseline 0.6 6.9 1.8
Triglycerides n=183 n=307 n=123
Change from baseline -17.4 -4.9 -8.3
Proportion of patients With Shifts
Cholesterol 2.7% 4.3% 6.3%
(<200 mg/dL to ≥240 mg/dL) (10/368) (22/516) (6/96)
Triglycerides 1.1% 2.7% 2.5%
(<500 mg/dL to ≥500 mg/dL) (2/180) (8/301) (3/121)
Table 2b. Change in Fasting Lipids From Three Placebo-Controlled, 3- to 6-Week, Fixed-Dose Studies in Children and Adolescents With Schizophrenia (13 to 17 Years of Age), Bipolar Mania (10 to 17 Years of Age), or Autistic Disorder (5 to 17 Years of Age)
Risperidone
Placebo 0.5 to 6 mg/day
Mean change from baseline (mg/dL)
Cholesterol n=74 n=133
Change from baseline 0.3 -0.3
LDL n=22 n=22
Change from baseline 3.7 0.5
HDL n=22 n=22
Change from baseline 1.6 -1.9
Triglycerides n=77 n=138
Change from baseline -9.0 -2.6
Proportion of patients with shifts
Cholesterol 2.4% 3.8%
(<170 mg/dL to ≥200 mg/dL) (1/42) (3/80)
LDL 0% 0%
(<110 mg/dL to ≥130 mg/dL) (0/16) (0/16)
HDL 0% 10%
(≥40 mg/dL to <40 mg/dL) (0/19) (2/20)
Triglycerides 1.5% 7.1%
(<150 mg/dL to ≥200 mg/dL) (1/65) (8/113)
Table 3a. Mean Change in Body Weight (kg) and the Proportion of Subjects with ≥7% Gain in Body Weight From Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adult Subjects With Schizophrenia or Bipolar Mania
Risperidone
Placebo
(n=597)
1 to 8 mg/day
(n=769)
>8 to 16 mg/day
(n=158)
Weight (kg)
Change from baseline -0.3 0.7 2.2
Weight Gain
≥7% increase from baseline 2.9% 8.7% 20.9%
Table 3b. Mean Change in Body Weight (kg) and the Proportion of Subjects With ≥7% Gain in Body Weight From Nine Placebo-Controlled, 3- to 8-Week, Fixed-Dose Studies in Children and Adolescents With Schizophrenia (13 to 17 Years of Age), Bipolar Mania (10 to 17 Years of Age), Autistic Disorder (5 to 17 Years of Age) or Other Psychiatric Disorders (5 to 17 Years of Age)
Placebo
(n=375)
Risperidone 0.5 to 6 mg/day
(n=448)
Weight (kg)
Change from baseline 0.6 2.0
Weight Gain
≥7% increase from baseline 6.9% 32.6%

Risperidone may induce orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope, especially during the initial dose-titration period, probably reflecting its alpha-adrenergic antagonistic properties. Syncope was reported in 0.2% (6/2607) of risperidone- treated patients in Phase 2 and 3 studies in adults with schizophrenia. The risk of orthostatic hypotension and syncope may be minimized by limiting the initial dose to 2 mg total (either once daily or 1 mg twice daily) in normal adults and 0.5 mg twice daily in the elderly and patients with renal or hepatic impairment [see Dosage and Administration (2.1, 2.4)]. Monitoring of orthostatic vital signs should be considered in patients for whom this is of concern. A dose reduction should be considered if hypotension occurs. Risperidone should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and conditions which would predispose patients to hypotension, e.g., dehydration and hypovolemia. Clinically significant hypotension has been observed with concomitant use of risperidone and antihypertensive medication.

Table 4. Adverse Reactions in ≥ 1% of Risperidone-Treated Adult Patients with Schizophrenia in Double-Blind, Placebo-Controlled Trials
Percentage of Patients Reporting Event
Risperidone
System/Organ Class Adverse Reaction 2 to 8 mg per day (N = 366) >8 to 16 mg per day (N = 198) Placebo (N = 225)
Blood and Lymphatic System Disorders
Anemia < 1 1 0
Cardiac Disorders
Tachycardia 1 3 0
Ear and Labyrinth Disorders
Ear pain < 1 1 0
Eye Disorders
Vision blurred 3 1 1
Gastrointestinal Disorders
Nausea 9 4 4
Constipation 8 9 6
Dyspepsia 8 6 5
Vomiting 7 5 7
Dry mouth 4 0 1
Abdominal discomfort 3 1 1
Salivary hypersecretion 2 1 < 1
Diarrhea 2 1 1
Abdominal pain 1 1 0
Abdominal pain upper 1 1 0
Stomach discomfort 1 1 1
General Disorders
Fatigue 3 1 0
Chest pain 2 2 1
Asthenia 2 1 < 1
Immune System Disorders
Hypersensitivity < 1 1 0
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
Weight increased 1 1 0
Blood creatine phosphokinase increased 1 2 < 1
Heart rate increased < 1 2 0
Metabolism and Nutrition Disorders
Decreased appetite 1 0 < 1
Musculoskeletal and Connective Tissue Disorders
Back pain 4 1 1
Arthralgia 2 3 < 1
Pain in extremity 2 1 1
Joint stiffness 1 1 0
Nervous System Disorders
Parkinsonism* 14 17 8
Akathisia* 10 10 3
Dizziness 7 4 2
Somnolence 7 2 1
Dystonia* 3 4 2
Sedation 3 3 1
Tremor* 2 3 1
Dizziness postural 2 0 0
Dyskinesia* 1 2 2
Syncope 1 1 0
Psychiatric Disorders
Insomnia 32 25 27
Anxiety 16 11 11
Nervousness 1 1 < 1
Renal and Urinary Disorders
Urinary incontinence 1 1 0
Reproductive System and Breast Disorders
Ejaculation failure < 1 1 0
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
Dandruff 1 1 0
Seborrheic dermatitis < 1 1 0
Hyperkeratosis 0 1 1
Vascular Disorders
Orthostatic hypotension 2 1 0
Hypotension 1 1 0
Table 5. Adverse Reactions in ≥ 5% of Risperidone-Treated Pediatric Patients with Schizophrenia in a Double-Blind Trial
Percentage of Patients Reporting Event
System/Organ Class Adverse Reaction Risperidone Placebo (N = 54)
1 to 3 mg per day (N = 55) 4 to 6 mg per day (N = 51)
Gastrointestinal Disorders
Salivary hypersecretion 0 10 2
Nervous System Disorders
Parkinsonism* 16 28 11
Sedation 13 8 2
Somnolence 11 4 2
Tremor 11 10 6
Akathisia* 9 10 4
Dizziness 7 14 2
Dystonia* 2 6 0
Psychiatric Disorders
Anxiety 7 6 0

A dult Patients with Bipolar Mania

Table 6 lists the adverse reactions reported in 1% or more of risperidone-treated adult patients with bipolar mania in four 3-week, double-blind, placebo-controlled monotherapy trials.

Table 6. Adverse Reactions in ≥ 1% of Risperidone-Treated Adult Patients with Bipolar Mania in Double-Blind, Placebo-Controlled Monotherapy Trials
Percentage of Patients Reporting Event
System/Organ Class Adverse Reaction Risperidone 1 to 6 mg per day (N = 448) Placebo (N = 424)
Cardiac Disorders
Tachycardia 1 < 1
Eye Disorders
Vision blurred 2 1
Gastrointestinal Disorders
Nausea 5 2
Diarrhea 3 2
Salivary hypersecretion 3 1
Dyspepsia 2 2
Stomach discomfort 2 < 1
General Disorders
Fatigue 2 1
Asthenia 1 1
Pyrexia 1 1
Infections and Infestations
Nasopharyngitis 1 1
Investigations
Aspartate aminotransferase increased 1 < 1
Nervous System Disorders
Parkinsonism* 25 9
Akathisia* 9 3
Tremor* 6 3
Dizziness 6 5
Sedation 6 2
Somnolence 5 2
Dystonia* 5 1
Lethargy 2 1
Dyskinesia* 1 < 1
Reproductive System and Breast Disorders
Galactorrhea 1 0
Skin and Subcutaneous Tissue Disorders
Acne 1 0
Table 7. Adverse Reactions in ≥ 2% of Risperidone-Treated Adult Patients with Bipolar Mania in Double-Blind, Placebo-Controlled Adjuvant Therapy Trials
Percentage of Patients Reporting Event
Risperidone + Placebo +
System/Organ Class Mood Stabilizer Mood Stabilizer
Adverse Reaction (N = 127) (N = 126)
Cardiac Disorders
Palpitations 2 0
Gastrointestinal Disorders
Dyspepsia 9 8
Nausea 6 4
Diarrhea 6 4
Dry mouth 4 4
Vomiting 4 6
Constipation 3 3
Salivary hypersecretion 2 0
General Disorders
Chest pain 2 1
Fatigue 2 2
Infections and Infestations
Nasopharyngitis 2 3
Urinary tract infection 2 1
Investigations
Weight increased 2 2
Nervous System Disorders
Parkinsonism* 14 4
Headache 14 15
Akathisia* 8 0
Dizziness 7 2
Sedation 6 3
Tremor 6 2
Somnolence 3 1
Lethargy 2 1
Psychiatric Disorders
Insomnia 4 8
Anxiety 3 2
Respiratory, Thoracic and Mediastinal Disorders
Pharyngolaryngeal pain 5 2
Cough 2 0
Table 8. Adverse Reactions in ≥ 5% of Risperidone-Treated Pediatric Patients with Bipolar Mania in Double-Blind, Placebo-Controlled Trials
Percentage of Patients Reporting Event
System/Organ Class Adverse Reaction Risperidone Placebo (N = 58)
0.5 to 2.5 mg per day (N = 50) 3 to 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
Somnolence 22 30 12
Sedation 20 23 7
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

Table 9 lists the adverse reactions reported in 5% or more of risperidone-treated pediatric patients treated for irritability associated with autistic disorder in two 8-week, double-blind, placebo-controlled trials.

*Parkinsonism includes musculoskeletal stiffness, extrapyramidal disorder, muscle rigidity, cogwheel rigidity, and muscle tightness. In another study with patients treated for irritability associated with autistic disorder, headache (6%), epistaxis (6%) and pyrexia (6%) were also observed in risperidone-treated pediatric subjects.

Table 9. Adverse Reactions in ≥ 5% of Risperidone-Treated Pediatric Patients Treated for Irritability Associated with Autistic Disorder in Double-Blind, Placebo-Controlled Trials
Percentage of Patients Reporting Event
System/Organ Class Adverse Reaction Risperidone 0.5 to 4.0 mg per day (N = 76) Placebo (N = 80)
Cardiac Disorders
Tachycardia 5 0
Gastrointestinal Disorders
Vomiting 25 21
Constipation 21 8
Dry mouth 15 6
Salivary hypersecretion 9 0
Nausea 8 6
General Disorders
Fatigue 42 13
Feeling abnormal 5 0
Infections and Infestations
Nasopharyngitis 21 10
Rhinitis 13 10
Upper respiratory tract infection 8 3
Investigations
Weight increased 5 0
Metabolism and Nutrition Disorders
Increased appetite 47 19
Nervous System Disorders
Somnolence 49 18
Sedation 29 3
Drooling 16 5
Tremor 12 1
Parkinsonism* 11 1
Dizziness 9 3
Dyskinesia 7 3
Lethargy 5 3
Respiratory, Thoracic and Mediastinal Disorders
Cough 24 18
Rhinorrhea 16 13
Nasal congestion 13 5
Skin and Subcutaneous Tissue Disorders
Rash 11 8

The following adverse reactions occurred in < 1% of the adult patients and in < 5% of the pediatric patients treated with risperidone in the above double-blind, placebo-controlled clinical trial data sets. In addition, the following also includes adverse reactions reported in  risperidone-treated patients who participated in other studies, including double-blind, active-controlled and open-label studies in schizophrenia and bipolar mania studies in pediatric patients with psychiatric disorders other than schizophrenia, bipolar mania, or autistic disorder, and studies in elderly patients with dementia. Blood and Lymphatic System Disorders: 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: 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 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: polydipsia, anorexia Musculoskeletal and Connective Tissue Disorders: joint swelling, musculoskeletal chest pain, posture abormal, myalgia, neck pain, muscular weakness, rhabdomyolysis Nervous System Disorders: balance disorder, disturbance in attention, dysarthria, unresponsive to stimuli, depressed level of consciousness, movement disorder, hypersomnia, transient ischemic attack, coordination abnormal, cerebrovascular accident, speech disorder, loss of consciousness, hypoesthesia, tardive dyskinesia, cerebral ischemia, cerebrovascular disorder, neuroleptic malignant syndrome, diabetic coma, head titubation Psychiatric Disorders: agitation, blunted affect, confusional state, middle insomnia, sleep disorder, listless, libido decreased, anorgasmia Renal and Urinary Disorders: enuresis, dysuria, pollakiuria Reproductive System and Breast Disorders: menstruation irregular, amenorrhea, gynecomastia, 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 Vascular Disorders: flushing

Table 10. Adverse Reactions Associated With Discontinuation in 2 or More Risperidone-Treated Adult Patients in Schizophrenia Trials
Risperidone
Adverse Reaction 2 to 8 mg/day (N = 366) > 8 to 16 mg/day (N = 198) Placebo (N = 225)
Dizziness 1.4% 1% 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%
Table 11. Adverse Reactions Associated With Discontinuation in 2 or More Risperidone-Treated Adult Patients in Bipolar Mania Clinical Trials
Adverse Reaction Risperidone 1 to 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%

Extrapyramidal SymptomsData from two fixed-dose trials in adults with schizophrenia provided evidence of dose relatedness for extrapyramidal symptoms associated with risperidone treatment. Two methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial comparing 4 fixed doses of risperidone (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:

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

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 ReactionsAdverse event data elicited by a checklist for side effects from a large study comparing 5 fixed doses of risperidone (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.

Dose Groups Placebo Risperidone
2 mg
Risperidone
6 mg
Risperidone
10 mg
Risperidone
16 mg
Parkinsonism 1.2 0.9 1.8 2.4 2.6
EPS Incidence 13% 17% 21% 21% 35%
Dose Groups Risperidone
1 mg
Risperidone
4 mg
Risperidone
8 mg
Risperidone
12 mg
Risperidone
16 mg
Parkinsonism 0.6 1.7 2.4 2.9 4.1
EPS Incidence 7% 12% 17% 18% 20%

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, diabetes mellitus, diabetic ketoacidosis in patients with impaired glucose metabolism, drug withdrawal syndrome neonatal, dysgeusia, hypoglycemia, hypothermia, inappropriate antidiuretic hormone secretion, intestinal obstruction, jaundice, mania, pancreatitis, priapism, QT prolongation, sleep apnea syndrome, thrombocytopenia, urinary retention, and water intoxication. Other adverse events reported since market introduction, which were temporally related to risperidone but not necessarily causally related, include the following: pituitary adenoma, pulmonary embolism, precocious puberty, cardiopulmonary arrest, and sudden death.

Amitriptyline did not affect the pharmacokinetics of risperidone or risperidone and 9-hydroxyrisperidone combined.

Chronic administration of clozapine with risperidone may decrease the clearance of risperidone.

Carbamazepine co-administration decreased the steady-state plasma concentrations of risperidone and 9-hydroxyrisperidone by about 50%. Plasma concentrations of carbamazepine did not appear to be affected. The dose of risperidone may need to be titrated accordingly for patients receiving carbamazepine, particularly during initiation or discontinuation of carbamazepine therapy. Co-administration of other known enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital) with risperidone may cause similar decreases in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone, which could lead to decreased efficacy of risperidone treatment.

In vitro studies indicate that risperidone is a relatively weak inhibitor of CYP 2D6. Therefore, risperidone is not expected to substantially inhibit the clearance of drugs that are metabolized by this enzymatic pathway. In drug interaction studies, risperidone did not significantly affect the pharmacokinetics of donepezil and galantamine, which are metabolized by CYP 2D6.

Pregnancy Category C.The teratogenic potential of risperidone was studied in three Segment II studies in Sprague- Dawley and Wistar rats (0.63 to 10 mg/kg or 0.4 to 6 times the maximum recommended human dose [MRHD] on a mg/m basis) and in one Segment II study in New Zealand rabbits (0.31 to 5 mg/kg or 0.4 to 6 times the MRHD on a mg/m basis). The incidence of malformations was not increased compared to control in offspring of rats or rabbits given 0.4 to 6 times the MRHD on a mg/m basis. In three reproductive studies in rats (two Segment III and a multigenerational study), there was an increase in pup deaths during the first 4 days of lactation at doses of 0.16 to 5 mg/kg or 0.1 to 3 times the MRHD on a mg/m basis. It is not known whether these deaths were due to a direct effect on the fetuses or pups or to effects on the dams. There was no no-effect dose for increased rat pup mortality. In one Segment III study, there was an increase in stillborn rat pups at a dose of 2.5 mg/kg or 1.5 times the MRHD on a mg/m basis. In a cross-fostering study in Wistar rats, toxic effects on the fetus or pups, as evidenced by a decrease in the number of live pups and an increase in the number of dead pups at birth (Day 0), and a decrease in birth weight in pups of drug-treated dams were observed. In addition, there was an increase in deaths by Day 1 among pups of drug-treated dams, regardless of whether or not the pups were cross-fostered. Risperidone also appeared to impair maternal behavior in that pup body weight gain and survival (from Day 1 to 4 of lactation) were reduced in pups born to control but reared by drug-treated dams. These effects were all noted at the one dose of risperidone tested, i.e., 5 mg/kg or 3 times the MRHD on a mg/m basis. Placental transfer of risperidone occurs in rat pups. There are no adequate and well-controlled studies in pregnant women. However, there was one report of a case of agenesis of the corpus callosum in an infant exposed to risperidone in utero. The causal relationship to risperidone therapy is unknown. Non-Teratogenic Effects Neonates exposed to antipsychotic drugs (including risperidone) during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization. Risperidone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Premarketing experience included eight reports of acute risperidone overdosage with estimated doses ranging from 20 to 300 mg and no fatalities. In general, reported signs and symptoms were those resulting from an exaggeration of the drug's known pharmacological effects, i.e., drowsiness and sedation, tachycardia and hypotension, and extrapyramidal symptoms. One case, involving an estimated overdose of 240 mg, was associated with hyponatremia, hypokalemia, prolonged QT, and widened QRS. Another case, involving an estimated overdose of 36 mg, was associated with a seizure. Post-marketing experience includes reports of acute risperidone overdosage, with estimated doses of up to 360 mg. In general, the most frequently reported signs and symptoms are those resulting from an exaggeration of the drug's known pharmacological effects, i.e., drowsiness, sedation, tachycardia, hypotension, and extrapyramidal symptoms. Other adverse reactions reported since market introduction related to risperidone overdose include prolonged QT interval and convulsions. Torsade de pointes has been reported in association with combined overdose of risperidone and paroxetine.

In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation and ventilation. Gastric lavage (after intubation, if patient is unconscious) and administration of activated charcoal together with a laxative should be considered. The possibility of obtundation, seizures, or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide, and quinidine carry a theoretical hazard of QT-prolonging effects that might be additive to those of risperidone. Similarly, it is reasonable to expect that the alpha-blocking properties of bretylium might be additive to those of risperidone, resulting in problematic hypotension. There is no specific antidote to risperidone. Therefore, appropriate supportive measures should be instituted. The possibility of multiple drug involvement should be considered. Hypotension and circulatory collapse should be treated with appropriate measures, such as intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should not be used, since beta stimulation may worsen hypotension in the setting of risperidone-induced alpha blockade). In cases of severe extrapyramidal symptoms, anticholinergic medication should be administered. Close medical supervision and monitoring should continue until the patient recovers.

The clinical effect from risperidone results from the combined concentrations of risperidone and its major metabolite, 9-hydroxyrisperidone [see Clinical Pharmacology (12.3)]. Antagonism at receptors other than D and 5HT [see Clinical Pharmacology (12.1)] may explain some of the other effects of risperidone.

      Multiples of Maximum
Human Dose in mg/m2 (mg/kg)
Tumor Type Species Sex Lowest
Effect Level
Highest
No-Effect Level
Pituitary adenomas mouse female 0.75 (9.4) 0.2 (2.4)
Endocrine pancreas adenomas rat male 1.5 (9.4) 0.4 (2.4)
Mammary gland adencarcinomas mouse female 0.2 (2.4) none
rat female 0.4 (2.4) none
rat male 6 (37.5) 1.5 (9.4)
Mammary gland neoplasm, Total rat male 1.5 (9.4) 0.4 (2.4)

AdultsThe efficacy of risperidone in the treatment of acute manic or mixed episodes was established in two short-term (3-week) placebo-controlled trials in patients who met the DSM-IV criteria for Bipolar I Disorder with manic or mixed episodes. These trials included patients with or without psychotic features. The primary rating instrument used for assessing manic symptoms in these trials was the Young Mania Rating Scale (YMRS), an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology (irritability, disruptive/aggressive behavior, sleep, elevated mood, speech, increased activity, sexual interest, language/thought disorder, thought content, appearance, and insight) in a range from 0 (no manic features) to 60 (maximum score). The primary outcome in these trials was change from baseline in the YMRS total score. The results of the trials follow: (1) In one 3-week placebo-controlled trial (n=246), limited to patients with manic episodes, which involved a dose range of risperidone 1 to 6 mg/day, once daily, starting at 3 mg/day (mean modal dose was 4.1 mg/day), risperidone was superior to placebo in the reduction of YMRS total score. (2) In another 3-week placebo-controlled trial (n=286), which involved a dose range of 1 to 6 mg/day, once daily, starting at 3 mg/day (mean modal dose was 5.6 mg/day), risperidone was superior to placebo in the reduction of YMRS total score. PediatricsThe efficacy of risperidone in the treatment of mania in children or adolescents with Bipolar I disorder was demonstrated in a 3-week, randomized, double-blind, placebo-controlled, multicenter trial including patients ranging in ages from 10 to 17 years who were experiencing a manic or mixed episode of bipolar I disorder. Patients were randomized into one of three treatment groups: risperidone 0.5 to 2.5 mg/day (n = 50, mean modal dose = 1.9 mg), risperidone 3 to 6 mg/day (n = 61, mean modal dose = 4.7 mg), or placebo (n = 58). In all cases, study medication was initiated at 0.5 mg/day and titrated to the target dosage range by Day 7, with further increases in dosage to the maximum tolerated dose within the targeted dose range by Day 10. The primary rating instrument used for assessing efficacy in this study was the mean change from baseline in the total YMRS score. Results of this study demonstrated efficacy of risperidone in both dose groups compared with placebo, as measured by significant reduction of total YMRS core. The efficacy on the primary parameter in the 3 to 6 mg/day dose group was comparable to the 0.5 to 2.5 mg/day dose group. Doses higher than 2.5 mg/day did not reveal any trend towards greater efficacy.

The efficacy of risperidone with concomitant lithium or valproate in the treatment of acute manic or mixed episodes was established in one controlled trial in adult patients who met the DSM-IV criteria for Bipolar I Disorder. This trial included patients with or without psychotic features and with or without a rapid-cycling course. (1) In this 3-week placebo-controlled combination trial, 148 in-or outpatients on lithium or valproate therapy with inadequately controlled manic or mixed symptoms were randomized to receive risperidone, placebo, or an active comparator, in combination with their original therapy. Risperidone, in a dose range of 1 to 6 mg/day, once daily, starting at 2 mg/day (mean modal dose of 3.8 mg/day), combined with lithium or valproate (in a therapeutic range of 0.6 mEq/L to 1.4 mEq/L or 50 mcg/mL to 120 mcg/mL, respectively) was superior to lithium or valproate alone in the reduction of YMRS total score. (2) In a second 3-week placebo-controlled combination trial, 142 in- or outpatients on lithium, valproate, or carbamazepine therapy with inadequately controlled manic or mixed symptoms were randomized to receive risperidone or placebo, in combination with their original therapy. Risperidone, in a dose range of 1 to 6 mg/day, once daily, starting at 2 mg/day (mean modal dose of 3.7 mg/day), combined with lithium, valproate, or carbamazepine (in therapeutic ranges of 0.6 mEq/L to 1.4 mEq/L for lithium, 50 mcg/mL to 125 mcg/mL for valproate, or 4 to 12 mcg/mL for carbamazepine, respectively) was not superior to lithium, valproate, or carbamazepine alone in the reduction of YMRS total score. A possible explanation for the failure of this trial was induction of risperidone and 9-hydroxyrisperidone clearance by carbamazepine, leading to subtherapeutic levels of risperidone and 9-hydroxyrisperidone.

Patients should be advised of the risk of orthostatic hypotension, especially during the period of initial dose titration [see Warnings and Precautions (5.7)].

Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy [see Use in Specific Populations (8.1)].

Patients should be advised not to breast-feed an infant if they are taking risperidone [see Use in Specific Populations (8.3)].

Patients should be advised to avoid alcohol while taking risperidone [see Drug Interactions (7.1)].

Manufactured by: Wockhardt Limited,Mumbai, India. Distributed by: Wockhardt USA LLC.20 Waterview Blvd.Parsippany, NJ 07054 USA. Rev.101011

Manufacturer

WOCKHARDT LIMITED

Active Ingredients

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