Approval date: August 04, 2010
Date of revision.
Risperidone Dispersible Tablets Instructions
Please read the instructions carefully and use under the guidance of a doctor
Warnings
Increased Mortality in Elderly Patients with Dementia-Related Psychosis – Elderly patients with dementia-related psychosis are at increased risk of mortality when using atypical antipsychotics compared to placebo. An analysis of 17 placebo-controlled clinical studies (mean plural treatment duration of 10 weeks) in elderly patients with dementia-related psychosis found that the risk of death was 1.6 to 1.7 times greater in the drug-treated group than in the placebo-controlled group. In a typical 10-week controlled clinical study, the mortality rate was approximately 4.5% in the drug-treated group and 2.6% in the placebo-controlled group. Although the causes of death varied, most deaths originated from cardiovascular disease (e.g., heart failure, sudden death) or infection (e.g., pneumonia). Risperidone is not approved for the treatment of dementia-related psychosis.
Drug Name
Generic name: Risperidone Dispersible Tablets
Trade Name: Tavis@
English Name: Risperidone Dispersible Tablets
Hanyu Pinyin: Lipeitong Fensan Pian
Ingredients
The main ingredient of this product is Risperidone, whose chemical name is: 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one
The chemical structure formula is
Molecular formula: C23H27FN4O2
Molecular weight: 410.49
【Properties】.
This product is white or off-white tablet.
Indications
1. For the treatment of acute and chronic schizophrenia and various other psychotic states with marked positive symptoms (such as hallucinations, delusions, thought disorders, hostility, suspicion) and marked negative symptoms (such as unresponsiveness, emotional and social indifference, oligophrenia). Affective symptoms associated with schizophrenia (e.g., depression, guilt, anxiety) may also be reduced. In patients who are effectively treated in the acute phase, the product may continue to be clinically effective in maintenance treatment.
2. It can be used to treat manic episodes of bipolar disorder, which are characterized by elevated mood, exaggeration or irritability, excessive self-evaluation, reduced sleep requirements, accelerated speech, racing thoughts, distraction or poor judgment (including disorganized or excessive behavior).
Specification
1mg
Dosage]
1. Schizophrenia
If the patient is using other antipsychotic drugs, he/she should discontinue the antipsychotic drugs he/she was using when he/she starts using this product. If the patient was using a long-acting antipsychotic, this product may be used as a substitute for the next course of treatment. The need to continue the anti-Parkinsonian syndrome medication should be re-evaluated periodically.
Adults: 1 time daily or twice daily. The starting dose is 1 mg, which is gradually increased to 2-4 mg daily over a period of about 1 week, and then gradually increased to 4-6 mg daily during the second week, after which the dose may be maintained or further adjusted according to individual circumstances. In general, the optimal dose is 2-6 mg per day. the daily dose is usually not more than 10 mg.
2. Treatment of manic episodes of bipolar disorder
The recommended starting dose is 1 to 2 mg once daily, and the dose can be adjusted according to individual needs. The dose should be increased by 1 to 2 mg per day, and the dose should be increased at least every other day or more days apart. The ideal dose for most patients is 2 to 6 mg daily. the need for continued use of this product should be continually evaluated during all symptomatic treatment.
3. Patients with hepatic or renal impairment
Patients with renal impairment have a lower ability to clear antipsychotics than healthy adults; patients with hepatic impairment have increased plasma concentrations of free risperidone. Regardless of the indication, starting and maintenance doses should be halved and dose adjustments should be slowed in patients with renal impairment or patients with hepatic impairment. Caution should be exercised when using this product in such patients.
Adverse reactions]
Risperidone oral formulation has not been approved in China for indications other than manic episodes of schizophrenia and bipolar disorder. The following adverse reactions are derived from the information in the original drug specification.
The most common adverse reactions in clinical trials (incidence >5% and twice the incidence of the placebo group) were Parkinson’s syndrome, inability to sit still, dystonia, tremor, sedation, dizziness, anxiety, blurred vision, nausea, vomiting, epigastric pain, gastric distress, dyspepsia, diarrhea, hypersalivation, constipation, dry mouth, increased appetite, weight gain, fatigue, rash, nasal congestion, upper respiratory tract infections, nasopharyngitis, and sore throat.
The most common adverse reactions causing discontinuation (> 1% of adults discontinuing and/or > 2% of children discontinuing) were nausea, drowsiness, sedation, vomiting, dizziness, and inability to sit still.
The data described in this section were obtained from the Clinical Trials Database, which includes a clinical trial to evaluate the safety of risperidone. 9803 patients with different types of psychiatric disorders (including adults, patients with Alzheimer’s disease, and children) received at least one dose of risperidone. Of these patients, 2687 received risperidone while participating in a double-blind, placebo-controlled trial. There was substantial variation in treatment status and duration, including inpatients and outpatients in double-blind, quantitative and indeterminate, placebo- or active-controlled trials and open-phase trials with short-term (up to 12 weeks) and long-term (up to 3 years) dosing (cross-classification). Most adverse reactions were mild to moderate.
Clinical trial experience
Because clinical trials are conducted under a variety of different conditions, the incidence of adverse reactions observed in clinical trials cannot be directly compared with the incidence in clinical trials of another drug and does not reflect the incidence observed in clinical practice.
Double-blind, placebo-controlled trials – adult patients with schizophrenia
In three double-blind, placebo-controlled trials of adult schizophrenic patients receiving risperidone for 4-8 weeks, no less than 2% of patients in the risperidone group reported adverse reactions as listed in Table 1.
Table 1. Adverse reactions reported in no less than 2% of adult schizophrenia patients in the risperidone group in a double-blind, placebo-controlled trial
Risperidone
Risperidone
Placebo organism system/organ classification
Adverse reaction name 2-8 mg/day
(N=366)
%>8-16mg/day
(N=198)
%
(N=225)
% Heart organ disease Tachycardia 130 Eye organ disease Blurred vision 311 Gastrointestinal system disease Nausea 944 Constipation 896 Indigestion 865 Dry mouth 401 Abdominal discomfort 311 Excessive salivation 21<1 Diarrhea 211 Systemic diseases and various reactions at the site of administration Fatigue 310 Chest pain 221 Weakness 21<1 Infectious and invasive diseases Nasopharyngitis 343 Upper respiratory tract infections231 sinusitis121 urinary tract infections130 various tests elevated blood creatine phosphokinase12<1 increased heart rate<120 various musculoskeletal and connective tissue disorders back pain411 arthralgia23<1 very severe pain211 various neurological disorders Parkinson’s syndrome*14178 inability to sit still*10103 sedation1052 dizziness742 muscle tone disorders*342 tremor*231 upright vertigo200 psychiatric disorders insomnia322527 anxiety161111 respiratory, thoracic and mediastinal disorders nasal congestion462 dyspnea120 rhinorrhea<120 skin and subcutaneous tissue disorders rash141 dry skin130 vascular and lymphatic vessel disorders postural hypotension210* Parkinson’s syndrome including extrapyramidal disorders, musculoskeletal rigidity, tremor palsy, cogwheel-like tonicity, temporary muscle paralysis, bradykinesia, hypokinesia, mask face, muscle tonus, and Parkinson’s disease. Sedentary inability includes inability to sit still and fidgeting.
Dystonia includes dystonia, muscle spasm, involuntary muscle contraction, muscle contracture, kinetic crisis, and tongue muscle paralysis.
Tremor includes tremor and resting tremor of Parkinson’s disease.
Double-blind, placebo-controlled trial-children with schizophrenia
In a double-blind, placebo-controlled trial of 6 weeks of treatment with risperidone in pediatric schizophrenia patients, no less than 5% of patients in the risperidone group reported adverse reactions as listed in Table 2.
Table 2 Adverse reactions reported in no less than 5% of patients in the risperidone group in a double-blind, placebo-controlled trial in pediatric schizophrenic patients
Risperidone
Risperidone
Placebo organism system/organ classification
Adverse reaction name 1-3 mg/day
(N=55)
%4-6mg/day
(N=51)
%
(N=54)
% Gastrointestinal disorders Hypersalivation 0102 Various neurological disorders Sedation 24124 Parkinson’s syndrome* 162811 Tremor 11106 Sedentary inability* 9104 Dizziness 7142 Dystonia* 260 Psychiatric category Anxiety 760* Parkinson’s syndrome includes extrapyramidal disorders, muscle rigidity, musculoskeletal stiffness and hypokinesia. Sedentary inability includes inability to sit still and fidgeting. Dystonia includes myotonia and kinetic crisis.
Double-blind, placebo-controlled trial – adult bipolar disorder patients with manic episodes
In four double-blind, placebo-controlled trials of adult bipolar disorder patients with manic episodes receiving risperidone monotherapy for 3 weeks, no less than 2% of the patients in the risperidone group reported adverse reactions as listed in Table 3.
Table 3 Adverse reactions reported by no less than 2% of adult patients in the risperidone group in a double-blind, placebo-controlled monotherapy trial
Risperidone
Placebo Organism System/Organ Classification
Adverse reaction name 1-6 mg daily
(N=448)
% (N=424)
% Ocular organ disease Blurred vision 21 Gastrointestinal system disease Nausea 52 Diarrhea 32 Hypersalivation 31 Stomach discomfort 2<1 Systemic diseases and various reactions at the site of administration Fatigue 21 Various neurological disorders Parkinson’s syndrome* 259 Sedation 114 Inability to sit still* 93 Tremor* 63 Dizziness 65 Dystonia* 51 Drowsiness 21 * Parkinson’s syndrome disease including extrapyramidal disorders, tremor palsy, musculoskeletal rigidity, hypokinesia, muscle rigidity, muscle tension, bradykinesia, and cogwheel-like tonicity. Inability to sit still includes inability to sit still and fidgeting. Tremor includes tremor and resting tremor of Parkinson’s disease. Dystonia includes dystonia, muscle spasms, kinetic crisis, and slanting neck.
In 2 double-blind, placebo-controlled trials of adult bipolar disorder patients with manic episodes receiving adjunctive treatment with risperidone for 3 weeks, no less than 2% of patients in the risperidone group reported adverse reactions as listed in Table 4.
Table 4 Adverse reactions reported by no less than 2% of patients in the risperidone group over the years in a double-blind, placebo-controlled adjunctive treatment trial
Risperidone + mood stabilizer Placebo + mood stabilizer Organism system/organ classification
Name of adverse reactions (N=127)
%(N=126)
% Heart organ disorders Palpitations20 Gastrointestinal system disorders Indigestion98 Nausea64 Diarrhea64 Excessive salivation20 Systemic disorders and various reactions at the site of administration Chest pain21 Infectious and invasive diseases Urinary tract infections21 Various neurological disorders Parkinson’s syndrome*144 Sedation94 Inability to sit still*80 Dizziness72 Tremor62 Drowsiness21 Psychiatric disorders Anxiety32 Respiratory, thoracic and mediastinal Diseases sore throat 52 cough 20* Parkinson’s syndrome includes extrapyramidal disorders, hypokinesia, and bradykinesia. Sedentary inability includes hypermobility and sedentary inability.
Double-blind, placebo-controlled trial – manic episodes in children with bipolar disorder
In a double-blind, placebo-controlled trial of pediatric bipolar disorder patients with manic episodes treated with risperidone for 3 weeks, no less than 5% of patients in the risperidone group reported adverse reactions as listed in Table 5.
Table 5 Adverse reactions reported in no less than 5% of pediatric patients in the risperidone group in a double-blind, placebo-controlled trial
Risperidone
Risperidone
Placebo system/organ classification
Adverse reactions 0.5-2.5 mg/day
(N=50)
%3-6mg/day
(N=61)
%
(N=58)
% Eye organ disorders Blurred vision 470 Gastrointestinal system disorders Epigastric pain 16135 Nausea 16137 Vomiting 10105 Diarrhea 872 Dyspepsia 1032 Stomach discomfort 602 Systemic disorders and various reactions at the site of administration Fatigue 18303 Metabolic and nutritional disorders Increased appetite 472 Various neurological disorders Sedation 425619 Dizziness 16135 Parkinson’s syndrome* 6123 dystonia*650 inability to sit still*082 psychiatric disorders anxiety083 respiratory, thoracic and mediastinal disorders sore throat1035 skin and subcutaneous tissue disorders rash072* Parkinson’s syndrome includes musculoskeletal stiffness, extrapyramidal disorders, bradykinesia and cervical rigidity. Dystonia includes dystonia, laryngospasm, and muscle spasms. Sedentary inability includes fidgeting and inability to sit still.
Double-blind, placebo-controlled trial – patients with autism
In 2 double-blind, placebo-controlled trials of pediatric autism patients treated with risperidone for 8 weeks and 1 pediatric autism patient treated with risperidone for 6 weeks, no less than 5% of patients in the risperidone group reported adverse reactions as listed in Table 6.
Table 6 Adverse reactions reported in no less than 5% of pediatric patients in the risperidone group in a double-blind, placebo-controlled trial
Risperidone
Placebo system/organ classification
Adverse reactions 0.5-4 mg/day
(N=107)
%
(N=115)
% Gastrointestinal system disorders Vomiting2017 Constipation176 Dry mouth104 Nausea85 Excessive salivation71 Systemic disorders and various reactions at the site of administration Fatigue319 Fever1613 Thirst74 Infectious and invasive disorders Nasopharyngitis199 Rhinitis97 Upper respiratory tract infections83 Various examinations Weight gain82 Metabolic and nutritional disorders Increased appetite4415 Various neurological disorders Sedation6315 Salivation124 Headache1210 Tremor81 Dizziness82 Parkinson’s syndrome*81 Renal and urinary disorders Enuresis1610 Respiratory, thoracic, and mediastinal disorders Cough1712 Runny nose1210 Nasal congestion104 Skin and subcutaneous tissue disorders Rash85* Parkinson’s syndrome includes musculoskeletal rigidity, extrapyramidal disorders, muscle rigidity, cogwheel-like tonicity, and muscle tension.
Other adverse reactions seen in clinical trials of risperidone
Other adverse reactions that have occurred in all placebo-controlled, positive-controlled, open studies conducted in adult and pediatric patients are listed below.
Hematologic and lymphatic disorders: anemia, granulocytopenia, neutropenia
Heart organ disease: sinus bradycardia, sinus tachycardia, degree I AV block, left bundle branch block, right bundle branch block, atrioventricular block
Ear and vagus disorders: ear pain, tinnitus
Endocrine disorders: hyperprolactinemia
Ocular system disorders: ocular congestion, ocular discharge, conjunctivitis, eye rolling, eyelid edema, eye swelling, crusting at eyelid margin, dry eye, increased tearing, photophobia, glaucoma, decreased visual acuity
Gastrointestinal system disorders: dysphagia, fecal tumor, fecal incontinence, gastritis, lipomegaly, labyrinthitis, saliva deficiency
Systemic diseases and various reactions at the drug administration site: peripheral edema, thirst, unsteady gait, flu-like illness, acupressure edema, edema, chills, slowness of movement, general weakness, chest tightness, facial edema, discomfort, generalized edema, drug withdrawal syndrome, peripheral cold, sensory abnormalities
Immune system disorders: drug allergy
Infectious and infectious diseases: pneumonia, influenza, ear infection, viral infection, pharyngitis, tonsillitis, bronchitis, eye infection, local infection, cystitis, cellulitis, otitis media, gray nail, mite dermatitis, bronchopneumonia, respiratory infection, tracheobronchitis, chronic otitis media
Various tests: elevated body temperature, elevated blood prolactin, elevated alanine aminotransferase, abnormal electrocardiogram, increased eosinophil count, increased white blood cell count, elevated blood sugar, decreased hemoglobin, decreased red blood cell pressure, decreased body temperature, decreased blood pressure, increased transaminases
Metabolic and nutritional disorders: loss of appetite, excessive drinking, anorexia
Various musculoskeletal and connective tissue disorders: joint stiffness, joint swelling, musculoskeletal chest pain, postural abnormalities, myalgia, neck pain, muscle weakness, rhabdomyolysis
Neurological disorders: balance disorders, attention disorders, dysarthria, unresponsiveness to stimuli, decreased consciousness, movement disorders, transient ischemic attacks, coordination abnormalities, cerebrovascular accidents, speech disorders, syncope, loss of consciousness, sensory retardation, delayed movement disorders, motor disorders, cerebral ischemia, cerebrovascular disorders, malignant syndrome, diabetic coma, staggering pace
Psychiatric disorders: anxiety, sluggish reactions, confusion, moderate insomnia, nervousness, sleep disorders, mental depression, decreased libido, frigidity
Renal and urinary disorders: enuresis, dysuria, dysuria, urinary frequency, incontinence
Reproductive system and breast disorders: irregular menstruation, amenorrhea, gynecomastia, breast overflow, vaginal discharge, menstrual disorders, erectile dysfunction, retrograde ejaculation, ejaculatory disorders, sexual dysfunction, breast enlargement
Respiratory, thoracic and mediastinal disorders: asthma, aspiration pneumonia, sinusitis, dysphonia, cough, pulmonary bruising, airway congestion, blistering sounds, dyspnea, hyperventilation, nasal edema
Skin and subcutaneous tissue disorders: erythema, skin discoloration, skin damage, pruritus, dermatosis, rash erythema, papules, rash eruption, maculopapular rash, acne, hyperkeratosis, seborrheic dermatitis
Vascular and lymphatic disorders: hypotension, facial flushing
Discontinuation of medication due to adverse reactions
Schizophrenia – adults
The rate of discontinuation due to adverse reactions in the double-blind, placebo treatment trial was approximately 7% (39/564) in the risperidone treatment group relative to the 4% (10/225) discontinuation rate in the placebo control group.
Table 7 Adverse reactions causing discontinuation in more than 2 trials of risperidone for schizophrenia in adults
Risperidone
Risperidone
Placebo 2-8 mg/day > 8-16 mg/day Adverse reactions (N=366)
% (N=198)
% (N=225)
% Dizziness 1.4% 1.0% 0% 0% Nausea 1.4% 0% 0% 0% Vomiting 0.8% 0% 0% 0% Parkinson’s syndrome 0.8% 0% 0% 0% Drowsiness 0.8% 0% 0% Dystonia 0.5% 0% 0% Anxiety 0.5% 0% 0% 0% Abdominal pain 0.5% 0% 0% Postural hypotension 0.3% 0.5% 0% In a double-blind, placebo and positive control trials, the incidence of extrapyramidal reactions causing discontinuation was 1% in the placebo control group and 3.4% in the positive control drug group.
Schizophrenia – Children
In the double-blind, placebo treatment trial, the rate of discontinuation due to adverse reactions was approximately 7% (7/106) in the risperidone treatment group relative to the 4% (2/54) discontinuation rate in the placebo control group. At least one of the adverse reactions associated with discontinuation in the risperidone-treated group was dizziness (2%), drowsiness (1%), sedation (1%), somnolence (1%), anxiety (1%), balance disturbance (1%), hypotension (1%), and palpitations (1%).
Manic episodes of bipolar disorder – adults
In a double-blind placebo-controlled trial of patients receiving risperidone tablets as monotherapy, the discontinuation rate due to adverse effects was 6% (25/448) in the risperidone-treated group and 5% (19/424) in the placebo group. The discontinuation rates for patients in the risperidone treatment group associated with adverse reactions were as follows.
Table 8 Discontinuation rates associated with adverse reactions in more than 2 trials of risperidone for manic episodes in adults with bipolar disorder
Risperidone
Placebo 1-6 mg/day Adverse reactions (N=448)
% (N=424)
% Parkinson’s syndrome 0.4% 0% Drowsiness 0.2% 0% Dizziness 0.2% 0% Increase in alanine aminotransferase 0.2% 0.2% Increase in aspartate aminotransferase 0.2% 0.2% Manic episodes in bipolar disorder – children
In the double-blind, placebo-controlled trial, the discontinuation rate for adverse reactions was 12% (13/111) in the risperidone-treated group and 7% (4/58) in the placebo group. The adverse reactions that caused at least one discontinuation in the risperidone treatment group were: nausea (3%), drowsiness (2%), sedation (2%), and vomiting (2%).
Autism – Children
In two autism-related, irritable, 8-week, double-blind, placebo-controlled trials of risperidone treatment, one patient in the risperidone-treated group discontinued due to an adverse reaction (Parkinson’s syndrome) and one patient in the placebo-controlled group discontinued due to an adverse event.
Dose-dependence of adverse reactions in clinical trials
Extrapyramidal reactions
Data from two fixed-dose trials conducted in adult patients with schizophrenia confirmed the dose dependence of extrapyramidal symptoms with risperidone treatment.
Two methods were used to measure extrapyramidal symptoms (EPS) in 1 trial treated for 8 weeks and comparing 4 fixed doses of risperidone (2, 6, 10 and 16 mg/day), including (1) Parkinson’s syndrome score (change from baseline) based on the Extrapyramidal Symptom Rating Scale (2) the incidence of EPS spontaneous disease.
Table 9
Dose group placebo risperidone
2mg Risperidone
6mg risperidone
10mg Risperidone
16mg Parkinson’s syndrome 1.20.91.82.42.6 EPS incidence 13% 17% 21% 21% 35% In a trial treating for 8 weeks and comparing 5 fixed risperidone doses (1, 4, 8, 12 and 16mg /day), a similar approach was used to examine extrapyramidal symptoms (EPS).
Table 10
Dose Groups Risperidone
1mg Risperidone
4mg Risperidone
8mg Risperidone
12mg Risperidone
16mg Parkinson’s syndrome 0.61.72.42.94.1EPS incidence 7% 12% 17% 18% 20% Dystonia
Symptoms of dystonia, abnormal contraction of muscle groups, may occur in susceptible individuals during the first few days of treatment. Symptoms of dystonia include: neck muscle spasms, sometimes progressing to throat tension, dysphagia, dyspnea, and/or tongue protrusion. Although these symptoms can occur at low doses, these symptoms are more frequent and severe at higher doses in first-generation antipsychotic therapy. The risk of acute dystonia is greater in males and in younger age groups.
Other adverse effects
In 1 large clinical study comparing 5 fixed doses of risperidone, adverse event data were derived from an inventory and used to explore the dose-relatedness of adverse events. Cochran-Armitage tests for trends in these data showed a positive trend (p <0.05) for the following adverse reactions: drowsiness, abnormal vision, dizziness, palpitations, weight gain, erectile dysfunction, ejaculatory dysfunction, abnormal sexual dysfunction, fatigue, and skin hypopigmentation.
Changes in body weight
Weight gain has been observed in short-term controlled trials and long-term uncontrolled studies in adult and pediatric patients.
Changes in electrocardiographic parameters
Pooling placebo-controlled trials in adult subjects for between-group comparisons showed no statistically significant differences from baseline in mean changes in ECG parameters in the risperidone and placebo groups, including: QT, QTc and PR intervals, and heart rate. Pooling all of the risperidone randomized controlled trials revealed a mean increase in heart rate of 1 beats per minute for patients in the risperidone group relative to no change in heart rate for patients in the placebo group. In short-term schizophrenia trials, the mean increase in heart rate was higher in the high-dose risperidone (8-16 mg/day) group (4-6 beats/minute) compared to the placebo group. A placebo-controlled clinical trial in adult patients with acute mania showed a small decrease in mean heart rate values that were comparable across treatment groups.
Two placebo-controlled trials conducted in pediatric and adolescent patients with autism (5-16 years of age) showed a mean increase in heart rate of 8.4 beats/min in the risperidone group and 6.5 beats/min in the placebo group. There were no other significant electrocardiographic changes.
One placebo-controlled acute mania trial in pediatric and adolescent (10-17 years of age) patients showed no significant changes in ECG parameters except for a transient increase in pulse (<6 beats/min) in the risperidone group. Two controlled trials conducted in adolescent patients with schizophrenia (13-17 years of age) showed no clinically meaningful changes in ECG parameters (including corrected QT intervals) between or within treatment groups.
Post-marketing experience
The following adverse reactions have been identified after the marketing of risperidone. Because these adverse events were spontaneously reported by patients and the number of patients is uncertain, it is difficult to estimate with certainty the incidence of these adverse events or to determine their causal relationship with drug exposure. These adverse reactions include: alopecia, allergic reactions, angioedema, atrial fibrillation, cardiac arrest, diabetic ketoacidosis with impaired glucose metabolism, taste disturbance, hypoglycemia, decreased body temperature, intestinal obstruction, abnormal secretion of antidiuretic hormone, intestinal obstruction, jaundice, mania, pancreatitis, pituitary adenoma, precocious puberty, pulmonary embolism, prolonged QT interval, sleep apnea syndrome, sudden death, thrombocytopenia thrombocytopenia, thrombotic thrombocytopenic purpura, urinary retention and water intoxication.
Contraindications
Risperidone, paliperidone or any of the excipients of this product are contraindicated. Hypersensitivity reactions, including allergic reactions and angioedema, have been reported in patients treated with risperidone or paliperidone. Paliperidone is a metabolite of risperidone.
Precautions]
Risperidone oral formulation has not been approved in China for indications other than manic episodes of schizophrenia and bipolar disorder. The following precautions are taken from the information in the original drug insert.
Increased Mortality in Elderly Patients with Dementia-Related Psychosis
Older patients with dementia-related psychosis are at increased risk of mortality. An analysis of 17 placebo-controlled clinical studies (mean plural treatment duration of 10 weeks) in elderly patients with dementia-related psychosis found that the risk of death was 1.6-1.7 times greater in the drug-treated group than in the placebo-controlled group. In a typical 10-week controlled clinical study, the mortality rate was approximately 4.5% in the drug-treated group and 2.6% in the placebo-controlled group. Although the causes of death varied, most deaths were due to cardiovascular disease (e.g., heart failure, sudden death) or infection (e.g., pneumonia). Observational studies have shown that, similar to atypical antipsychotics, conventional antipsychotics cause increased mortality in patients. The increased mortality found in observational studies may be attributable to the antipsychotic rather than the patient’s condition, but this cannot yet be conclusively demonstrated.
In placebo-controlled studies of patients with Alzheimer’s disease on risperidone, mortality was higher in patients on risperidone in combination with furosemide than in patients on risperidone or furosemide alone, and increased mortality in patients on combined furosemide and risperidone was observed in 2 of 4 clinical trials. No clear pathophysiologic mechanism has been identified to explain this phenomenon, and the causes of death in patients differed.
Risperidone is not approved for the treatment of dementia-related psychosis.
Cerebrovascular accidents (including stroke) in elderly patients with dementia-related psychosis
In a placebo-controlled study in patients with Alzheimer’s disease (mean age 85 years, range 73-97 years), a higher incidence of adverse cerebrovascular events (cerebrovascular accidents and transient ischemic attacks), including death, was observed in the risperidone group compared to the placebo group. Risperidone is not approved for the treatment of patients with dementia-related psychosis.
Malignant syndrome of antipsychotics (NMS)
The administration of antipsychotic medications, including risperidone, can cause a malignant syndrome (NMS). clinical manifestations of NMS include hyperthermia, myoclonus, altered mental status, and autonomic dysregulation (irregular pulse or blood pressure, tachycardia, sweating, and arrhythmias). Other symptoms may include elevated creatine phosphokinase (CPK), myoglobinuria, rhabdomyolysis, and acute renal failure. The diagnostic evaluation of patients with this syndrome is complex. It is important to distinguish the following conditions in the differential diagnosis, including cases of severe medical disease (e.g., pneumonia, systemic infections, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary CNS pathology.
Treatment of NMS should include (1) immediate discontinuation of antipsychotic medications and other unnecessary comorbidities, (2) intensive symptomatic treatment and medical monitoring, and (3) treatment of any serious complications with a specific treatment regimen. There is no consensus on specific pharmacologic treatment options for NMS without comorbidities.
If a patient requires antipsychotic medication after recovery from NMS, the potential problems with medication should be carefully considered. Patients should be monitored closely, as relapse of NMS has been reported.
Late-onset movement disorders
Patients treated with antipsychotic medications may develop a potentially irreversible involuntary dyskinesia syndrome. As the duration of treatment and the total cumulative dose of antipsychotic medication used by the patient increases, the risk of developing delayed dyskinesia and its potential to become irreversible increases. However, the syndrome may also occur after relatively short periods of treatment at low doses, although this is less common.
There is no known treatment for diagnosed cases of tardive dyskinesia, but the syndrome may remit partially or completely if antipsychotic medication is discontinued. However, antipsychotic medication itself may suppress (or partially suppress) the signs and symptoms of the syndrome, which may obscure the pathogenesis of the underlying movement disorder syndrome. The impact of symptom suppression on the long-term course of the movement disorder syndrome is unknown.
Given these considerations, risperidone should be prescribed in a manner that is most likely to reduce the risk of developing movement disorder syndrome. Chronic antipsychotic treatment is usually indicated for patients with chronic disease who (1) are known to respond to antipsychotic medications and (2) have no available alternative, equivocal, low-risk treatment options. In patients requiring long-term treatment, the minimum dose and shortest duration of treatment required for the desired clinical outcome should be sought. The need for continued treatment should be reassessed periodically.
If a patient treated with risperidone develops signs and symptoms of delayed dyskinesia, discontinuation of the drug is considered. However, some patients may still require risperidone therapy despite the presence of the syndrome.
Metabolic changes
Atypical antipsychotics are associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and weight gain. Although all of these drugs cause some metabolic changes, each drug has its own specific risks.
Hyperglycemia and diabetes
Hyperglycemia and diabetes mellitus have been reported in some extreme cases in patients treated with atypical antipsychotics (including risperidone), which have been associated with ketoacidosis or hyperosmolar coma or death. The inherent high risk of diabetes in schizophrenia and the rising incidence of diabetes in the general population complicate the assessment of the correlation between atypical antipsychotic use and glucose abnormalities. Because of these confounding factors, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not fully understood. However, epidemiological studies suggest that patients treated with atypical antipsychotics are at increased risk for treatment-related hyperglycemic adverse events. There is no precise risk assessment for hyperglycemia-related adverse events in patients treated with atypical antipsychotics.
Patients with diagnosed diabetes who are still on atypical antipsychotics (including risperidone) should be monitored closely for deterioration in glycemic control. Patients with risk factors for diabetes (e.g., obesity, family history of diabetes) should be monitored for fasting glucose at the start of treatment with atypical antipsychotics (including risperidone) and periodically during treatment. Any patient receiving atypical antipsychotics (including risperidone) should be monitored for symptoms of hyperglycemia, including polydrinking, polyuria, polyphagia, and malaise. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics (including risperidone) should have fasting glucose testing. In some cases, hyperglycemia can subside when atypical antipsychotics (including risperidone) are discontinued; however, some patients require continued glucose-lowering therapy despite discontinuation of risperidone.
Table 11 presents summary data from three double-blind, placebo-controlled studies in schizophrenia and four double-blind, placebo-controlled studies of manic episode monotherapy in bipolar disorder.
Table 11 Glycemic changes in 7 placebo-controlled, 3-8 week, fixed or flexible dose studies conducted in adult patients with manic episodes of schizophrenia or bipolar disorder
Placebo Risperidone 1-8 mg/day>8-16 mg/day
Blood glucose
n=555 Mean change from baseline (mg/dL)
n=748
n=164 -1.40.80.6 Proportion of patients with a change Blood glucose
(<140mg/dL to ≥200mg/dL) 0.6%
(3/525) 0.4%
(3/702)0%
(0/158) In controlled or uncontrolled studies of long-term treatment, the mean change from baseline in blood glucose associated with risperidone treatment was +2.8 mg/dL at 24 weeks (n=151) and +4.1 mg/dL at 48 weeks (n=50).
Data from clinical studies conducted in pediatric and adolescent patients with schizophrenia (13-17 years), manic episodes of bipolar disorder (10-17 years), or autism (5-17 years) for 3-6 weeks of treatment are shown in Table 12.
Table 12 Changes in fasting glucose in three placebo-controlled, 3-6-week, pediatric and adolescent patients with schizophrenia (13-17 years of age) with manic episodes of bipolar disorder (10-17 years of age) or autism (5-17 years of age)
Placebo risperidone 0.5-6 mg/day
Blood glucose
n=76 Mean change from baseline (mg/dL)
n=135 -1.32.6 Proportion of patients who experienced a change Blood glucose
(<100mg/dL to ≥126mg/dL)
0%
(0/64)
0.8%
(1/120) Mean change in fasting glucose + 5.2 mg / dL at week 24 (n = 119) compared with baseline in 1 long-term, uncontrolled, open, extended pediatric study associated with risperidone
Dyslipidemia
Lipid alterations were observed in patients treated with atypical antipsychotics.
Table 13 presents summary data from seven placebo-controlled, 3-8 week treatment, fixed-dose or flexible-dose studies conducted in adult patients with manic episodes of schizophrenia or bipolar disorder.
Table 13 Changes in lipids in 7 placebo-controlled, 3-8 week, fixed-dose or flexible-dose studies in adult patients with manic episodes of schizophrenia or bipolar disorder
Risperidone Placebo 1-8 mg/day>8-16 mg/day
Cholesterol
n=559 Mean change relative to baseline (mg/dL)
n=742
n=156 Change from baseline 0.66.91.8 Triglycerides n=183 n=307 n=123 Change from baseline -17.4-4.9-8.3
Cholesterol
2.7% Proportion of patients with a change
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) In long-term treatment, controlled and uncontrolled studies, risperidone was associated with a mean change in non-fasting cholesterol of +4.4 mg / dL at week 24 (n = 231) and +5.5 mg / dL at week 48 (n = 86); and (b) non-fasting triglycerides of +19.9 mg / dL at week 24 (n = 52).
Summary data from 3 placebo-controlled, 3-6 weeks of treatment, fixed-dose studies in children and adolescents with schizophrenia (13-17 years), manic episodes of bipolar disorder (10-17 years), or autism (5-17 years) are presented in Table 14.
Table 14 Changes in fasting lipids in 3 placebo-controlled, treatment 3-6 week, fixed-dose studies conducted in children and adolescents with schizophrenia (13-17 years), manic episodes of bipolar disorder (10-17 years), or autism (5-17 years)
Placebo Risperidone
0.5-6 mg/day Mean change from baseline (mg/dL) Cholesterol
Change from baseline n = 74
0.3n =133
-0.3LDL
Change from baseline n =22
3.7n =22
0.5HDL
Change from baseline n =22
1.6n =22
-1.9Triglycerides
Change from baseline n = 77
-9.0n =138
-2.6 Proportion of patients with a change in cholesterol
(<170 mg/dL to ≥200 mg/dL) 2.4%
(1/42)3.8%
(3/80)LDL
(<110 mg/dL to ≥130 mg/dL)0%
(0/16)0%
(0/16)HDL
(≥40 mg/dL to <40 mg/dL)0%
(0/19)10%
(2/20)Triglycerides
(<150 mg/dL to ≥200 mg/dL)1.5%
(1/65)7.1%
(8/133) In the long-term treatment, uncontrolled, open, extended pediatric study, risperidone was associated with (a) mean change in fasting cholesterol + 2.1 mg / dL at week 24 (n = 114); (b) mean change in fasting LDL – 0.2 mg / dL at week 24 (n = 103); (c) mean change in fasting HDL + 0.4 mg / dL at week 24 (n = 103) dL; (d) at week 24 (n = 120) the mean change in fasting triglycerides + 6.8 mg/dL was correlated with the mean change.
Weight gain
Weight gain has been observed in atypical antipsychotic use. Clinical monitoring of body weight is recommended. data on mean change in body weight and the proportion of subjects with a 7% or greater weight gain from 7 placebo-controlled, 3-8 week, fixed-dose or flexible-dose studies in adults with manic episodes of schizophrenia or bipolar disorder are presented in Table 15.
Table 15 Proportion of subjects with mean levels of weight change and weight gain of 7% or greater in 7 placebo-controlled, 3-8 week treatment, fixed-dose, or flexible-dose studies in adult patients with manic episodes of schizophrenia or bipolar disorder
Risperidone Placebo
(n = 597) 1-8 mg/day
(n = 769)>8-16 mg/day
(n = 158) Weight (kg) Change from baseline -0.30.72.2 Weight gain
Increase from baseline ≥7%
2.9%
8.7%
20.9% In long-term controlled and uncontrolled studies, risperidone was associated with a + 4.3 kg mean change in body weight at week 24 (n = 395) and a + 5.3 kg mean change in body weight at week 48 (n = 203).
Data on the mean change in body weight and the proportion of subjects with ≥ 7% weight gain in 9 clinical studies conducted in children and adolescents with schizophrenia (13-17 years), manic episodes of bipolar disorder (10-17 years), autism (5-17 years), or other psychiatric disorders (5-17 years) treated for 3-8 weeks with placebo-controlled, fixed-dose therapy are shown in Table 16.
Table 16 Proportion of subjects with mean change in body weight and weight gain ≥7% in 9 clinical studies conducted in children and adolescents with schizophrenia (13-17 years), manic episodes of bipolar disorder (10-17 years), autism (5-17 years), or other psychiatric disorders (5-17 years) treated for 3-8 weeks with placebo-controlled, fixed-dose
placebo
(n = 375) Risperidone
0.5-6 mg/day
(n = 448) Weight (kg) Change from baseline 0.62.0 Weight gain
Increase from baseline ≥7%
6.9%
32.6% In the long-term treatment, non-controlled, open, extended pediatric study, risperidone showed a correlation with a mean change in weight of +5.5 kg at week 24 (n = 748) and +8.0 kg at week 48 (n = 242).
Treatment-related weight gain adverse events occurred in 14% of patients in 1 long-term open extension study in adolescent schizophrenic patients. 103 adolescent schizophrenic patients treated with risperidone for 8 months had a mean weight gain of 9.0 kg. most of the gain was observed within the first 6 months. The mean percentile at baseline and 8 months were 56 and 72 for weight, 55 and 58 for height, and 51 and 71 for body mass index, respectively.
In open trials of long-term treatment (studies of patients with autism or other psychiatric disorders), a mean weight gain of 7.5 kg was observed after 12 months of risperidone application, which is higher than the expected normal weight gain (approximately 3-3.5 kg per year, according to the CDC normal). The majority of the increase occurred within the first 6 months of risperidone application treatment. The mean percentile at baseline and 12 months were 49 and 60 for weight, 48 and 53 for height, and 50 and 62 for body mass index, respectively.
In a 3-week placebo-controlled trial conducted in pediatric and adolescent patients with acute manic episodes or mixed episodes of bipolar I disorder, weight gain was higher in the risperidone group than in the placebo group, but was not dose-related (1.90 kg in the 0.5-2.5 mg risperidone group, 1.44 kg in the 3-6 mg risperidone group, and 0.65 kg in the placebo group). The mean change in body mass index from baseline showed a similar trend.
When treating pediatric patients with risperidone for any indication, weight gain should be assessed at the expected weight for normal growth.
Hyperprolactinemia
As with other dopamine D2 receptor antagonists, risperidone can increase prolactin levels and continue to be elevated during long-term administration. Risperidone is associated with higher prolactin levels compared to other antipsychotics.
Hyperprolactinemia may suppress hypothalamic GnRH, leading to a decrease in pituitary gonadotropin secretion. This in turn may inhibit reproductive function by reducing gonadal steroid production in both female and male patients. Overflow of breast milk, amenorrhea, gynecomastia and impotence have been reported in patients receiving prolactin-lifting compounds. Prolonged hyperprolactinemia associated with hypogonadism may lead to reduced bone mineral density in both female and male subjects.
Tissue culture experiments suggest that approximately one-third of human breast cancers are prolactin-dependent in vitro, which is potentially an important factor to consider if risperidone is prescribed in patients with previously detected breast cancer. Increased pituitary, mammary and pancreatic islet cell tumor formation (mammary adenocarcinoma, pituitary and pancreatic adenoma) has been observed in carcinogenicity studies with risperidone in mice and rats. Neither clinical studies nor epidemiological studies conducted to date have shown an association between long-term administration of this class of drugs and human tumorigenesis; the available evidence is too limited to be conclusive at this time.
Postural hypotension
Risperidone may induce postural hypotension associated with dizziness, tachycardia, and possibly syncope in some patients, especially during initial dose adjustment, possibly reflecting its alpha-adrenergic antagonistic properties. Syncope has been reported in 0.2% (6/2607) of patients in phase 2 and 3 studies of risperidone in adults with schizophrenia.
The risk of postural hypotension can be minimized by limiting the initial dose to 2 mg daily (once daily, or 1 mg twice daily) in general adult patients and limiting the dose administered to 0.5 mg twice daily in elderly patients or those with hepatic or renal impairment. Monitoring of postural vital signs in these patients should be considered. If hypotension occurs, dose reduction should be considered. 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 in patients predisposed to hypotension (e.g., dehydration and hypovolemia). Clinically significant hypotension has been observed with the combined use of risperidone and antihypertensive medications.
Falls
The use of antipsychotic medications, including risperidone, can lead to drowsiness, postural hypotension, motor and sensory instability, which may result in falls that can lead to fractures or other fall-related injuries. Patients with diseases, factors or medications that may exacerbate these effects, especially in the elderly, should be evaluated for fall risk at the initiation of antipsychotic therapy or periodically during long-term treatment.
Leukopenia, neutropenia and granulocyte deficiency
Leukopenia/neutropenia events associated with antipsychotics (including risperidone) have been reported in clinical trials and/or post-marketing experience. Granulocyte deficiency has also been reported.
Possible risk factors for leukopenia/neutropenia include a preexisting reduced white blood cell count (WBC) and a history of drug-induced leukopenia/neutropenia. Patients with a history of clinically significant WBC reduction or drug-induced leukopenia/neutropenia should be closely monitored for a complete blood count (CBC) during the first few months of therapy and should discontinue the product when clinically significant WBC reduction without other predisposing factors is first detected
.
Patients with clinically significant neutropenia should be carefully monitored for fever or signs and symptoms associated with infection and should be treated promptly if these signs or symptoms develop. Patients with severe neutropenia (absolute neutrophil count <1000 / mm3) should discontinue the product and then monitor the white blood cell count until recovery.
Potential cognitive and motor impairment
Drowsiness is a common adverse effect associated with risperidone therapy, particularly as determined by direct questioning of patients. This adverse reaction is dose-related, and in a study in which adverse events were identified with a checklist, 41% of patients on high doses (this product
16 mg/day) experienced drowsiness compared to 16% of placebo patients who experienced drowsiness. Direct questioning was more sensitive than spontaneous reporting for the detection of adverse events, with 8% of patients on risperidone 16 mg/day and 1% of patients in the placebo group experiencing drowsiness. Because risperidone may impair judgment, thinking ability, or motor skills, patients should be warned to avoid operating dangerous equipment, including cars, until it is determined that risperidone treatment will not adversely affect them.
Epilepsy
In premarketing trials in adults with schizophrenia, the proportion of seizures in patients treated with risperidone was 0.3% (9/2607), including 2 cases with hyponatremia. Risperidone should be used with caution in patients with a history of epilepsy.
Dysphagia
Esophageal dysmotility and aspiration are correlated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in patients with late-onset Alzheimer’s disease. Risperidone and other antipsychotic medications should be used with caution in patients at risk for aspiration pneumonia.
Abnormal penile erection
Abnormal penile erections have been reported during post-marketing surveillance. Severe penile anomalies may require surgical treatment.
Thermoregulation
Abnormalities in thermoregulation have been correlated with antipsychotic medications. Hyperthermia and hypothermia have been reported in association with oral risperidone. Caution should be exercised when prescribing risperidone in patients with extreme body temperatures.
Patients with phenylketonuria
Inform patients that risperidone contains phenylalanine. Phenylalanine is a component of the breakdown of aspartame in the body.
[For pregnant and lactating women].
Pregnant women
Pregnancy drug class C
Adequate and well-controlled studies of risperidone administration in pregnant women have not been conducted. Fetuses exposed to antipsychotics (including risperidone) at the end of pregnancy are at risk of developing extrapyramidal symptoms or withdrawal symptoms after birth. In rat and rabbit embryo-fetal toxicity studies, administration at doses 0.4-6 times the MHRD (maximum recommended human dose) did not result in increased rates of fetal malformations. In the rat perinatal toxicity study, all dose groups exhibited increased pup mortality. Risperidone should be administered during pregnancy only if the potential benefit outweighs the risk to the fetus.
Fetus/Newborn
Monitor neonates presenting with extrapyramidal and withdrawal symptoms. Some neonates recover within hours or days without special management; others may require extended hospitalization.
Fetuses exposed to antipsychotics (including risperidone) at the end of pregnancy are at risk of developing extrapyramidal or withdrawal symptoms after birth, which may vary in severity. These symptoms include agitation, hypertonia, hypotonia, tremor, lethargy, respiratory distress, and feeding disorders. In some cases, symptoms are self-limiting, in other cases, neonates require intensive care unit support and long-term hospitalization.
There has been one case of cerebral callosal hypoplasia in the neonatal period after fetal exposure to risperidone. Its causal relationship with risperidone treatment is unclear.
Labor and Delivery
The effects of risperidone on labor and delivery in humans are not known.
Lactation
Risperidone and 9-hydroxyrisperidone are excreted through breast milk. Due to the potentially serious adverse effects of risperidone on nursing infants, a comprehensive decision can be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
[Childhood medication].
For schizophrenia, there is a lack of adequate clinical experience with children under 15 years of age.
For manic episodes of bipolar disorder, there is a lack of adequate clinical experience in children and adolescents under 18 years of age.
Medication for the elderly]
Treatment of schizophrenia.
The recommended starting dose is 0.5 mg twice daily, and the dose may be adjusted according to individual needs. The dose may be increased from 0.5 mg twice daily to 1-2 mg twice daily.
[Drug Interactions].
Pharmacokinetic-related interactions
When combined with CYP2D6 enzyme inhibitors (e.g., fluoxetine and paroxetine) and enzyme inducers (e.g., carbamazepine), the dose of risperidone should be adjusted (see Table 17). No dose adjustment of risperidone is required when combined with ranitidine, cimetidine, amitriptyline, or erythromycin.
Table 17 Effect of combined dosing on exposure to the active product (risperidone + 9-hydroxyrisperidone) in healthy subjects or in patients with schizophrenia
Effect of combined drug doses on active ingredient (risperidone + 9-hydroxyrisperidone) (ratio) Risperidone dose recommendations Combined drug Risperidone AUCCmax enzyme inhibitor (CYP2D6) Fluoxetine 20 mg/day 2 or 3 mg twice daily 1.41.5 Re-evaluate dose. Do not exceed 8mg/day. Paroxetine 10mg/day 4mg/day 1.3- Re-evaluate dose. Do not exceed 8mg/day. 20mg/day 4mg/day 1.6- 40mg/day 4mg/day 1.8-Enzyme inducers (CYP3A/PgP inducers) Carbamazepine 573±168mg/day 3mg twice daily 0.510.55 Incremental dose. No more than twice the patient’s regular dose. Enzyme inhibitor (CYP3A) Ranitidine 150mg twice daily 1mg single dose 1.21.4 No dose adjustment required Cimetidine 400mg twice daily 1mg single dose 1.11.3 No dose adjustment required Erythromycin 500mg 4 times daily 1mg single dose 1.10.94 No dose adjustment required Other drugs Amitriptyline 50mg 4 times daily 3mg Twice daily 1.21.1 No dose adjustment required * Change relative to reference formulation
Effect of risperidone on other drugs
Lithium
Continuous oral administration of risperidone (3 mg twice daily) did not affect exposure (AUC) or the peak plasma concentration (Cmax) of lithium (n = 13). Dose adjustment of lithium is not recommended.
Valproate.
Continuous oral administration of risperidone (4 mg once daily) did not affect pre-dose or mean blood concentrations and exposure (AUC) of valproate (1000 mg/day in three divided doses) compared with the placebo group (n = 21). However, coadministration with risperidone increased peak plasma concentrations (Cmax) of valproate by 20%. Dose adjustment of valproate is not recommended.
Digoxin
Risperidone (0.25 mg twice daily) did not demonstrate a clinically relevant effect on the pharmacokinetics of digoxin. Dose adjustment for digoxin is not recommended.
Pharmacodynamically Relevant Interactions
Central Nervous System Drugs and Alcohol
Given the predominantly CNS effects exhibited by risperidone, caution should be exercised when risperidone is co-administered with other CNS drugs and alcohol.
Antihypertensive drugs
Due to the potential hypotension-inducing effects of risperidone, risperidone may increase the hypotensive effects of other drugs with antihypertensive effects.
L-dopa and dopamine agonists
Risperidone may antagonize the effects of levodopa and dopamine agonists.
Clozapine
Long-term use of clozapine with risperidone may reduce the clearance of risperidone.
[Drug Overdose].
Human experience
Premarketing experience, including 8 reports of severe overdose with risperidone at estimated doses ranging from 20 to 300 mg, did not cause death. In general, the signs and symptoms reported at overdose were due to extension of its pharmacological effects, including drowsiness and sedation, tachycardia and hypotension, and extrapyramidal symptoms. 1 case of overdose of 240 mg caused hyponatremia, hypokalemia, QT prolongation, and QRS widening. Another estimated overdose of 36 mg triggered seizures.
Postmarketing experience includes reports of severe overdose with risperidone at estimated doses up to 360 mg. In general, the most frequently reported signs and symptoms are due to extended pharmacologic effects and include drowsiness and sedation, tachycardia and hypotension, and extra-pyramidal symptoms. Other adverse reactions caused by postmarketing risperidone overdose include prolonged QT interval and convulsions. Torsade de pointes (tip-twisting ventricular tachycardia) has been reported in association with risperidone overdose and paroxetine co-administration.
Overdose management
Treatment should include general measures for overdose management; consideration of the possibility of polypharmacy; ensuring an open airway, adequate oxygen and ventilation; monitoring of cardiac rhythm and vital signs; and use of supportive and symptomatic measures. There is no specific antidote for risperidone.
Pharmacology and Toxicology
Mechanism of action
The mechanism of action of risperidone in the treatment of schizophrenia is not fully understood. However, it has been proposed that the pharmacotherapeutic activity in schizophrenia may be achieved through dual antagonism of dopamine type 2 receptors and 5-hydroxytryptamine receptors. The clinical efficacy of risperidone depends on the total plasma concentration of risperidone and its metabolite 9-hydroxyrisperidone. Antagonism of receptors other than D2 and 5HT2 may be related to other effects of risperidone.
Pharmacodynamics
Risperidone is a selective monoaminergic antagonist with high affinity (Ki 0.12-7.3 nM) for 5HT2 receptors, D2 receptors, α1 and α2 receptors, and H1 receptors. The antagonistic effect on other receptors was also observed, but was weak. Low to moderate affinity for 5HT1c, 5HT1D and 5HT1A (Ki 47-253 nM), weak affinity for D 1 and haloperidol-sensitive σ-receptors, no affinity for M-receptors or β1 and β2 receptors (when tested at concentrations > 10-5 M).
Non-clinical toxicology
Carcinogenicity, genotoxicity and reproductive toxicity
Carcinogenicity
Carcinogenicity tests were conducted in Swiss albino mice and Wistar rats in which risperidone was administered for 18 months (mice) and 25 months (rats) at 0.63 mg/kg, 2.5 mg/kg and 10 mg/kg by adulteration. These doses were 2, 9, and 38 times the recommended maximum human dose (MRHD, i.e., 16 mg/day) in mg/kg body weight, or 0.2, 0.75, and 3 times the MRHD in mg/m2 body surface area (mice), or 0.4, 1.5, and 6 times the MRHD in mg/m2 body surface area (rats), respectively, of risperidone for schizophrenia treatment. The study did not reach the maximum tolerated dose of risperidone in male mice. A statistically significant increase in the incidence of pituitary adenomas, endocrine pancreatic adenomas and mammary adenocarcinomas was seen. The table below summarizes the multiplicity of doses to human doses (in mg/m2 (mg/kg)) for the occurrence of the above tumors.
Tumor type species sex multiple of maximum human dose mg/m2 (mg/kg) tumorigenic dose no tumorigenic maximum dose pituitary adenoma mouse female 0.75 (9.4) 0.2 (2.4) endocrine pancreatic adenoma rat male 1.5 (9.4) 0.4 (2.4) mammary adenoma mouse female 0.2 (2.4) no rat female 0.4 (2.4) no rat male 6.0 (37.5) 1.5 (9.4) mammary adenoma (overall) rat male 1.5 (9.4) 0.4 (2.4) Antipsychotic drugs have been reported to cause prolactin levels to be chronically elevated in rodents. Prolactin levels were not measured in the risperidone carcinogenicity test, but measurements in the subchronic toxicity test showed that the same dose of risperidone as in the carcinogenicity test increased prolactin levels 5-6-fold in mice and rats. Increased mammary, pituitary, and pancreatic tumorigenesis has been found in rodents with long-term administration of other antipsychotics and is thought to be mediated by prolactin. It is not clear how the occurrence of prolactin-mediated endocrine tumors in rodents correlates with the risk of human use.
Genotoxicity
Risperidone was not found to be potentially genotoxic in the Ames bacterial reversion mutation assay, mouse lymphoma cell assay, in vitro rat hepatocyte DNA repair assay, in vivo mouse micronucleus assay, Drosophila sex-linked recessive lethality assay, human lymphocyte or Chinese hamster ovary cell chromosome aberration assay.
Reproductive toxicity
In three reproductive toxicity studies in Wistar rats (including two Segment I reproductive toxicity studies and one intergenerational study), risperidone was found to reduce mating frequency but not fertility at doses of 0.16-5 mg/kg (approximately 0.1-3 times the MRHD in mg/m2 body surface area). Since no effect on mating behavior was observed in the segment I test administered to male rats only, it is presumed that the above phenomenon occurred only in female rats. In a subchronic study in Beagle dogs, a decrease in sperm motility and concentration, as well as a dose-related decrease in serum testosterone levels, were observed at doses of 0.31-5 mg/kg (0.6-10 times the MRHD in mg/m2 body surface area); after discontinuation, serum testosterone levels and sperm parameters partially recovered, but remained lower than pre-dose levels. No no-effect dose was observed in rats or dogs.
Animal Toxicology
Risperidone was tested for toxicity in juvenile dogs administered orally for 40 weeks at doses of 0.31, 1.25, or 5 mg/kg/day. There was no side effect on the reduction of bone length and bone density at a dose of 0.31 mg/kg/day. The plasma exposure (AUC) of the active ingredient as risperidone + active metabolite 9-hydroxyrisperidone at this dose was comparable to that of children or adolescents when administered at MRHD (6 mg/day). In addition, delayed sexual maturation was seen in females and males at all doses tested, with only slight recovery or no recovery in females after a 12-week withdrawal period.
In a toxicity test in juvenile rats given risperidone orally from 12 to 50 days after birth, reversible effects on learning and memory were observed in females, except for a dose of 0.63 mg/kg/day. The plasma exposure (AUC) of the active ingredient in terms of risperidone + active metabolite 9-hydroxyrisperidone at this dose was approximately half of that at the MRHD dose. No persistent neurobehavioral or reproductive developmental effects were seen at the highest test dose of risperidone up to 1.25 mg/kg/day. The plasma exposure of the active ingredient as risperidone + active metabolite 9-hydroxyrisperidone at this dose was approximately 2/3 of that at the human MRHD dose.
Pharmacokinetics]
Absorption
Risperidone is well absorbed. The absolute oral bioavailability of risperidone is 70% (CV = 25%). The relative bioavailability of oral risperidone tablets was 94% (CV = 10%) compared to oral solution.
The blood concentrations of risperidone, 9-hydroxyrisperidone, the major metabolite of risperidone, and risperidone plus 9-hydroxyrisperidone were linearly related to dose at daily doses in the range of 1 to 16 mg (0.5 to 8 mg twice daily). The mean peak blood concentration of risperidone was reached approximately 1 hour after oral administration of the solution or tablet. 9-hydroxyrisperidone reached peak concentrations in approximately 3 hours in fast metabolizers and 17 hours in slow metabolizers. Risperidone reaches steady-state concentrations in fast metabolizers in about 1 day and in slow metabolizers in about 5 days. 9-hydroxyrisperidone reaches steady-state concentrations in 5-6 days (fast metabolizer assay).
Food effects
Food has no effect on the rate or extent of absorption of risperidone. Risperidone can be taken on an empty stomach or with food.
Distribution
Risperidone is rapidly distributed in the body. In plasma, risperidone is bound to albumin and α1-acidic glycoprotein. The plasma protein binding rate of risperidone is 90%, and the binding rate of its main metabolite, 9-hydroxyrisperidone, is 77%. Risperidone and 9-hydroxyrisperidone are not mutually substitutable at the plasma binding site. High therapeutic concentrations of sulfamethazine (100 mcg/ml), warfarin (10 mcg/ml) and carbamazepine (10 mcg/ml) caused a mild increase in the free fraction of risperidone (10 ng/ml) and 9-hydroxyrisperidone (50 ng/ml), the clinical significance of which is unknown.
Metabolism
Risperidone is metabolized by the liver. The primary metabolic pathway is the hydroxylation of risperidone to 9-hydroxyrisperidone by the action of the CYP2D6 enzyme. The secondary metabolic pathway is N-dealkylation. The main metabolite, 9-hydroxyrisperidone, has similar pharmacological activity to risperidone. Therefore, the clinical effect of the drug is achieved by the total blood concentration of risperidone and 9-hydroxyrisperidone.
CYP2D6, also known as isovaline hydroxylase, is the metabolizing enzyme for many antipsychotic, antidepressant, antiarrhythmic, and other drugs.CYP2D6 is genetically polymorphic (about 6-8% in Caucasians and a low percentage in Asians, with almost no activity, called slow metabolizers).CYP2D6 fast metabolizers rapidly metabolize risperidone to 9-hydroxyrisperidone, while slow metabolizers have a low metabolism rate. Although fast metabolizers have lower blood levels of risperidone and higher blood levels of 9-hydroxyrisperidone compared to slow metabolizers, the pharmacokinetics of the sum of risperidone and 9-hydroxyrisperidone after oral administration of single and multiple doses of risperidone are similar to those of slow metabolizers.
Risperidone can be subject to interactions between the two classes of drugs. First, inhibitors of CYP2D6 interfere with the metabolism of risperidone to 9-hydroxyrisperidone. This occurs when combined with quinidine, essentially giving the subject a pharmacokinetic profile typical of slow metabolizers after administration. The efficacy and adverse effects of risperidone in combination with quinidine have not been evaluated, but observational studies of risperidone in the treatment of patients with a slow metabolism (n ≈ 70) did not reveal significant differences between fast and chronic metabolizers. Second, it is known that the coadministration of enzyme-inducing agents (e.g., carbamazepine, phenytoin sodium, rifampin, and phenobarbital) and risperidone may reduce the total plasma concentrations of risperidone and 9-hydroxyrisperidone. Risperidone may also interfere with the metabolism of drugs metabolized by CYP2D6. However, the weak binding of risperidone to the enzyme again shows the impossibility of this feature.
In vitro studies have shown that risperidone is a relatively weak inhibitor of CYP2D6. Therefore, risperidone does not significantly inhibit the clearance of drugs metabolized by this enzyme. In drug interaction studies, risperidone does not significantly affect the pharmacokinetics of donepezil and galantamine metabolized by CYP2D6.
In vitro studies have shown that drugs metabolized by other CYP isozymes including 1A1, 1A2, C9, 2C19, and 3A4 are weak inhibitors of risperidone metabolism.
Excretion
Risperidone and its metabolites are excreted primarily in the urine and to a lesser extent in the feces. A single dose of 1 mg of 14C-risperidone solution in three healthy male volunteers resulted in a total radiological recovery of 84% after one week, including 70% recovery in urine and 14% recovery in feces.
The apparent half-life of risperidone was 3 hours (CV = 30%) in the fast metabolizers and 20 hours (CV = 40%) in the slow metabolizers. The apparent half-life of 9-hydroxyrisperidone was 21 hours (CV = 20%) in the fast metabolizers and 30 hours (CV = 25%) in the slow metabolizers. The pharmacokinetics of the sum of risperidone and 9-hydroxyrisperidone after administration of single and multiple doses of risperidone were similar between fast and slow metabolizers, with an overall mean elimination half-life of 20 hours.
Storage
Store under shade and seal.
Package
2×10 tablets/plate/box; 4×10 tablets/plate/box.
Expiration date
12 months
Execution Standard
Approval number】
State Drug Certificate H20100106
[Marketing license holder
Name: Jiangsu Enhua Pharmaceutical Co.
Address: No. 18, Yangshan Road, Xuzhou Economic Development Zone
Tel: 0516-87767115
Fax: 0516-87767118
【Manufacturer
Company Name: Jiangsu Enhua Pharmaceutical Co.
Production Address: No. 18, Yang Shan Road, Xuzhou Economic Development Zone
Postcode：221004
Telephone number: 4009002262
Fax number: 0516-87767118
Web
Address: www.nhwa-group.com