Risperidone Information
Risperidone ()
Risperidone () Dosage And Administration
The safety and effectiveness of Risperidone () in pediatric patients with autistic disorder less than 5 years of age have not been established.
The dosage of Risperidone () should be individualized according to the response and tolerability of the patient. The total daily dose of Risperidone () can be administered once daily, or half the total daily dose can be administered twice daily.
Dosing should be initiated at 0.25 mg per day for patients
In clinical trials, 90% of patients who showed a response (based on at least 25% improvement on ABC-I, ) received doses of Risperidone () between 0.5 mg and 2.5 mg per day. The maximum daily dose of Risperidone () in one of the pivotal trials, when the therapeutic effect reached plateau, was 1 mg in patients 45 kg. No dosing data is available for children who weighed less than 15 kg.
Once sufficient clinical response has been achieved and maintained, consideration should be given to gradually lowering the dose to achieve the optimal balance of efficacy and safety. The physician who elects to use Risperidone () for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient.
Patients experiencing persistent somnolence may benefit from a once-daily dose administered at bedtime or administering half the daily dose twice daily, or a reduction of the dose.
The recommended initial dose is 0.5 mg twice daily in patients who are elderly or debilitated, patients with severe renal or hepatic impairment, and patients either predisposed to hypotension or for whom hypotension would pose a risk. Dosage increases in these patients should be in increments of no more than 0.5 mg twice daily. Increases to dosages above 1.5 mg twice daily should generally occur at intervals of at least 1 week. In some patients, slower titration may be medically appropriate.
Elderly or debilitated patients, and patients with renal impairment, may have less ability to eliminate Risperidone () than normal adults. Patients with impaired hepatic function may have increases in the free fraction of Risperidone () , possibly resulting in an enhanced effect . Patients with a predisposition to hypotensive reactions or for whom such reactions would pose a particular risk likewise need to be titrated cautiously and carefully monitored , , . If a once-daily dosing regimen in the elderly or debilitated patient is being considered, it is recommended that the patient be titrated on a twice-daily regimen for 2-3 days at the target dose. Subsequent switches to a once-daily dosing regimen can be done thereafter.
Co-administration of carbamazepine and other enzyme inducers (e.g., phenytoin, rifampin, phenobarbital) with Risperidone () would be expected to cause decreases in the plasma concentrations of the sum of Risperidone () and 9-hydroxyRisperidone () combined, which could lead to decreased efficacy of Risperidone () treatment. The dose of Risperidone () needs to be titrated accordingly for patients receiving these enzyme inducers, especially during initiation or discontinuation of therapy with these inducers .
Fluoxetine and paroxetine have been shown to increase the plasma concentration of Risperidone () 2.5-2.8 fold and 3-9 fold, respectively. Fluoxetine did not affect the plasma concentration of 9-hydroxyRisperidone () . Paroxetine lowered the concentration of 9-hydroxyRisperidone () by about 10%. The dose of Risperidone () needs to be titrated accordingly when fluoxetine or paroxetine is co-administered .
Risperidone () Dosage Forms And Strengths
Risperidone () Oral Solution is available in a 1 mg/mL strength.
Risperidone () Contraindications
Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been observed in patients treated with Risperidone () . Therefore, Risperidone () is contraindicated in patients with a known hypersensitivity to the product.
Risperidone () Warnings And Precautions
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Risperidone () is not approved for the treatment of dementia-related psychosis .
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.
The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases in which the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, 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 central nervous system pathology.
The management of NMS should include: (1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and medical monitoring; and (3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.
If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.
A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.
The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.
There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.
Given these considerations, Risperidone () should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that: (1) is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.
If signs and symptoms of tardive dyskinesia appear in a patient treated with Risperidone () , drug discontinuation should be considered. However, some patients may require treatment with Risperidone () despite the presence of the syndrome.
Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with atypical antipsychotics including Risperidone () . Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available.
Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics, including Risperidone () , should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics, including Risperidone () , should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics, including Risperidone () , should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics, including Risperidone () , should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic, including Risperidone () , was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of Risperidone () .
As with other drugs that antagonize dopamine D receptors, Risperidone () elevates prolactin levels and the elevation persists during chronic administration. Risperidone () is associated with higher levels of prolactin elevation than other antipsychotic agents.
Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects.
Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent , a factor of potential importance if the prescription of these drugs is contemplated in a patient with previously detected breast cancer. An increase in pituitary gland, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) was observed in the Risperidone () carcinogenicity studies conducted in mice and rats . Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans; the available evidence is considered too limited to be conclusive at this time.
Clinical experience with Risperidone () in patients with certain concomitant systemic illnesses is limited. Patients with Parkinson's Disease or Dementia with Lewy Bodies who receive antipsychotics, including Risperidone () , are reported to have an increased sensitivity to antipsychotic medications. Manifestations of this increased sensitivity have been reported to include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with the neuroleptic malignant syndrome.
Caution is advisable in using Risperidone () in patients with diseases or conditions that could affect metabolism or hemodynamic responses. Risperidone () has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from clinical studies during the product's premarket testing.
Increased plasma concentrations of Risperidone () and 9-hydroxyRisperidone () occur in patients with severe renal impairment (creatinine clearance
Risperidone () Adverse Reactions
The following are discussed in more detail in other sections of the labeling:
The most common adverse reactions in clinical trials ( 10%) were somnolence, increased appetite, fatigue, insomnia, sedation, parkinsonism, akathisia, vomiting, cough, constipation, nasopharyngitis, drooling, rhinorrhea, dry mouth, abdominal pain upper, dizziness, nausea, anxiety, headache, nasal congestion, rhinitis, tremor, and rash.
The most common adverse reactions that were associated with discontinuation from clinical trials (causing discontinuation in >1% of adults and/or >2% of pediatrics) were nausea, somnolence, sedation, vomiting, dizziness, and akathisia .
The data described in this section are derived from a clinical trial database consisting of 9712 adult and pediatric patients exposed to one or more doses of Risperidone () for the treatment of schizophrenia, bipolar mania, autistic disorder, and other psychiatric disorders in pediatrics and elderly patients with dementia. Of these 9712 patients, 2626 were patients who received Risperidone () while participating in double-blind, placebo-controlled trials. The conditions and duration of treatment with Risperidone () varied greatly and included (in overlapping categories) double-blind, fixed- and flexible-dose, placebo- or active-controlled studies and open-label phases of studies, inpatients and outpatients, and short-term (up to 12 weeks) and longer-term (up to 3 years) exposures. Safety was assessed by collecting adverse events and performing physical examinations, vital signs, body weights, laboratory analyses, and ECGs.
Adverse events during exposure to study treatment were obtained by general inquiry and recorded by clinical investigators using their own terminology. Consequently, to provide a meaningful estimate of the proportion of individuals experiencing adverse events, events were grouped in standardized categories using MedDRA terminology.
Throughout this section, adverse reactions are reported. Adverse reactions are adverse events that were considered to be reasonably associated with the use of Risperidone () (adverse drug reactions) based on the comprehensive assessment of the available adverse event information. A causal association for Risperidone () often cannot be reliably established in individual cases. Further, because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
The majority of all adverse reactions were mild to moderate in severity.
Risperidone () Drug Interactions
Risperidone () is metabolized to 9-hydroxyRisperidone () by CYP 2D6, an enzyme that is polymorphic in the population and that can be inhibited by a variety of psychotropic and other drugs . Drug interactions that reduce the metabolism of Risperidone () to 9-hydroxyRisperidone () would increase the plasma concentrations of Risperidone () and lower the concentrations of 9-hydroxyRisperidone () . Analysis of clinical studies involving a modest number of poor metabolizers (n≅70) does not suggest that poor and extensive metabolizers have different rates of adverse effects. No comparison of effectiveness in the two groups has been made.
In vitro
In vitro
Risperidone () Use In Specific Populations
The efficacy and safety of Risperidone () in the treatment of schizophrenia were demonstrated in 417 adolescents, aged 13 - 17 years, in two short-term (6 and 8 weeks, respectively) double-blind controlled trials , , Additional safety and efficacy information was also assessed in one long-term (6-month) open-label extension study in 284 of these adolescent patients with schizophrenia.
Safety and effectiveness of Risperidone () in children less than 13 years of age with schizophrenia have not been established.
The efficacy and safety of Risperidone () in the short-term treatment of acute manic or mixed episodes associated with Bipolar I Disorder in 169 children and adolescent patients, aged 10 - 17 years, were demonstrated in one double-blind, placebo-controlled, 3-week trial , , .
Safety and effectiveness of Risperidone () in children less than 10 years of age with bipolar disorder have not been established.
The efficacy and safety of Risperidone () in the treatment of irritability associated with autistic disorder were established in two 8-week, double-blind, placebo-controlled trials in 156 children and adolescent patients, aged 5 to 16 years , . Additional safety information was also assessed in a long-term study in patients with autistic disorder, or in short- and long-term studies in more than 1200 pediatric patients with psychiatric disorders other than autistic disorder, schizophrenia, or bipolar mania who were of similar age and weight, and who received similar dosages of Risperidone () as patients treated for irritability associated with autistic disorder.
The safety and effectiveness of Risperidone () in pediatric patients less than 5 years of age with autistic disorder have not been established.
Clinical studies of Risperidone () in the treatment of schizophrenia did not include sufficient numbers of patients aged 65 and over to determine whether or not they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, a lower starting dose is recommended for an elderly patient, reflecting a decreased pharmacokinetic clearance in the elderly, as well as a greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy . While elderly patients exhibit a greater tendency to orthostatic hypotension, its risk in the elderly may be minimized by limiting the initial dose to 0.5 mg twice daily followed by careful titration . Monitoring of orthostatic vital signs should be considered in patients for whom this is of concern.
This drug is substantially excreted by the kidneys, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function .
Risperidone () Overdosage
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.
Postmarketing 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.
Risperidone () Description
Risperidone () , a psychotropic agent belonging to the chemical class of benzisoxazole derivatives. The chemical designation 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. Its molecular formula is CHFNO and its molecular weight is 410.49. The structural formula is:
Risperidone () is a white to slightly beige powder. It is practically insoluble in water, freely soluble in methylene chloride, and soluble in methanol and 0.1 HCl.
Risperidone () is available as a 1 mg/mL oral solution. Risperidone () Oral Solution contains the following inactive ingredients: benzoic acid, berry flavor, purified water, sorbitol crystalline, sodium hydroxide, sucralose liquid concentrate and tartaric acid.
Risperidone () Clinical Pharmacology
The mechanism of action of Risperidone () , as with other drugs used to treat schizophrenia, is unknown. However, it has been proposed that the drug's therapeutic activity in schizophrenia is mediated through a combination of dopamine Type 2 (D) and serotonin Type 2 (5HT) receptor antagonism.
Risperidone () is a selective monoaminergic antagonist with high affinity (Ki of 0.12 to 7.3 nM) for the serotonin Type 2 (5HT), dopamine Type 2 (D), and adrenergic, and H histaminergic receptors. Risperidone () acts as an antagonist at other receptors, but with lower potency. Risperidone () has low to moderate affinity (Ki of 47 to 253 nM) for the serotonin 5HT, 5HT, and 5HT receptors, weak affinity (Ki of 620 to 800 nM) for the dopamine D and haloperidol-sensitive sigma site, and no affinity (when tested at concentrations >10 M) for cholinergic muscarinic or and adrenergic receptors.
Risperidone () How Supplied/storage And Handling
Risperidone () Oral Solution
Risperidone () Oral Solution 1 mg/mL (NDC 51672-1349-3) is supplied in 30 mL bottles with a calibrated (in milliliters) pipette. The minimum calibrated volume is 0.25 mL, while the maximum calibrated volume is 3 mL.
DIRECTIONS FOR OPENING THE BOTTLE AND USING THE DISPENSING PIPETTE (SYRINGE)
Using Your Risperidone () Dispensing-Pipette and Bottle
Use this product as indicated below, unless directed otherwise by your Physician.
IMPORTANT: Please read these instructions before using Risperidone () Oral Solution.
Risperidone () Oral Solution 1 mg/mL should be stored at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature]. Protect from light and freezing.
Keep out of reach of children.
Risperidone () Patient Counseling Information
Physicians are advised to discuss the following issues with patients for whom they prescribe Risperidone () :
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