RiteMED Risperidone

RiteMED Risperidone 2 mg Film-coated Tablet: Orange, circular, biconvex film-coated tablet.
Each film-coated tablet contains: Risperidone, USP 2 mg.

Antipsychotic.
Pharmacology: Pharmacodynamics: Risperidone is a selective monoaminergic antagonist with a high affinity for serotonergic 5-HT₂ and dopaminergic D₂ receptors. Risperidone binds also to α₁-adrenergic receptors, and with lower affinity, to H₁-histaminergic and α₂-adrenergic receptors. Risperidone does not bind to dopamine D₁ receptors and has no affinity for muscarinic cholinergic receptors. Due to the lack of muscarinic receptor binding, risperidone is not expected to produce anticholinergic adverse effects.
The antipsychotic activity of risperidone is considered to be attributable to both risperidone and its active metabolite 9-hydroxy risperidone. Central dopamine D₂-receptor antagonism is considered to be the mechanism of action by which conventional antipsychotics improve the positive symptoms of schizophrenia, but also induce extrapyramidal symptoms and release of prolactin.
Although risperidone antagonizes dopamine D₂ receptors and causes release of prolactin, it is less potent than classical antipsychotics for depression of motor activity and for induction of catalepsy in animals. Balanced central serotonin and dopamine antagonism may reduce extrapyramidal side effect liability and extend the therapeutic activity to the negative and affective symptoms of schizophrenia.
Pharmacokinetics: Risperidone is well absorbed after oral administration. The absolute oral bioavailability of risperidone is 70%. The relative oral bioavailability of risperidone from a tablet is 94% when compared to a solution. Mean peak plasma concentrations of risperidone and 9-hydroxyrisperidone were reached at about 1 and 3 hours, respectively, after administration. Food did not affect the extent of absorption; thus, risperidone can be given with or without meals.
Risperidone is rapidly distributed. The volume of distribution is 1 to 2 L/kg. Steady-state concentrations of risperidone and 9-hydroxyrisperidone were reached within 1 to 2 days and 5 to 6 days, respectively. In plasma, risperidone is bound to albumin and α₁-acid glycoprotein (AGP). The plasma protein binding of risperidone is approximately 88%, that of the metabolite 77%. Neither risperidone nor 9-hydroxyrisperidone displaces each other from plasma binding sites.
Risperidone is extensively metabolized in the liver by CYP2D6 to a major active metabolite, 9-hydroxyrisperidone, which appears approximately equi-effective with risperidone with respect to receptor-binding activity. Consequently, the clinical effect of the drug likely results from the combined concentrations of risperidone plus 9-hydroxyrisperidone. CYP2D6, also called debrisoquin hydroxylase, is the enzyme responsible for the metabolism of many antipsychotics, antidepressants, antiarrhythmics, and other drugs. CYP2D6 is subject to genetic polymorphism (about 6 to 8% of Caucasians, and a very low percentage of Asians, have little or no activity and are "poor metabolizers") and to inhibition by a variety of substrates and some non-substrates, notably quinidine. Extensive CYP2D6 metabolizers convert risperidone rapidly into 9-hydroxyrisperidone, whereas poor CYP2D6 metabolizers convert it much more slowly.
Another metabolic pathway of risperidone is N-dealkylation. In vitro studies in human liver microsomes showed that risperidone at clinically relevant concentration does not substantially inhibit the metabolism of medicines metabolized by cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5.
Risperidone and its metabolites are eliminated via the urine and, to a much lesser extent, via the feces. One week after administration, 70% of the dose is excreted in the urine and 14% in the feces. In urine, risperidone plus 9-hydroxyrisperidone represents 35 to 45% of the dose. The remainder is inactive metabolites. The apparent half-life of risperidone was three hours in extensive metabolizers and 20 hours in poor metabolizers. The apparent half-life of 9-hydroxyrisperidone was about 21 hours in extensive metabolizers and 30 hours in poor metabolizers. Although extensive metabolizers have lower risperidone and higher 9-hydroxyrisperidone concentrations than poor metabolizers, the pharmacokinetics of risperidone and 9-hydroxyriperidone combined, after single and multiple doses, are similar in extensive and poor metabolizers, with an overall mean elimination half-life of about 20 hours.
Special Population: Children: The pharmacokinetics of risperidone and 9-hydroxydsperidone in children were similar to those in adults after correcting for the difference in body weight.
Elderly: In healthy elderly subjects, renal clearance of both risperidone and 9-hydroxyrisperidone was decreased, and elimination half-lives were prolonged compared to young healthy subjects. Dosing should be modified accordingly in the elderly patients.
Hepatic Impairment: Risperidone plasma concentrations were normal in patients with liver insufficiency, but the mean free fraction of risperidone in plasma was increased by about 35%.
Renal Impairment: In patients with moderate to severe renal disease, clearance of the sum of risperidone and its active metabolite decreased by 60% compared to young healthy subjects. Risperidone doses should be reduced in these patients.
Race and Gender: There is no specific pharmacokinetic study conducted to investigate race and gender effects, but a population pharmacokinetic analysis did not identify important differences in the disposition of risperidone due to gender (whether corrected for body weight or not) or race.

Schizophrenia: Acute and maintenance treatment of schizophrenia and related psychotic disorders.
Bipolar Mania: Monotherapy for the acute management of manic or mixed episodes associated with Bipolar I disorder; In combination with lithium or valproate for the treatment of acute manic or mixed episodes associated with Bipolar I Disorder.
Severe Dementia of the Alzheimer Type: Short-term (up to 6 weeks) symptomatic management of aggression or psychotic symptoms in patients with severe dementia of the Alzheimer type unresponsive to nonpharmacological approaches and when there is a risk of harm to self or others.
Physicians are advised to assess the risks and benefits of the use of risperidone in elderly patients with dementia of the Alzheimer type, taking into account risk predictors for stroke or existing cardiovascular comorbidities in the individual patient.
Conduct and Other Disruptive Behavior Disorder: Short-term treatment (up to 6 weeks) of conduct and other disruptive behavior disorders in children (over 5 years), adolescents, and adults with sub-average intellectual functioning or mental retardation in whom destructive behaviors (e.g., aggression, impulsivity and self-injurious behaviors) are prominent.
Irritability Associated with Autistic Disorder: Treatment of behavioral disorders associated with autism in children and adolescents.

General Dosing Recommendations: Risperidone may be given with or without meals.
Switching from other antipsychotics: It is recommended that gradual discontinuation of the previous treatment should be done when risperidone therapy is initiated. The period of overlapping antipsychotic administration should be minimized. If necessary, when switching patients from depot antipsychotics, initiate risperidone therapy in place of the next scheduled injection. The need for continuing existing anti-Parkinson drugs should be reevaluated periodically.
Recommended Oral Risperidone Dose: See Tables 1, 2 and 3.

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Irritability Associated with Autistic Disorder in Children and Adolescents 5 to 16 years old: The dosage of risperidone should be individualized according to response and tolerability of the patient.
The total daily dose of risperidone can be administered once per day, or half the total daily dose can be administered twice per day.
Initial Dose: Patient Weight: <20 kg: 0.25 mg per day.
≥20 kg: 0.5 mg per day.
After a minimum of four days from treatment initiation, the dose may be increased to a recommended dose of 0.5 mg per day for patients <20 kg and 1 mg per day for patients ≥20 kg. This dose should be maintained for a minimum of 14 days.
In patients not achieving sufficient clinical response, dose increases may be considered at ≥2-week intervals in increments of 0.25 mg per day for patients <20 kg or 0.5 mg per day for patients ≥20 kg. The effective dose range is 0.5 to 3 mg per day. No dosing data are available for children who weigh less than 15 kg.
Once sufficient response has been achieved and maintained, consider gradually lowering the dose to achieve optimum balance of effectiveness and tolerance. 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 per day dose administered at bedtime or administering half the daily dose twice per day, or a reduction of the dose.
As with all symptomatic treatments, the continued use of risperidone in children and adolescents with autism must be evaluated and justified on an ongoing basis.
Behavioral disturbances in patients with dementia: Physicians are advised to assess the risks and benefits of the use of risperidone in elderly patients with dementia of the Alzheimer type, taking into account risk predictors for stroke or existing cardiovascular comorbidities in the individual patient.
Discontinuation should be considered if signs and symptoms of cerebrovascular adverse events occur.
Initial Dose: 0.25 mg twice per day.
This dosage can be individually adjusted by increments of 0.25 mg twice per day, not more frequently than every other day, if needed. The optimum dose is 0.5 mg twice per day for most patients. Some patients, however, may benefit from doses up to 1 mg twice per day.
Periodic dosage adjustment (increase or decrease) or discontinuation of treatment should be considered because of the instability of the symptoms treated.
Once patients have reached their target dose, a once per day dosing regimen can be considered. As with all symptomatic treatments, the continued use of risperidone must be evaluated and justified on an on-going basis.
Special Population: Patients with severe renal (CL_cr<30 mL/min) or hepatic impairment (10 to 15 points on Child Pugh System): Initial Dose: 0.5 mg twice per day.
The dose may be increased in increments of 0.5 mg or less administered twice per day. For doses above 1.5 mg twice per day, increase in intervals of one week or greater.
Elderly: The doses of risperidone should be adjusted slowly from a 0.25 mg twice per day starting dose to a maximum daily dose of 3 mg. Since the elimination of risperidone is somewhat slower in these patients, the potential for accumulation should be considered.
Patients prone to hypotension: Caution should be exercised in patients prone to hypotension and the use of lower starting doses of 0.25 to 0.5 mg twice per day should be considered.
Dose adjustment for specific drug interactions: When risperidone is concomitantly use with enzyme inducers (e.g., carbamazepine), the dose of risperidone should be increased up to double the patient's usual dose. It may be necessary to decrease the risperidone dose when enzyme inducers such as carbamazepine are discontinued. Similar effect may be expected with concomitant use of risperidone with other enzyme inducers (e.g., phenytoin, rifampicin, and phenobarbital).
When fluoxetine or paroxetine is concomitantly use with risperidone, the dose of risperidone should be reduced. The risperidone dose should not exceed 8 mg per day in adults when concomitantly used with these drugs. When initiating therapy, risperidone should be titrated slowly. It may be necessary to increase the risperidone dose when enzyme inhibitors such as fluoxetine or paroxetine are discontinued.
Or, as prescribed by a physician.

Signs and symptoms of risperidone overdosage include drowsiness and sedation, tachycardia and hypotension, and EPS. Some cases have been associated with hyponatremia, hypokalemia, prolonged QT, widened QRS, and seizure. Torsade de Pointes has been reported in association with combined overdose of risperidone and paroxetine. No fatalities have been reported in overdosage of 20 to 300 mg risperidone.
Establish and maintain a clear airway and ensure adequate oxygenation and ventilation in case of acute overdosage. Consider gastric lavage (after intubation if the patient is unconscious) and use of charcoal together with laxative. There may be risk of aspiration with induced emesis because of the possibility of obtundation, seizures or dystonic reaction of the head and neck following overdose. Start cardiovascular monitoring immediately and include continuous ECG monitoring to detect possible arrhythmias. Alpha-blocking properties of bretylium might be additive to those of risperidone which may result in problematic hypotension.
There is no specific antidote to risperidone overdose. Institute appropriate supportive measures. Consider the possibility of multiple drug involvement. Treat hypotension and circulatory collapse with appropriate measures such as IV fluids and/or sympathomimetic agents. Do not use epinephrine and dopamine since β-stimulation may worsen hypotension in the setting of risperidone-induced α-blockade. Administer anticholinergic medication in cases of severe EPS. Continue close medical supervision and monitoring until the patient recovers.

Known hypersensitivity to risperidone or to other ingredients in the formulation.

Increased Mortality in Elderly Patients with Dementia: Elderly patients with dementia treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. Analyses of thirteen placebo-controlled trials with various atypical antipsychotics (modal duration of 10 weeks) in these patients showed a mean 1.6-fold increase in the death rate in the drug-treated patients. Although the cause 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.

Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer's dementia. Risperidone and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.
Suicide: The possibility of suicide or attempted suicide is inherent in psychosis and bipolar mania, and thus, close supervision and appropriate clinical management of high-risk patients should accompany drug therapy.
Neuroleptic Malignant Syndrome (NMS): NMS is a potentially fatal symptom complex that has been reported in association with antipsychotic drugs, including risperidone.
Clinical manifestations of NMS are hyperthermia, muscle rigidity, altered mental status (including catatonic signs) and evidence of autonomic instability (irregular blood pressure, tachycardia, cardiac arrhythmias, and diaphoresis). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.
In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms. Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system (CNS) pathology.
The management of NMS should include: immediate discontinuation of all antipsychotic drugs including risperidone, and other drugs not essential to concurrent therapy; intensive symptomatic treatment and medical monitoring; and 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 recurrence of NMS has been reported.
Tardive Dyskinesia (TD): A syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with conventional antipsychotic drugs. Although TD appears to be most prevalent in the elderly, particularly elderly females, it is impossible to predict at the onset of treatment which patients are likely to develop TD. It has been suggested that the occurrence of parkinsonian side effects is a predictor for the development of TD. In clinical studies, the observed incidence of drug-induced parkinsonism was lower with risperidone than with haloperidol. The risk of developing TD may be less with risperidone. In longer-term clinical studies, risperidone was associated with a lower incidence of treatment-emergent dyskinesia compared to haloperidol.
The risk of developing TD 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 less commonly, after relatively brief periods of treatment at low doses. There is known treatment for established cases of TD. The syndrome may remit, partially or completely, if antipsychotic drug treatment is withdrawn. However, antipsychotic drug treatment itself may suppress the signs and symptoms of TD, thereby masking the underlying process. The effect of symptom suppression upon the long-term course of TD is unknown.
In view of these considerations, risperidone should be prescribed in a manner that is most likely to minimize the risk of TD. As with any antipsychotic drug, risperidone should be reserved for patients who appear to be obtaining substantial benefit from the drug. In such patients, the smallest dose and the shorted duration of treatment should be sought. The need for continued treatment should be reassessed periodically.
If signs and symptoms of TD develop during treatment with risperidone, withdrawal of the drug should be considered. However, some patients may require treatment with risperidone despite the presence of the syndrome.
Seizures: Antipsychotic drugs are known to lower the seizure threshold. In clinical trials, seizures have occurred in a few patients treated with risperidone. Therefore, caution should be used in administering risperidone to patients having a history of seizures or other predisposing factors.
Akathisia: The presentation of akathisia may be variable and comprises subjective complaints of restlessness and an overwhelming urge to move and either distress or motor phenomena such as pacing, swinging of the legs while seated, rocking from foot to foot, or both. Particular attention should be paid to the monitoring for such symptoms and signs as, left untreated, akathisia is associated with poor compliance and an increased risk of relapse.
Use in Patients with Parkinson's Disease or Dementia with Lewy Bodies (DLB): Physicians should weigh the risks versus the benefits when prescribing antipsychotics, including risperidone, to patients with Parkinson's Disease or DLB since both groups may be at increased risk of NMS as well as having an increased sensitivity to antipsychotic medications. Manifestation of this increased sensitivity can include confusion, obtundation, and postural instability with frequent falls, in addition to extrapyramidal symptoms.
Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.
Hyperglycemia and Diabetes Mellitus: As with some other antipsychotics, hyperglycemia, diabetes mellitus and exacerbation of pre-existing diabetes, in some cases serious and associated with ketoacidosis or hyperosmolar coma or death, have been reported during the use of risperidone. Diabetic ketoacidosis has occurred in patients treated with antipsychotics with no reported history of hyperglycemia. Appropriate clinical monitoring of patients treated with antipsychotics is advisable in accordance with utilized antipsychotic guidelines.
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.
Any patient treated with atypical antipsychotics, including risperidone, should be monitored for symptoms of hyperglycemia and diabetes mellitus including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia and diabetes mellitus during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect drug. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control.
Dyslipidemia: Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.
Weight Gain: Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.
When treating pediatric patients with risperidone for any indication, weight gain should be assessed against the expected with normal growth.
Hyperprolactinemia: As with other drugs that antagonize dopamine D₂ 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.
Since tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, risperidone should only be administered to patients with previously detected breast cancer if the benefits outweigh the potential risks. Caution should also be exercised when considering risperidone treatment in patients with pituitary tumors. Possible manifestations associated with elevated prolactin levels are amenorrhea, galactorrhea, and menorrhagia. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone mineral density in both female and male subjects.
Orthostatic Hypotension: Risperidone has been observed to cause orthostatic hypotension and tachycardia, particularly during the initial dose titration period and the first few weeks of treatment, during clinical trials. Rare cases of syncope, cardiac arrhythmias and first degree AV-block have been reported. Clinically significant hypotension has also been observed post-marketing with concomitant use of risperidone and antihypertensive treatment. The likelihood of excessive hypotension or syncope can be minimized by limiting the initial dose of the drug to 1 to 2 mg per day, once or twice daily, in adult patients and to 0.25 to 0.5 mg twice per day in special patient populations, and by increasing the dose slowly. A dose reduction should be considered if hypotension occurs.
Risperidone should be used with caution in patients with cardiovascular diseases (e.g., heart failure, history of myocardial infarction or ischemia, cerebrovascular disease, conduction abnormalities) and other conditions such as dehydration and hypovolemia. Special care should be taken to avoid hypotension in patients with a history of cerebrovascular insufficiency or ischemic heart disease, and in patients taking medications to lower blood pressure. Monitoring of orthostatic vital signs should be considered in all such patients.
QT interval: As with other antipsychotics, caution should be exercised when risperidone is prescribed in patients with a history of cardiac arrhythmias, in patients with congenital long QT syndrome, and in concomitant use with drugs known to prolong the QT interval.
Leukopenia, Neutropenia, and Agranulocytosis Class Effect: In clinical trial and/or post-marketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including risperidone. Granulocytopenia and agranulocytosis have also been reported.
Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or a drug-induced leukopenia/neutropenia should be monitored during the first few months of therapy and discontinuation of risperidone should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors.
Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur.
Patients with severe neutropenia (absolute neutrophil count <1 x 10⁹/L) should discontinue risperidone and have their WBC followed until recovery.
Venous thromboembolism (VTE): VTE, including fatal pulmonary embolism, has been reported with antipsychotic drugs, including risperidone, in case reports and/or observational studies. When prescribing risperidone all potential risk factors for VTE should be identified and preventive measures undertaken.
Priapism: Drugs with α-adrenergic blocking effects have been reported to induce priapism. Priapism has been reported with risperidone during post-marketing surveillance. This adverse reaction, as with other psychotropic drugs, did not appear to be dose dependent and did not correlate with the duration of treatment.
Body temperature regulation: Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic drugs. Appropriate care is advised when prescribing risperidone for patients who will be experiencing conditions which may contribute to an elevation or reduction of core temperature, e.g., exercising strenuously, exposure to extreme heat or cold, receiving concomitant drug with anticholinergic activity, or being subject to dehydration.
Antiemetic effect: Consistent with its dopamine antagonistic effects, risperidone may have an antiemetic effect. Such an effect may mask signs of toxicity due to overdosage with other drugs, or may mask symptoms of disease such as brain tumor, or intestinal obstruction or Reye's syndrome.
Intraoperative Floppy Iris Syndrome (IFIS): IFIS has been observed during cataract surgery in patients treated with medicines with α₁-adrenergic antagonist effect, including risperidone.
This variant of small pupil syndrome is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs and potential prolapse of the iris toward the phacoemulsification incisions. IFIS may increase the risk of eye complications during and after the operation. Current or past use of medicines with α₁-adrenergic antagonist effect should be made known to the ophthalmic surgeon in advance of surgery. The potential benefit of stopping α₁ blocking therapy prior to cataract surgery has not been established and must be weighed against the risk of stopping the antipsychotic therapy.
Use in Patients with Concomitant Illness: As clinical experience is limited, risperidone should be used with caution in patients with dehydration, hypokalemia, and hypovolemia.
Effects on Ability to Drive and Use Machine: Since risperidone may cause somnolence, patients should be cautioned against driving a car or operating hazardous machinery until they are reasonably certain that risperidone does not affect them adversely.
Use in Children: Before risperidone is prescribed to a child or adolescent with conduct disorder, they should be fully assessed for physical and social causes of the aggressive behavior such as pain or inappropriate environmental demands.
The sedative effect of risperidone should be closely monitored in this population because of possible consequences on learning ability. A change in the time of administration of risperidone could improve the impact of the sedation on attention faculties of children and adolescents.
Risperidone treatment for up to three years showed no adverse effects on growth and sexual maturation. No differences were observed between risperidone and placebo groups in measurements of sexual maturation, using the Tanner scale, and no adverse events suggestive of delayed pubertal maturation were reported. The mean change in height after one year of treatment with risperidone was within the expected growth range in this population.
Weight gain has been observed with atypical antipsychotic use in pediatric and adolescent patient populations. Independent of any drug-specific effects, weight gain can be associated with adverse changes in other metabolic parameters (e.g., glucose and lipid metabolism). Abnormal childhood weight and metabolic status can have adverse effects on cardiovascular outcomes in adulthood. Weight gain and adverse effects on other metabolic parameters associated with typical antipsychotics can be more frequent or more severe in pediatric and adolescent patients than in the adult patients.
During treatment with risperidone, regular examination for extrapyramidal symptoms and other movement disorders should also be conducted.
Safety and effectiveness of risperidone in children less than 13 years old with schizophrenia have not been established.
Safety and effectiveness of risperidone in children less than 10 years old with bipolar disorder have not been established.
Use in Elderly: Elderly patients generally have decreased renal, hepatic and cardiac function, and an increased tendency to postural hypotension. Therefore, lower starting doses, lower rates of dose adjustment and lower maximal doses are recommended in these patients.
Risperidone is substantially excreted by the kidneys. Thus, the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Caution should be taken in dose selection and titration since elderly patients are more likely to have decreased real function. Monitoring of renal function in these patients is also recommended.
Patients with Parkinson's Disease or Lewy Body Dementia: Patients with Parkinson's Disease or Dementia with Lewy Bodies can experience increased sensitivity to risperidone. Manifestations can include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with neuroleptic malignant syndrome.
Use in Geriatric Patients with Dementia of the Alzheimer Type: Increased Mortality in Elderly Patients with Dementia-Related Psychosis: Elderly patients with dementia-related psychosis treated with atypical 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 cause 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 drugs as opposed to some characteristics of the patients is not clear.
Concomitant Use With Furosemide: In risperidone placebo-controlled trials in elderly patients with dementia, a higher incidence of mortality was observed in patients treated with furosemide plus risperidone (7.3%) when compared to patients treated with risperidone alone (3.1%), furosemide alone (4.1%), or placebo without furosemide (2.9%). The increase in mortality in patients treated with furosemide plus risperidone was observed in two of the four clinical trials. No pathophysiological mechanism has been identified to explain this finding, and no consistent pattern for cause of death observed.
Nevertheless, caution should be exercised and the risks and benefits of this combination should be considered prior to the decision to use. There was no increased incidence of mortality among patients taking other diuretics as concomitant medication with risperidone. Irrespective of treatment, dehydration was an overall risk factor for mortality and should therefore be carefully avoided in elderly patients with dementia. Risperidone is not approved for the treatment of dementia-related psychosis.
Cardiovascular Adverse Events (CVAEs) in Elderly Patients with Dementia: Analysis of clinical trials in elderly patients with dementia suggests that the use of risperidone in dementia patients may be associated with an increased incidence of reports of CVAEs such as stroke and transient ischemic attacks, including fatalities. In placebo-controlled trials, there was a significantly higher incidence of CVAEs in patients treated with risperidone compared to placebo-treated patients. There is insufficient information to determine whether CVAEs in elderly patients with dementia are associated specifically with risperidone or other antipsychotic agents.
Therefore, physicians are advised to assess the risks and benefits of the use of risperidone in elderly patients with dementia taking into account risk predictors for stroke in the individual patient. Patients/caregivers should be advised to immediately report signs and symptoms of potential CVAEs such as sudden weakness or numbness in the face, arms or legs, and speech or vision problems. In placebo-controlled trials, there was a significantly higher incidence of CVAEs in patients treated with risperidone compared to placebo-treated patients. There is insufficient information to determine whether CVAEs in elderly patients with dementia are associated specifically with risperidone or other antipsychotic agents.
All treatment options should be considered without delay, including discontinuation. Furthermore, caution should be exercised in prescribing risperidone to patients with vascular comorbidities, such as hypertension and cardiovascular disease.

Pregnancy: Pregnancy Category C.
Adequate and well controlled studies with risperidone have not been conducted in pregnant women. Neonates exposed to antipsychotic drugs, including risperidone, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery.
Neonates exposed to antipsychotic drugs, including risperidone, during the third trimester of pregnancy are at risk of experiencing extrapyramidal neurological disturbances and/or withdrawal symptoms following delivery. Monitor neonates exhibiting extrapyramidal or withdrawal symptoms. Some neonates recover within hours or days without specific treatment; others may require prolonged hospitalization.
There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder in neonates following in utero exposure to antipsychotics in the third trimester. 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. 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.
Risperidone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Labor and Delivery: The effect of risperidone on labor and delivery in humans in unknown.
Lactation: Risperidone and 9-hydroxyrisperidone are present in human breast milk. Due to the potential for serious adverse reactions in breastfeeding infants from risperidone, a decision should be made whether to discontinue breastfeeding or to discontinue the drug, taking into account the importance of the drug to the mother.
Fertility: As with other drugs that antagonize dopamine D2 receptors, risperidone elevates prolactin level. 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.

Infections and infestations: Localized infection, infection, influenza, viral infection.
Neoplasms benign, malignant and unspecified (incl cysts and polyps): Pituitary adenoma.
Blood and Lymphatic System Disorders: Agranulocytosis, anemia, eosinophil count increased, granulocytopenia, hematocrit decreased, neutropenia, thrombocytopenia, thrombotic thrombocytopenic purpura, white blood cell count decreased.
Immune System Disorders: Anaphylactic reaction, hypersensitivity.
Endocrine Disorders: Hyperprolactinemia, inappropriate antidiuretic hormone secretion.
Metabolism and Nutrition Disorders: Anorexia, appetite decreased, appetite increased, blood cholesterol increased, blood triglycerides increased, diabetic ketoacidosis, diabetes mellitus, hyperglycemia, hyperinsulinemia, hypoglycemia, polydipsia, weight decreased/increased, water intoxication.
Psychiatric Disorders: Agitation, aggressive reaction, akathisia, anorgasmia, anxiety, blunted affect, confusional state, depression, dysarthria, hypersomnia, insomnia, middle insomnia, listlessness, mania, nervousness, nightmare, psychosis, sleep disorder, suicide attempt.
Nervous System Disorders: Balance disorder, cerebral ischemia, cerebrovascular accident, cerebrovascular disorder, convulsion, coordination abnormal, depressed level of consciousness, diabetic coma, disturbance in attention, dizziness, dizziness postural, drooling, dysgeusia, dyskinesia, dystonia, head titubation, headache, hypoesthesia, hyperkinesia, hypokinesia, lethargy, loss of consciousness, muscle contractions involuntary, neuroleptic malignant syndrome, oculogyric crisis, paresthesia, parkinsonism, psychomotor hypersensitivity, rigidity, sedation, sleep apnea syndrome, somnolence, speech disorder, syncope, tardive dyskinesia, tremor, unresponsive to stimuli.
Eye Disorders: Blepharospasm, conjunctivitis, dry eye, eye discharge, eye edema, eye infection, eye movement disorder, eye rolling, eye swelling, eyelid margin crusting, floppy iris syndrome (intraoperative), glaucoma, lacrimation increased, ocular hyperemia, photophobia, vision blurred, visual acuity reduced.
Ear and Labyrinth Disorders: Ear infection, ear pain, tinnitus, vertigo.
Cardiac Disorders: Atrial fibrillation, atrioventricular block, bradycardia, bundle branch block left, bundle branch block right, chest discomfort, conduction disorder, electrocardiogram abnormal, electrocardiogram QT prolonged, palpitations, postural orthostatic tachycardia syndrome, sinus arrhythmia, sinus bradycardia, sinus tachycardia, tachycardia, transient ischemic attack.
Vascular Disorders: Flushing, hypertension, hypotension, orthostatic hypotension, venous thrombosis.
Respiratory, Thoracic and Mediastinal Disorders: Bronchitis, bronchopneumonia, cough, dysphonia, dyspnea, epistaxis, hyperventilation, nasal congestion, nasal edema, nasopharyngitis, otitis media chronic, pharyngitis, pharyngolaryngeal pain, pneumonia, pneumonia aspiration, pulmonary congestion, pulmonary embolism, rales, respiratory disorder, respiratory tract congestion, rhinitis, rhinorrhea, sleep apnea syndrome, sinus congestion, sinusitis, upper respiratory tract infection, tracheobronchitis, wheezing.
Gastrointestinal Disorders: Abdominal discomfort, abdominal pain, aptyalism, cheilitis, constipation, diarrhea, dry mouth, dyspepsia, dysphagia, fecal incontinence, fecaloma, flatulence, gastritis, gastroenteritis, ileus, intestinal obstruction, lip swelling, nausea, pancreatitis, salivary hypersecretion, swollen tongue, tongue spasm, tonsillitis, toothache, vomiting.
Hepatobiliary Disorders: Gamma-glutamyltransferase increased, hepatic enzyme increased, jaundice, transaminase increased.
Skin and subcutaneous Tissue Disorders: Acrodermatitis, acne, alopecia, angioedema, cellulitis, dandruff, drug eruption, dry skin, eczema, erythema, hyperkeratosis, onychomycosis, pruritus, rash, seborrhoeic dermatitis, skin discoloration, skin disorder, skin lesion, urticaria.
Musculoskeletal and Connective Tissue Disorders: Arthralgia, back pain, button pain, joint stiffness, joint swelling, muscle spasms, muscular weakness musculoskeletal pain, myalgia, neck pain, pain in extremity, posture abnormal, rhabdomyolysis.
Renal and Urinary Disorders: Cystitis, dysuria, enuresis, pollakiuria, urinary incontinence, urinary retention, urinary tract infection.
Pregnancy, Puerperium and Perinatal Conditions: Drug withdrawal syndrome neonatal.
Reproductive System and Breast Disorders: Amenorrhea, breast discharge, breast discomfort, breast engorgement, breast enlargement, breast pain, ejaculation disorder, ejaculation failure, erectile dysfunction, galactorrhea, gynecomastia, lactation nonpuerperal, libido decreased, menstrual disorder (menstruation delayed, oligomenorrhea), precocious puberty, priapism, retrograde ejaculation, sexual dysfunction, vaginal discharge.
General Disorders and Administration Site Conditions: Asthenia, body temperature increased, body temperature decreased, chest discomfort, chest pain, chills, discomfort, drug withdrawal syndrome, edema (peripheral, face, pitting), fatigue, feeling abnormal, gait abnormal, gait disturbance, hypothermia, induration, malaise, pain, peripheral coldness, pyrexia, sluggishness, sudden death, thirst.
Investigations: Blood creatinine phosphokinase increased, blood prolactin increased, body temperature decreased/increased, glucose urine present.
Injury, poisoning and procedural complications: Fall, procedural pain.

Centrally-acting drugs and alcohol: Given the primary CNS effects of risperidone, caution should be exercised when risperidone is concomitantly used with other centrally-acting medicines or alcohol.
Drugs with hypotensive effects: Because of its potential for inducing hypotension, risperidone may enhance the hypotensive effects of other therapeutic agents. Clinically significant hypotension has been observed post-marketing with concomitant use of risperidone and antihypertensive treatment.
Drugs known to prolong the QT interval: Caution should be exercised when risperidone is prescribed in combination with other medicine that are thought to prolong the QT interval or medicines known to cause electrolyte imbalance.
Strong CYP2D6 inhibitors (e.g., paroxetine): Concomitant use of risperidone with a strong CYP2D6 inhibitor may increase the plasma concentrations of risperidone, but less so of the active antipsychotic fraction. Higher doses of a strong CYP2D6 inhibitor may elevate concentrations of the risperidone active antipsychotic fraction. When concomitant paroxetine or another strong CYP2D6 inhibitor, particularly at higher doses, is initiated or discontinued, the physician should re-evaluate the dosing of risperidone.
CYP3A4 and/or P-gp inhibitors (e.g., itraconazole, ketoconazole): Concomitant use of risperidone with a strong CYP3A4 and P-gp inhibitor may substantially elevate plasma concentrations of the risperidone active antipsychotic fraction. When concomitant itraconazole or another strong CYP3A4 and/or P-gp inhibitor is initiated or discontinued, the physician should re-evaluate the dosing of risperidone.
Ketoconazole increased the plasma concentrations of risperidone and decreased the plasma concentrations of 9-hydroxyrisperidone.
CYP3A4 and/or P-gp inducers (e.g., carbamazepine): Concomitant use of risperidone with a strong CYP3A4 and/or P-gp inducer may decrease the plasma concentrations of the risperidone active antipsychotic fraction. When concomitant carbamazepine or another strong CYP3A4 and/or P-gp inhibitor is initiated or discontinued, the physician should re-evaluate the dosing of risperidone.
Highly protein-bound drugs: When risperidone is concomitantly used with highly protein-bound drugs, there is no clinically relevant displacement of either drug from the plasma proteins.
Tricyclic antidepressants (e.g., amitriptyline): May increase the plasma concentrations of risperidone but not those of the active antipsychotic fraction. Amitriptyline does not affect the pharmacokinetics of risperidone or the active antipsychotic fraction.
Selective serotonin reuptake inhibitors (e.g., fluoxetine, fluvoxamine, sertraline): Fluoxetine increases the plasma concentration of risperidone but less so of risperidone and 9-hydroxyrisperidone combined. When concomitant fluoxetine is initiated or discontinued, the physician should re-evaluate the dosing of risperidone. Sertraline at dosages up to 100 mg per day is not associated with clinically significant changes in concentrations of the risperidone active antipsychotic fraction.
However, doses higher 100 mg per day of sertraline or fluvoxamine may elevate concentrations of the risperidone active antipsychotic fraction.
Clozapine: Chronic administration of clozapine with risperidone may decrease the clearance of risperidone.
Levodopa and dopamine agonists: Risperidone may antagonize the effects of levodopa and other dopamine agonists.
Antibacterials (e.g., erythromycin, rifampicin): Erythromycin did not change the pharmacokinetics of risperidone or risperidone and 9-hydroxyrisperidone combined.
Rifampicin decreased the plasma concentrations of the active antipsychotic fraction.
Anticholinesterases (e.g., galantamine, donepezil): Did not show an effect on the pharmacokinetics of risperidone or risperidone and 9-hydroxyrisperidone combined.
Antiepileptics (e.g., topiramate): Modestly reduced the bioavailability of risperidone, but not that of the active antipsychotic fraction. Therefore, this interaction is unlikely to be of clinical significance. Risperidone does not show a clinically relevant effect on the pharmacokinetics of topiramate.
Antipsychotics (e.g., phenothiazines, aripiprazole): Phenothiazines may increase the plasma concentrations of risperidone but not those of the active antipsychotic fraction.
Risperidone did not affect the pharmacokinetics of the sum of aripiprazole and its active metabolite, dehydroaripiprazole.
Antivirals (e.g., ritonavir): Since ritonavir is a strong CYP3A4 inhibitor and a weak CYP2D6 inhibitor, ritonavir and ritonavir-boosted protease inhibitors potentially raise concentrations of the risperidone active antipsychotic fraction.
Beta-blockers: Some beta-blockers may increase the plasma concentrations of risperidone but not those of the active antipsychotic fraction.
Calcium channel blockers (e.g., verapamil): Increase the plasma concentration of risperidone and the active antipsychotic fraction.
Sodium channel blockers (e.g., quinidine): May increase the plasma concentrations of risperidone but not those of the active antipsychotic fraction.
Digitalis glycosides: Risperidone does not show a clinically relevant effect on the pharmacokinetics of digoxin.
Lithium: Repeated oral doses of risperidone did not affect the C_max of lithium. Dose adjustment for lithium is not recommended.
Valproate: Repeated oral doses of risperidone did not affect the pre-dose or average plasma concentrations and exposure of valproate compared to placebo. However, there was a 20% increase in valproate peak plasma concentration after concomitant administration of risperidone. Dose adjustment for valproate is not recommended.
Digoxin: Risperidone did not show a clinically relevant effect on the pharmacokinetics of digoxin. Dose adjustment for digoxin is not recommended.

Store at temperatures not exceeding 30°C.

Antipsychotics

N05AX08 - risperidone ; Belongs to the class of other antipsychotics.

Rx