RISPERDAL (Brand for RISPERIDONE)

General Administration Information
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
-NIOSH 2016 List: Group 2
-NIOSH reviewed data from studies provided by the manufacturer and determined it is unlikely that drug poses a carcinogenic, reproductive, or developmental hazard to workers in a healthcare setting and is no longer considered a hazardous drug.

Route-Specific Administration

Oral Administration
-May administer without regard to meals.
Oral Solid Formulations
Orally-disintegrating tablets
-Do not open the blister or child-resistant pouch until ready to administer.
-Peel back foil to expose the tablet. Do not push the tablet through the foil.
-Using dry hands, immediately place the entire tablet on the tongue. Allow the tablet to disintegrate in the mouth (will occur within seconds); the patient can then swallow the dissolved medicine with or without liquid.
-Do not split or chew the tablet.

Oral Liquid Formulations
Oral solution
-Administer directly from the calibrated oral dosing syringe or mix with a beverage prior to administration. The provided oral syringe can accurately measure volumes ranging from 0.25 to 3 mL.
-Compatible beverages for dilution include water, coffee, orange juice, and low-fat milk.
-The solution is NOT compatible with cola or tea.



Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intramuscular Administration
Risperidone long-acting injection (Risperdal Consta single-use dose pack)
NOTE: Risperdal Consta injection is not FDA-approved for use in pediatric patients.
-For deltoid or gluteal intramuscular injection only. Avoid inadvertent injection into a blood vessel.
-Do not substitute any components of the dose pack.
-Allow the dose pack to come to room temperature for at least 30 minutes prior to preparation.
-Connect the vial adapter to the vial and remove the sterile blister. Keep the vial vertical to prevent leakage. Do not shake.
-Connect the prefilled syringe to the vial adapter. Hold the syringe by the white collar at the tip of the syringe (not the glass barrel). Hold the white collar and snap the white cap off. Do not twist or cut off the cap.
-Insert the syringe tip into the luer opening of the vial adapter and attach with a firm clockwise twisting motion.
-Inject the entire amount of diluent from syringe into vial. The vial contents will now be under pressure. Keep holding down the plunger rod with thumb.
-While holding down the plunger rod, shake vigorously for at least 10 seconds. The suspension should appear uniform, thick, and milky in color. Microspheres will be visible.
-Invert the vial and slowly pull plunger rod down to withdraw entire contents from the vial into syringe. Hold the white collar on the syringe and unscrew from the vial adapter.
-Attach a needle to the syringe; use a 1-inch needle for deltoid and a 2-inch needle for gluteal administration.
-Immediately inject (to avoid settling) the entire contents of syringe. Just before injection, shake the syringe vigorously.
-Storage: Do not store the suspension after reconstitution.

Subcutaneous Administration
Risperidone extended-release injectable suspension (Perseris single-dose kit)
NOTE: Perseris injection is not FDA-approved for use in pediatric patients.
-For abdominal subcutaneous injection only. Do not administer by any other route.
-Each injection must be administered by a healthcare professional using the prepackaged injection syringe and enclosed safety needle.
-Allow the package to come to room temperature for at least 15 minutes prior to preparation.
-Only prepare the medication when you are ready to administer the dose.
-Hold syringe upright and tap the barrel of the syringe to dislodge packed powder.
-Remove the caps from both the liquid and powder syringes.
-Place liquid syringe on top of the powder syringe and connect by twisting approximately three-fourths turn.
-Transfer contents of the liquid syringe into the powder syringe.
-Gently push the powder syringe plunger until you feel resistance (to wet powder and avoid compacting).
-Repeat this gentle back-and-forth process for 5 cycles.
-Continue mixing syringes for an additional 55 cycles. Mixing can be more vigorous than when premixing.
-When fully mixed, the suspension should be cloudy and uniform in color. Color may vary from white to yellow-green.
-Transfer all contents into the liquid syringe. Simultaneously maintain slight pressure on the powder syringe plunger and pull back gently on the liquid syringe plunger while twisting the syringes apart. Attach the safety needle.
-After administration, lock the needle guard into place by pushing it against a hard surface.
-Advise the patient that they may have a lump for several weeks that will decrease in size over time. It is important that the patient not rub or massage the injection site and to be aware of the placement of any belts or clothing waistbands.

Anxiety (0% to 8%) has been reported during pediatric clinical trials for oral risperidone. Anxiety was associated with discontinuation in 1% of risperidone-treated pediatric patients. Agitation, blunted affect, confusion, depression, nervousness, feeling abnormal, and listlessness were also observed during clinical trials. Mania, aggression, and suicidal behaviors including suicidal ideation have been reported during postmarketing use of risperidone; however, causality to the drug has not been established.

Drowsiness (somnolence) was frequently observed in pediatric clinical trials. Most cases were mild to moderate and transient, occurring during the first 2 weeks of treatment with a median duration of 16 days. Patients experiencing persistent somnolence may benefit from a change in the dosing regimen. Sedation (12% to 63%), fatigue (18% to 31%), drooling or sialorrhea (12%), headache (12%), lethargy, and dizziness (7% to 16%) were also reported in pediatric patients receiving oral risperidone. Gait disturbance, asthenia, paresthesias, vertigo, balance disorder, disturbance in attention, dysarthria, insomnia, hypersomnia, abnormal coordination, speech disorder, depressed level of consciousness, unresponsive to stimuli, unconsciousness, sleep disorder (unspecified), head titubation, and hypoesthesia have also been observed during risperidone clinical trials. Restlessness and teeth grinding (bruxism) have been reported during adult clinical trials of the extended-release injectable suspension. Somnambulism, catatonia, and sleep apnea syndrome have been reported during postmarketing use.

Extrapyramidal symptoms (EPS) are less commonly associated with second generation antipsychotics than first generation antipsychotics; however, among the second generation antipsychotics, risperidone has the highest antidopaminergic potency and therefore carries the highest risk of EPS. In pediatric trials, the following EPS were reported: pseudoparkinsonism (6% to 28%), tremor (8% to 12%), akathisia (0% to 10%), and dystonic reaction (2% to 6%). Movement disorder and dyskinesia were also reported. In addition, reversible EPS (unspecified) of varying severity have been reported in neonates exposed to risperidone in the third trimester. Data suggests that the development of EPS is dose-related. Acute EPS usually respond to antipsychotic dose reduction, but may require additional pharmacologic treatment. Dystonia, manifesting as torticollis with or without throat tightness, difficulty swallowing or breathing, oculogyric crisis, trismus, or protrusion of the tongue, may occur in susceptible individuals during the first few days of treatment. Acute dystonia can be effectively prevented or reversed with anticholinergic medication. Risk factors for dystonia include young age and male gender, history of substance abuse, family history of dystonia, and the use of high potency antipsychotics. Pseudoparkinsonism including akinesia may occur days to months after initiation of antipsychotic therapy and is more common in elderly patients and those with cognitive deficits. Treatment of choice is not established, but dose reduction and anticholinergic medications may be helpful. Akathisia is common (one-half of all cases of EPS) and difficult to treat. It usually develops within the first 3 months of treatment and may respond to antipsychotic dose reduction or concomitant administration of a benzodiazepine and/or beta-blocker; akathisia does not respond to anticholinergic medication. If pharmacologic treatment of EPS is required, continued necessity should be periodically evaluated.

Tardive dyskinesia (TD) is associated with antipsychotic therapy and is most likely to occur during long-term use of the drugs. Manifestations of TD may include involuntary movements of the tongue, face, or neck muscles, and upper or lower extremities. It is possible that risperidone may mask the signs and symptoms of developing TD. These symptoms may emerge upon discontinuation of the drug. In general, the risk of developing TD and the likelihood that it will become irreversible appears to increase with the duration of treatment and the cumulative dose. However, TD has occasionally been reported after short periods of treatment and with low dosages, and it may also occur after discontinuation of treatment. The manifestations of TD may be permanent, even after discontinuation of the antipsychotic. Nevertheless, discontinuation of therapy should be considered if signs or symptoms of TD develop, as TD may remit, partially or completely, if the antipsychotic medication is discontinued. Routine monitoring for tardive dyskinesia (e.g., AIMS assessment) is recommended for all patients receiving chronic treatment with an antipsychotic. In clinical trials that included 1,885 children and adolescents, 2 (0.1%) patients were reported to experience TD while receiving oral risperidone; the symptoms resolved upon discontinuation of the drug. The incidence reported from premarketing clinical trials may not be reflective of the higher incidence of TD noted by practitioners in clinical practice; general estimates from studies and systematic reviews in various patient populations estimate annual incidences of persistent, emergent TD with second generation antipsychotics at 0.8% to 5.3%, with the higher incidences noted in older adults.

Increased and decreased body temperature have been reported in adults and children receiving risperidone. Antipsychotics have been reported to disrupt the body's ability to reduce core body temperature presumably through effects in the hypothalamus, and they predispose patients to hyperthermia. Patients receiving risperidone should be advised of conditions that contribute to an elevation in core body temperature (e.g., strenuous exercise, ambient temperature increase, or dehydration). A less frequently described alteration in thermoregulatory processes reported with both conventional and atypical antipsychotics is hypothermia. Thermoregulation is multi-factorial; however, the dopaminergic system appears to have a primary role, and serotonin may also have modulatory activity (5-HT2a receptors). Most cases of hypothermia associated with antipsychotics have occurred in conjunction with other potential precipitating factors such as hypothyroidism, sepsis, organic brain injury, or environmental temperature. Hypothermia appears to occur more frequently during initiation of antipsychotic therapy or after dose increases.

Antipsychotic drugs, including risperidone, can cause a potentially fatal symptom complex referred to as neuroleptic malignant syndrome (NMS). NMS is characterized by 4 main symptoms: hyperthermia, muscle rigidity, altered mental status (including delirium), and autonomic instability (irregular pulse or blood pressure, diaphoresis, cardiac dysrhythmia). Increased serum creatine phosphokinase (CPK), myoglobinuria, acute renal failure, and leukocytosis may also occur. NMS typically develops over days to weeks. Diagnosis is complicated; if NMS is suspected, immediately discontinue risperidone and any other nonessential drug. Initiate aggressive symptomatic treatment and monitoring. If a patient requires an antipsychotic after recovery from NMS, carefully consider potential reintroduction, as recurrence of NMS has been reported. Monitor those who reinitiate treatment closely. The cause of NMS is not completely understood; however, dopamine receptor blockade is one of the mechanisms by which NMS is thought to occur. A primary risk factor for developing NMS appears to be the initiation or increase in dose of an antipsychotic. High potency and depot antipsychotics carry the greatest risk. Environmental risk factors include conditions that inhibit heat dissipation such as an elevated ambient room temperature, prolonged heat exposure, the use of patient restraints, or dehydration. NMS occurs more frequently in young adults, which is most likely the result of age of first exposure rather than an age-related risk. NMS occurs more frequently in men, which is thought to be related to the higher likelihood of male versus female exposure to the causative agent. Risk factors for recurrent NMS include a personal history of NMS, increasing age, and certain medical comorbidities (e.g., electrolyte imbalances, dehydration).

Thirst and polydipsia have occurred during treatment with antipsychotics. Polydipsia may be psychogenic in nature or a result of antipsychotic-induced metabolic complications such as diabetes; therefore, careful evaluation is recommended. Hyponatremia can develop from polydipsia which can progress to water intoxication, with symptoms such as confusion, lethargy, psychosis, and in severe cases, convulsions or death. Some data suggest antipsychotic-induced hyponatremia is most likely the result of syndrome of inappropriate antidiuretic hormone (SIADH). Thirst (7%) and polydipsia have been reported during clinical trial evaluation of risperidone; SIADH and water intoxication have been reported with postmarketing use.

Seizures were reported in a small number of adult patients (0.3%) during risperidone clinical trials, with 2 cases occurring in association with hyponatremia. Use risperidone cautiously in patients with a seizure disorder.

Pain, extremity pain, chills, night sweats, sluggishness, malaise, facial edema, generalized edema, peripheral edema, pitting edema, discomfort (unspecified), and peripheral coldness have been reported during clinical trial evaluation of risperidone.

For pediatric patients, the mean increase in heart rate was 8.4 beats/minute in risperidone-treated patients vs. 6.5 beats/minute for placebo in controlled clinical trials for autism. In other pediatric populations, there were no significant changes in ECG parameters. Sinus tachycardia, bradycardia, first degree AV block, chest discomfort, chest pain (unspecified), abnormal ECG, right or left bundle-branch block, hypotension, hypertension, syncope, and AV block (unspecified) have been observed during premarketing clinical trial evaluation of risperidone. Orthostatic hypotension is more likely to occur during the initiation of therapy, and is likely the result of the potent alpha-1 adrenergic antagonist properties of the drug. Symptoms of orthostatic hypotension may include lightheadedness, sinus arrhythmia, or syncope. Careful monitoring of orthostatic vital signs is recommended in patients for whom orthostasis is a concern. During postmarketing use of risperidone, atrial fibrillation, cardiopulmonary arrest (cardiac arrest), and sudden death have been reported. Data from risperidone trials in adult and pediatric patients indicate that there are no statistically significant differences in mean changes from baseline in ECG parameters including QT, QTc, and PR intervals when risperidone is compared to placebo. Postmarketing reports indicate that QT prolongation has occurred, primarily in association with risperidone overdose. Causality to the drug has not been determined; however, one expert source considers the drug to have a conditional risk for QT prolongation and torsade de pointes (TdP) because there are reports of TdP in risperidone-treated patients who also have bradycardia, hypokalemia, hypomagnesemia, or are receiving other drugs that prolong the QT interval.

Hematologic effects that were reported during premarketing evaluation of risperidone included neutropenia, anemia, granulocytopenia, decreased hemoglobin, decreased hematocrit, and/or decreased white blood cell count (leukopenia). Agranulocytosis (severe neutropenia), thrombocytopenia, and thrombotic thrombocytopenic purpura (TTP) have been reported during postmarketing use of risperidone. Epistaxis (2% or less) was reported during adult clinical trials. It has been suggested such bleeding events may occur due to drug-induced thrombocytopenia and/or risperidone's high affinity for serotonin 5-HT2A receptors, which may reduce platelet aggregation and vasoconstrictor release for platelets in microcirculation. Patients with a history of drug-induced leukopenia or neutropenia or a history of clinically significant low white blood cell (WBC) count should be carefully monitored while receiving an antipsychotic, including regular laboratory monitoring of the complete blood count (CBC) during the first few months of therapy. Consideration should be given to discontinuing treatment if a clinically significant decline in WBC occurs in the absence of an identifiable cause. Risperidone should be discontinued in patients who develop severe neutropenia (ANC less than 1,000/mm3); follow the WBC count until recovery.

Rash was reported in 0% to 8% of risperidone-treated patients during pediatric trials. Erythema, pruritus, generalized pruritus, erythematous rash, papular rash, generalized rash, maculopapular rash, and eosinophilia have also been reported during clinical trials. Anaphylactoid reactions, angioedema, toxic epidermal necrolysis (TEN), and Stevens-Johnson syndrome (SJS) have been reported with postmarketing use. Rarely, cases of anaphylactoid reactions have been reported in patients receiving injectable risperidone after previously tolerating oral risperidone.

Skin discoloration, xerosis, atopic dermatitis, skin lesion, hyperkeratosis, seborrhea, acne vulgaris, and skin disorder (unspecified) have been reported during clinical trial evaluation of risperidone. Alopecia has been reported with postmarketing use. Unlike phenothiazines, risperidone does not have an established risk of photosensitivity. However, there is one case report of probable photosensitivity to risperidone; the patient was receiving multiple medications, but only risperidone was temporally related to the adverse reaction.

Weight gain may be significant during treatment with risperidone. Weight gain (8%) and appetite stimulation (4% to 44%) occurred more frequently with risperidone than placebo during pediatric clinical trials. Anorexia and weight loss are uncommon adverse reactions. In children and adolescents for all indications studied, the mean change in weight from baseline was +2 kg with risperidone 0.5 to 6 mg/day, and +0.6 kg with placebo. A weight gain of at least 7% from baseline occurred in 33% of pediatric patients receiving risperidone and 7% of those receiving placebo. In long-term pediatric studies, the mean change in weight in patients receiving risperidone was +5.5 kg at Week 24 and +8 kg at Week 48. Inform patients of the potential for weight gain prior to initiation of risperidone. Monitoring of weight is recommended. Evaluate weight gain periodically against expected normal growth patterns in pediatric patients.

Hyperglycemia and diabetes mellitus, in some cases extreme and associated with diabetic ketoacidosis (DKA), hyperosmolar coma, or death, have been reported in patients with or without preexisting diabetes treated with atypical antipsychotics including risperidone. Related events including increased blood glucose, glycosuria, polydipsia, and exacerbation of diabetes have also been reported during treatment with oral or injectable risperidone. Increased glycosylated hemoglobin A1C was reported during adult clinical trials for risperidone extended-release subcutaneous injectable suspension. While causal relationships and incidences have not been determined, temporal associations of risperidone therapy with the aggravation of diabetes mellitus have been reported. An elevated risk of diabetes mellitus is also present in patients with schizophrenia and is being reported with greater frequency in the general population, which makes causality difficult to assign. Atypical antipsychotics may have effects on glucose metabolism that are independent of their effect on weight gain; one study noted that patients taking atypical agents were 9% more likely to have a new diagnosis of diabetes mellitus than patients taking older therapies. Additionally, a large retrospective cohort of young Medicaid patients showed users of antipsychotics (n = 28,858; mean age: 14.5 years [age range: 6 to 24 years]) had a 3-fold increased risk for type 2 diabetes mellitus (HR = 3.03 [95% CI 1.73 to 5.32]) within the first year of follow-up (HR = 2.49 [95% CI 1.27 to 4.88]) compared to those who took other medications for the same disorders (n = 14,429). Patients with pre-existing diabetes and schizophrenia, as well as other conditions for which antipsychotics are considered the only recommended treatment were excluded. Risk increased with the cumulative dose during follow-up (p less than 0.04) and remained elevated for up to 1 year after antipsychotic discontinuation (HR = 2.57 [95% CI 1.34 to 4.91]). When restricted to pediatric patients 6 to 17 years of age, antipsychotic users had a more than 3-fold increased risk for type 2 diabetes (HR = 3.14 [95% CI 1.5 to 6.56]). Again, risk increased significantly with cumulative dose, from a HR of 2 (95% CI 0.76 to 5.3) for chlorpromazine equivalent doses less than 5 grams to an HR of 7.05 (95% CI 2.63 to 18.89) for cumulative doses of 100 grams or more (p less than 0.03). The risk was increased for use restricted to risperidone (HR = 2.2 [95% CI 1.14 to 4.26]) or atypical antipsychotics in general (HR = 2.89 [95% CI 1.64 to 5.1]). During clinical trials of children and adolescents with schizophrenia, bipolar mania, or autistic disorder, the change in fasting glucose was -1.3 mg/dL in the placebo group and +2.6 mg/dL in the risperidone 0.5 to 6 mg/day group. A change in serum glucose from less than 100 mg/dL to at least 126 mg/dL occurred in 0% of placebo-treated patients and 0.8% of risperidone-treated patients. In long-term pediatric studies, the mean change in fasting glucose in risperidone-treated patients was +5.2 mg/dL at week 24. Hypoglycemia has been reported during postmarketing use; although causality to the drug has not been established. Consider the possibility of impaired glucose tolerance in patients receiving risperidone who develop symptoms of hyperglycemia or diabetes, such as polydipsia, polyuria, polyphagia, and weakness. Consider discontinuation of risperidone therapy if symptoms are severe.

Hyperlipidemia, including hypercholesterolemia and hypertriglyceridemia, has been observed in patients receiving atypical antipsychotics. In children and adolescents with schizophrenia, bipolar mania, or autistic disorder, pooled study data indicated the following changes from baseline in fasting lipids in the risperidone 0.5 to 6 mg/day group versus the placebo group, respectively: cholesterol (-0.3, 0.3), LDL (0.5, 3.7), HDL (-1.9, 1.6), and triglycerides (-2.6, -9). The percentage of patients with changes in fasting lipids in the risperidone 0.5 to 6 mg/day group and the placebo group, respectively, were as follows: cholesterol less than 170 mg/dL to 200 mg/dL or more (3.8%, 2.4%), LDL less than 110 mg/dL to 130 mg/dL or more (0%, 0%), HDL 40 mg/dL or more to less than 40 mg/dL (10%, 0%), and triglycerides less than 150 mg/dL to 200 mg/dL or more (7.1%, 1.5%). In long-term pediatric studies, the following mean changes in fasting lipids were observed in risperidone-treated patients at Week 24: cholesterol (+2.1 mg/dL), LDL (-0.2 mg/dL), HDL (+0.4 mg/dL), and triglycerides (+6.8 mg/dL). Increased blood cholesterol and increased blood triglycerides have been reported during postmarketing use of risperidone; however, the frequencies are unknown.

Hypersalivation (0% to 10%), upper abdominal pain (13% to 16%), nausea (8% to 16%), vomiting (10% to 20%), diarrhea (7% to 8%), constipation (17%), dyspepsia (3% to 10%), xerostomia (10%), and stomach discomfort (0% to 6%) have been reported during pediatric clinical trials of oral risperidone. Fecaloma, fecal incontinence, gastritis, lip swelling, dental pain (toothache), cheilitis, and aptyalism have also been reported during clinical evaluation of risperidone. Decreased oral sensitivity and tongue movement disturbance have been reported in adult patients receiving risperidone extended-release injectable suspension during clinical trials. Intestinal GI obstruction, ileus, and dysgeusia have been reported during postmarketing use. Dysphagia and esophageal dysmotility have also been reported and occasionally have been associated with the development of aspiration of the stomach contents and aspiration pneumonitis.

Hyperprolactinemia, a response to the dopaminergic antagonism caused by risperidone, is considered a common effect of the drug. Increased levels of prolactin are associated with galactorrhea, gynecomastia, menstrual irregularity (e.g., menorrhagia), amenorrhea, or infertility (i.e., anovulation in adult females). Adverse reactions related to hyperprolactinemia may be particularly prevalent in females. Chronic hyperprolactinemia may result in loss of bone density (osteopenia) in both males and females. During clinical trials in patients 5 to 17 years of age with autism or a psychiatric disorder other than schizophrenia or bipolar disorder, 49% of risperidone-treated patients had elevated prolactin concentrations versus 2% who received placebo. Other study data in children and adolescents with bipolar disorder or schizophrenia indicated that 82% to 87% of patients receiving risperidone experienced elevated prolactin levels versus 3% to 7% of those who received placebo. In clinical trials that included 1,885 children and adolescents, galactorrhea and gynecomastia were reported in 0.8% and 2.3% of risperidone-treated patients, respectively. In addition, hypomenorrhea, oligomenorrhea, delayed menstruation, polymenorrhea, menstrual disorder (unspecified), vaginal discharge, breast enlargement, breast pain or tenderness (mastalgia), breast engorgement, and breast discharge have been reported during other clinical trial evaluation of risperidone; however, the frequencies are unknown. Benign pituitary adenomas and precocious puberty have been reported during postmarketing use of risperidone. Although the long-term effects of risperidone on growth and sexual maturation have not been fully evaluated in children and adolescents, a retrospective analysis evaluating patients 5 to 15 years of age found no statistically or clinically significant growth failure (n = 350) or delay in pubertal onset or progression (n = 222) during risperidone treatment for 11 to 12 months.

Enuresis (16%) occurred more frequently with risperidone than placebo during pediatric clinical trials. Dysuria, urinary incontinence, cystitis, and pollakiuria (increased urinary frequency) have also been reported during clinical trial evaluation of risperidone. Urinary retention and priapism have been reported during postmarketing use. Severe priapism may require surgical intervention.

Joint swelling, joint stiffness, musculoskeletal chest pain, abnormal posture, myalgia, neck pain, myasthenia, arthralgia, back pain, and rhabdomyolysis have been reported during clinical trial evaluation of oral risperidone. Musculoskeletal pain and stiffness, muscle cramps/spasms, and extremity pain have been reported in adult patients receiving risperidone extended-release injectable suspension during clinical trials.

Blurred vision was reported in 4% to 7% of pediatric patients receiving risperidone during monotherapy clinical trials. Conjunctivitis, reduced visual acuity resulting in visual impairment, conjunctival hyperemia, ocular discharge, eye rolling, blepharospasm, eyelid edema (blepharedema), eye swelling, eyelid margin crusting, increased lacrimation, photophobia, glaucoma (ocular hypertension), xerophthalmia, tinnitus, otalgia (ear pain), and acute or chronic otitis media have also been reported during clinical trial evaluations; however, the exact incidences are unknown.

Elevated hepatic enzymes have been reported during use of oral risperidone. Jaundice and pancreatitis have been reported during postmarketing use of risperidone; however, causality to the drug has not been established.

Flushing, transient ischemic attack, cerebral ischemia, cerebrovascular disorder (unspecified), and stroke have been reported during clinical trial evaluation of risperidone. Cerebrovascular events have primarily occurred in elderly patients with dementia-related psychosis receiving atypical antipsychotics.

Pulmonary embolism, dyspnea, wheezing, hyperventilation, dysphonia, and pulmonary congestion have been reported during use of risperidone. The frequencies are unknown and causality to the drug has not been established.

Pharyngolaryngeal pain (3% to 10%), naso-pharyngitis (19%), rhinitis (9%), upper respiratory tract infection (8%), cough (17%), rhinorrhea (12%), fever (16%), and nasal congestion (10%) have been reported during pediatric clinical trials for risperidone. Pneumonia, aspiration pneumonia, influenza, influenza-like illness, ear infection, viral infection, pharyngitis, tonsillitis, bronchitis, ocular infection, localized infection, cellulitis, onychomycosis, acarodermatitis, bronchopneumonia, respiratory tract infection, tracheobronchitis, sinus congestion, sinusitis, productive cough, respiratory tract congestion, rales, respiratory disorder (unspecified), and nasal edema have also been observed during clinical trial evaluation of risperidone.

The adverse effect data for use of long-acting injectable antipsychotic agents in pediatric patients are not extensive due to off-label use. Systemic adverse reactions occurring with risperidone injections in adults are generally similar to those observed during clinical trials with oral therapy. Injection site reaction (e.g., injection site pain, induration, swelling) occurred during premarketing evaluation of injectable risperidone in adults, generally at an incidence of 1% to 4%. Injection site itching, bruising (ecchymosis), erythema, inflammation, and irritation have also been reported during premarketing evaluation of the subcutaneous product. Serious injection site reactions including abscess, cellulitis, cyst, hematoma, tissue necrosis, nodule, and skin ulcer have been reported during postmarketing use of the intramuscular product. In rare instances, surgical intervention has been required.

A drug withdrawal or discontinuation syndrome has been reported during clinical trial evaluation of oral risperidone in adultand pediatric patients. A neonatal withdrawal syndrome has been reported during postmarketing use of the drug. Adverse effects such as extrapyramidal effects, agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported after delivery in neonates exposed to antipsychotics in utero during the third trimester. These effects have varied in severity ranging from self-limited to requiring neonatal intensive care unit stays and prolonged hospitalization.

The American Psychiatric Association does not recommend the maintenance use of antipsychotic medications, such as risperidone, as first-line therapy for children and adolescents with any diagnosis other than psychotic disorders. Routine use in clinical circumstances that are not endorsed by available clinical practice guidelines or FDA-approval should be questioned. Antipsychotics may be unnecessary when they are prescribed without a comprehensive assessment, accurate diagnosis, and initial trial of non-pharmacologic interventions (e.g., family-based, behavioral and environmental interventions). For some young patients, the use of an antipsychotic medication may be an appropriate choice if the clinical benefits are judged to outweigh any potential harm (e.g., weight gain, metabolic or cardiovascular adverse reactions). Antipsychotics should not be prescribed for any indication without appropriate initial evaluation and ongoing monitoring. Routine use of multiple concurrent antipsychotics is discouraged.

Risperidone is contraindicated in patients with a known hypersensitivity to risperidone or paliperidone, or to any of the excipients in the risperidone formulation. There is a risk of serious hypersensitivity reactions or anaphylaxis. Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been observed in patients treated with risperidone and in patients treated with paliperidone. Paliperidone is a metabolite of risperidone, so cross-sensitivity is likely.

Risperidone has the potential to impair cognitive and motor skills. The sedative effects of risperidone may be most evident in the initial days of treatment. Advise patients to use caution when engaging in activities requiring coordination and concentration, until they know how this drug affects their cognition. Somnolence, postural hypotension, and motor and sensory instability have also been reported with the use of antipsychotics; such effects may lead to falls and related injuries. Assess the risk of falls during treatment initiation and periodically throughout therapy in patients with diseases, conditions, or concurrent medications that could exacerbate these effects. In general, avoid use in patients who exhibit severe CNS depression. Given the primary CNS effects of risperidone, caution should be used during coadministration with other CNS depressants and alcohol. Ethanol ingestion may further impair cognitive and motor skills and patients should be advised to avoid use of alcoholic beverages. Adverse psychiatric effects, including aggression and suicidal behaviors (e.g., suicidal ideation, suicide attempt), have occurred in pediatric patients receiving risperidone. Although causality to the drug has not been established, careful monitoring for changes in mood and behavior is advisable as well as prescribing risperidone in the smallest quantity consistent with good management in order to reduce the risk of overdose.

Abrupt discontinuation of antipsychotics is generally not advisable unless required by the patient's medical condition. Abrupt cessation of second generation antipsychotics, like risperidone, can be associated with withdrawal dyskinesias and a risk of developing neuroleptic malignant syndrome. Because of risperidone's alpha-adrenergic receptor blocking effects, rebound anxiety, restlessness, sweating, tremors, abdominal pain, heart palpitations, headache, and hypertension may also occur. Patients and their caregivers should be counseled on the importance of medication adherence. If discontinuance is necessary, risperidone should be gradually tapered to minimize withdrawal effects and patients should be carefully observed for the recurrence of psychiatric symptoms. A drug withdrawal syndrome (unspecified) was reported during clinical trial evaluation of risperidone.

Tardive dyskinesia is a syndrome of potentially irreversible, involuntary, dyskinetic movements that may develop in patients treated with antipsychotics. Regular evaluation for movement disorders is recommended (e.g., AIMS, DISCUS). Factors associated with a greater susceptibility to tardive dyskinesia include female gender, white or African ethnicity, presence of a mood disorder, intellectual disability, CNS injury, prior or current akathisia, significant parkinsonism, or acute dystonic reaction. The rate of tardive dyskinesia in adults treated with a first generation antipsychotic appears to be at least 3 times that observed with second generation antipsychotics. In general, the risk of developing TD and the likelihood that it will become irreversible appears to increase with the duration of treatment and the cumulative dose. However, the syndrome can develop, although much less commonly, after relatively brief periods at low doses or may arise after drug discontinuation. Antipsychotics may suppress the signs and symptoms of tardive dyskinesia and thereby mask the underlying process; however, the syndrome may also remit partially or completely if the antipsychotic is withdrawn. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. If signs and symptoms of tardive dyskinesia appear, risperidone discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome.

Secondary to alpha-blockade, risperidone can inhibit vasoconstriction and can produce vasodilation. The resultant drop in blood pressure through decreased peripheral resistance can precipitate orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope. This effect may especially occur during the initial dose-titration period. Limiting the initial risperidone dose and titration of the dosage according to recommended schedules might minimize the risk of orthostatic hypotension and syncope. Monitoring of orthostatic vital signs should be considered in patients for whom hypotension is of concern. Orthostatic hypotension could lead to falls with the potential for fractures and other injuries. Complete a fall risk assessment upon antipsychotic initiation in patients with conditions, diseases, or taking concurrent medications that could exacerbate orthostasis and recurrently during long-term therapy in at-risk patients. Patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning, or rising slowly from a seated position. Consider dose reduction if hypotension occurs. Use with particular caution in patients with known cardiac disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, or with conditions that would predispose patients to hypotension (e.g., dehydrated state and hypovolemia). Of note, heart failure and myocardial infarction may also increase the risk of prolonging the QT interval when using risperidone. Patients should avoid sodium depletion, alcohol intake, or high ambient temperatures. Clinically significant hypotension has been observed with concomitant use of risperidone and antihypertensive medications.

Use risperidone with caution in patients with conditions that may increase the risk of QT prolongation including congenital long QT syndrome, bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, abnormally low body temperature, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation. Pooled data from controlled trials indicate there are no statistically significant differences in mean changes from baseline in ECG parameters including QT, corrected QT (QTc), and PR intervals when risperidone is compared to placebo. However, postmarketing reports of overdose indicate that QT prolongation and torsade de pointes (TdP) have occurred. Paliperidone, the active metabolite of risperidone, modestly increases the QTc interval. Causality has not been established; however, one expert source considers risperidone to have a conditional risk for QT prolongation and TdP because there are reports of TdP in risperidone-treated patients who also have bradycardia, hypokalemia, hypomagnesemia, or are receiving other drugs that prolong the QT interval.

Risperidone should be used with caution in patients with a hematological disease. Hematologic effects including leukopenia, neutropenia, and agranulocytosis have been associated with antipsychotic use. A history of drug-induced leukopenia or neutropenia or pre-existing low white blood cell (WBC) count may increase the likelihood of developing hematologic effects during treatment with an antipsychotic medication. Patients with a history of clinically significant low WBC count or drug-induced leukopenia/neutropenia should have frequent complete blood count (CBC) assessments during the first few months of treatment. Consider discontinuation of the antipsychotic if a clinically significant decline in WBC occurs in the absence of an identifiable cause. Monitor patients with clinically significant neutropenia closely for fever and infection, and institute appropriate medical intervention if necessary. Discontinue risperidone in patients with severe neutropenia (ANC less than 1,000/mm3); provide ongoing medical care and follow the WBC count until neutropenia resolves.

In clinical trials, risperidone was associated with seizures in a small number of adult patients (0.3%); two cases occurred in association with hyponatremia. Seizures have also been reported during post-marketing use. For these reasons, patients with a seizure disorder, condition that lowers seizure threshold, or uncorrected hyponatremia should be treated cautiously with risperidone. The incidence of seizures in pediatric patients is unknown.

The clearance of risperidone is reduced in patients with moderate to severe renal disease. Reduce the dosage of risperidone in patients with severe renal impairment or renal failure.

The mean free fraction of plasma risperidone is increased in patients with hepatic disease due to diminished concentrations of both albumin and alpha1-acid glycoprotein. Reduce the dosage of risperidone in patients with severe hepatic impairment.

Pediatric patients with dysphagia or who are at risk for aspiration should be closely monitored while receiving risperidone. Antipsychotics have been associated with esophageal dysmotility and aspiration of gastric contents, which may increase the incidence of aspiration pneumonia in susceptible patient populations.

Antipsychotics can cause motor and sensory instability, which may lead to falls with the potential for fractures and other injuries. A fall risk assessment should be completed when initiating an antipsychotic in patients with diseases (e.g., neurological disease), conditions, or concurrent medication use that could exacerbate motor and sensory instability. A fall risk assessment should be completed recurrently in at-risk patients on long-term antipsychotic therapy. Risperidone should be used with caution in patients with Parkinson's disease because of possible development of extrapyramidal symptoms. Patients with Parkinson's disease are thought to experience an increased sensitivity to antipsychotics manifest as confusion, obtundation, postural instability with frequent falls, extrapyramidal effects, and symptoms resembling neuroleptic malignant syndrome. Parkinson's disease is very rare in pediatric patients; when it does occur, there is usually a family history of the illness.

Atypical antipsychotics, including risperidone, have been associated with metabolic changes that may increase cardiovascular or cerebrovascular risk over time, including loss of blood glucose control, dyslipidemia, and weight gain. Use risperidone with caution in patients with pre-existing conditions such as obesity, pre-diabetes, established diabetes mellitus, or hyperlipidemia. All patients treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia (polydipsia, polyuria, polyphagia, weakness), worsening of glucose control, dyslipidemia, and weight gain. Weight gain in children and adolescents may be substantial, particularly during chronic treatment. Evaluate weight gain against expected normal growth patterns in pediatric patients. Perform fasting blood glucose testing at the beginning of treatment in patients with risk factors for diabetes mellitus (e.g., obesity, family history). Patients who develop symptoms of hyperglycemia during treatment should undergo fasting blood glucose testing. Hyperglycemia or diabetes was reported in rare instances during risperidone clinical trials. Hyperglycemia, in some cases associated with diabetic ketoacidosis or hyperosmolar hyperglycemic state (HHS) with coma or death, has been reported in patients treated with atypical antipsychotics. Hyperglycemia resolved in some cases when the antipsychotic was discontinued; however, some patients required continuation of antidiabetic agents despite discontinuation of the suspect drug. Metabolic changes in patients treated with atypical antipsychotics have also included dyslipidemias such as hypercholesterolemia and/or hypertriglyceridemia. Prior to initiating risperidone or shortly after that, obtain a fasting lipid profile. Periodic monitoring of serum lipids is recommended during long-term treatment. Inform all patients of the importance of maintaining a nutritionally balanced diet during treatment with an antipsychotic.

Antipsychotics have been reported to disrupt the body's ability to reduce core body temperature presumably through effects in the hypothalamus, and they predispose patients to hyperthermia. Patients receiving risperidone should be advised of conditions that contribute to an elevation in core body temperature (e.g., strenuous exercise, ambient temperature increase, or dehydration). A less frequently described alteration in thermoregulatory processes reported with both conventional and atypical antipsychotics is hypothermia. Thermoregulation is multi-factorial; however, the dopaminergic system appears to have a primary role, and serotonin may also have modulatory activity (5-HT2a receptors). Most cases of hypothermia associated with antipsychotics have occurred in conjunction with other potential precipitating factors such as hypothyroidism, sepsis, organic brain injury, or environmental temperature. Hypothermia appears to occur more frequently during initiation of antipsychotic therapy or after dose increases. Hypothermia may increase the risk of prolonging the QT interval when using risperidone.

Risperidone can cause hyperprolactinemia, likely due to central D2 antagonism, and is associated with higher elevations in prolactin than many other antipsychotics. Elevations in prolactin may result in endocrine abnormalities in pediatric patients, including changes in menstruation in females or breast enlargement in males. Close monitoring for adverse endocrine effects is advisable during use of risperidone in children and adolescents. In animal studies, an increase in pituitary gland, mammary gland, and pancreatic islet cell neoplasia was observed during risperidone administration. Some human breast cancers may be prolactin-dependent and therefore risperidone should be used cautiously in those who have a history of breast cancer.

Priapism has been reported during post-marketing use of risperidone. All male patients and their caregivers should be counseled on the signs and symptoms of priapism and the importance of seeking immediate medical attention if an erection lasting more than 4 hours occurs. Immediate diagnosis and treatment are essential to avoid tissue damage; severe priapism may require surgical intervention. Priapism can occur in males of any age; younger males, particularly those who have not reached puberty, may not recognize the problem or may be embarrassed to tell anyone if it occurs.

Risperidone orally disintegrating tablets (e.g., Risperdal M-Tab ODT, others) contain aspartame, a source of phenylalanine. For example, Risperdal M-Tabs contain phenylalanine in the following quantities: each 4 mg ODT contains 0.84 mg phenylalanine; each 3 mg ODT contains 0.63 mg phenylalanine; each 2 mg ODT contains 0.42 mg phenylalanine; each 1 mg ODT contains 0.28 mg phenylalanine; and each 0.5 mg ODT contains 0.14 mg phenylalanine. Caution is advised in patients with phenylketonuria.

Neonates with in utero exposure to antipsychotics in the third trimester have experienced adverse events such as extrapyramidal effects, agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder. These effects have varied in severity ranging from self-limited to requiring intensive care unit stays and prolonged hospitalization. There is one case report of agenesis of the corpus callosum in an infant exposed to risperidone in utero; however, causality to the drug has not been established.

Description: Risperidone is an atypical antipsychotic of the benzisoxazole class. Atypical antipsychotics are first-line treatment options for the management of schizophrenia and related psychotic disorders. Risperidone is approved for the treatment of schizophrenia in adolescents, bipolar disorder in pediatric patients 10 years and older, and irritability associated with autistic disorder in pediatric patients 5 years and older. Oral risperidone is used off label in pediatric patients with Tourette's syndrome, disruptive behavioral disorders, and delirium in the intensive care unit. The safety and efficacy of long-acting injectable risperidone formulations have not been established in children or adolescents for any indication. The American Academy of Neurology (AAN) practice guidelines and other publications state that risperidone is probably more likely than placebo to reduce tic severity in patients with Tourette's syndrome or chronic tic disorders; however, there is insufficient evidence to determine the efficacy of risperidone relative to other antipsychotics used to treat tics. In a comparative review of pediatric antipsychotic use, risperidone was more effective than haloperidol in reducing autistic symptoms in pervasive developmental disorders, and atypical antipsychotics (e.g., risperidone, olanzapine) were more effective than haloperidol in treating schizophrenia. Compared to many other atypical antipsychotics, risperidone is associated with a greater risk for postural hypotension, hyperprolactinemia, and extrapyramidal symptoms (EPS). However, the risk of EPS is less with risperidone than haloperidol and the risk of hyperlipidemia and weight gain is less with risperidone than olanzapine. Because of the risks associated with atypical antipsychotics, the American Academy of Child and Adolescent Psychiatry recommends a thorough pretreatment evaluation of personal and family history of diabetes, hyperlipidemia, seizures, cardiac abnormalities, and previous response or adverse reactions to atypical antipsychotics. The American Diabetes Association recommends baseline and periodic evaluation of weight, waist circumference, blood pressure, plasma glucose concentrations, and fasting lipid profile due to the potential for metabolic changes and associated cardiovascular risk. As with all antipsychotics, periodic evaluation for new or worsening tardive dyskinesia is highly recommended.

For the treatment of schizophrenia:
Oral dosage:
Children 8 to 12 years*: 0.5 mg/day PO initially. May give in divided doses to increase tolerability. Follow with gradual titration based on response and tolerability. Max: 6 mg/day PO. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In one randomized, controlled trial of pediatric patients with early-onset schizophrenia, schizoaffective disorder, or schizophreniform disorder, children 8 to 11 years received 0.5 mg/day PO on Day 1, with an increase to 1 mg/day on Day 6, 1.5 mg/day on Day 11, and 2 mg/day on Day 15 as clinically indicated; thereafter, gradual titration occurred as needed in increments of 1 mg/day up to a maximum of 6 mg/day. Children 12 years received 0.5 mg/day on Day 1, with titration up to 3 mg/day by Day 11, and titration thereafter as clinically indicated in increments of 1 mg/day up to a maximum of 6 mg/day.
Adolescents: 0.5 mg PO once daily initially. May administer in divided doses to increase tolerability. Adjust dose at intervals of at least 24 hours and in increments of 0.5 to 1 mg/day as tolerated to the recommended target dose of 3 mg/day. The effective dose range is 1 to 6 mg/day PO; however, doses above 3 mg/day do not appear to provide additional therapeutic benefits and may result in more adverse reactions. Max: 6 mg/day PO. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Responding patients should generally be maintained on their effective dose beyond the acute episode. Periodically reassess safety and efficacy during chronic use.

For the treatment of acute mania or mixed episodes associated with bipolar disorder:
Oral dosage:
Children and Adolescents 10 to 17 years: 0.5 mg PO once daily initially; may give dose in morning or evening. May administer in divided doses to increase tolerability. Adjust dose at intervals of at least 24 hours and in increments of 0.5 to 1 mg/day as tolerated to the target dose range of 1 to 2.5 mg/day PO. The effective dose range is 1 to 6 mg/day; however, doses above 2.5 mg/day do not appear to provide additional therapeutic benefits and may result in more adverse reactions. Max: 6 mg/day PO. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Although pharmacologic therapy is generally continued beyond the acute response period, long-term use of risperidone (i.e., beyond 3 weeks) for maintenance treatment or prevention of new manic episodes has not been formally evaluated.

For the treatment of irritability associated with autistic disorder:
Oral dosage:
Children and Adolescents 5 to 17 years weighing 15 to 19 kg: 0.25 mg PO once daily for at least 4 days, then may increase the dose to 0.5 mg PO once daily. May further increase the dose by 0.25 mg/day every 2 weeks or more as needed. Target dose: 0.5 mg/day. Dose range: 0.5 to 3 mg/day. Dosage may be divided in 2 doses for tolerability. Once sufficient clinical response has been achieved and maintained, consider gradually lowering the dose to achieve the optimal balance of efficacy and safety. Periodically reassess the need for continued treatment. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children and Adolescents 5 to 17 years weighing 20 kg or more: 0.5 mg PO once daily for at least 4 days, then may increase the dose to 1 mg PO once daily. May further increase the dose by 0.5 mg/day every 2 weeks or more as needed. Target dose: 1 mg/day. Dose range: 0.5 to 3 mg/day. Dosage may be divided in 2 doses for tolerability. Once sufficient clinical response has been achieved and maintained, consider gradually lowering the dose to achieve the optimal balance of efficacy and safety. Periodically reassess the need for continued treatment. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

For the treatment of moderate to severe tics associated with Tourette's syndrome* or chronic tic disorders*:
Oral dosage:
Children and Adolescents 7 to 17 years: Low initial doses are suggested (e.g., 0.25 to 0.5 mg/day PO); the usual effective dose range is 1 to 4 mg/day. Results from small randomized studies suggest the mean effective dose is approximately 2.5 mg/day. A separate study that included adolescents 14 years and older used a maximum of 6 mg/day PO; a median dose of 2.5 mg/day (range 1 to 6 mg/day) was superior to placebo. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. The American Academy of Child and Adolescent Psychiatry (AACAP) recommends atypical antipsychotics as a treatment option for patients with moderate to severe tics and in patients with tics with other comorbidities suitable for treatment with an antipsychotic. The American Academy of Neurology (AAN) practice guideline states that risperidone is probably more likely than placebo to reduce tic severity in patients with Tourette's syndrome or chronic tic disorders; however, there is insufficient evidence to determine the efficacy of risperidone relative to other antipsychotics used to treat tics.

For the treatment of moderate to severe disruptive behaviors* (e.g., aggression) associated with oppositional defiant disorder (ODD)* or other disruptive behavioral disorders (DBD)*:
NOTE: Due to the risks associated with antipsychotic use, treatment with risperidone should be reserved for patients with severe behavioral symptoms that have not improved with other pharmacologic treatments and psychosocial therapy.
Oral dosage:
Children 5 to 12 years: 0.01 mg/kg/day PO for at least 2 days is a suggested initial weight-based dose. Then, may titrate to 0.02 mg/kg/day for 5 days, and subsequently adjust weekly as clinically indicated by 0.02 mg/kg/day. Max: 0.06 mg/kg/day PO. In one study, body weight was used to determine dosage. Those weighing less than 50 kg received 0.25 mg/day PO initially; if weight was 50 kg or more, 0.5 mg/day PO was given initially. Thereafter, the dose was increased gradually by 0.25 mg for patients less than 50 kg or 0.5 mg for those 50 kg or more to a maximum daily dose of 0.75 mg/day PO for patients less than 50 kg or 1.5 mg/day PO for those 50 kg or more. The mean risperidone dosage was approximately 0.02 mg/kg/day. Doses have varied among studies, with mean risperidone doses ranging from 0.98 to 1.7 mg/day at the end of the studies. In a double-blind, placebo-controlled study of 110 children with a disruptive behavior disorder (DBD) and subaverage IQ, the decline in symptom ratings was 47.3% in the risperidone group vs. 20.9% in the placebo group. At study end, 25% of children in the placebo group were rated by the investigator as improved to some degree compared to 77% of children in the risperidone group. Some data have demonstrated sustained long-term improvement. In a 9-week randomized trial of 168 children (age: 6 to 12 years) with attention-deficit hyperactivity disorder (ADHD) and a DBD (ODD or conduct disorder), the addition of risperidone to a psychostimulant and parent training showed significant improvements in measures of aggression and serious behavioral problems compared to those receiving stimulant and parent training only. Risperidone therapy (mean dose: 1.7 +/- 0.75 mg/day) was added at weeks 4 to 6 only if there was a need for improvement. For children weighing less than 25 kg, risperidone 0.5 to 2.5 mg/day was given; for children 25 kg or more, doses ranged from 0.5 to 3.5 mg/day. In a post-hoc analysis of children with ADHD and a DBD, risperidone-treated children had clinically and statistically significant reductions in disruptive behavior and hyperactivity subscale scores compared to placebo, regardless of concomitant stimulant use. However, further study is needed on the use of risperidone in the treatment of ADHD. Efficacy in children with ADHD alone or in long term settings has not been established, and the drug is not without adverse reactions. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Adolescents: In one study, body weight was used to determine dosage. Those weighing less than 50 kg received 0.25 mg/day PO initially; if weight 50 kg or more, 0.5 mg/day PO was given initially. Thereafter, the dose was increased gradually by 0.25 mg for patients less than 50 kg or 0.5 mg for those 50 kg or more to a maximum daily dose of 0.75 mg/day PO for patients less than 50 kg or 1.5 mg/day PO for those 50 kg or more. The mean risperidone dosage was approximately 0.02 mg/kg/day. Doses have varied among studies. In a comprehensive review, the mean risperidone dose ranged from 0.98 to 1.5 mg/day at study end for all studies evaluated. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

For the treatment of delirium* in the pediatric intensive care unit (PICU):
Oral dosage:
Children and Adolescents: Limited data available, particularly in young children. Maintenance doses ranging from 0.2 to 2 mg/day PO have been reported as efficacious with no adverse reactions noted (n = 30; age range: 4 months to 17 years). One small case series (n = 11; age range: 4 months to 16 years) used a loading dose of 0.1 to 0.2 mg PO. Begin at the lower end of the dosing range for younger, smaller patients. A mode individual dose of 0.5 mg has been reported in a small case series of older children and adolescents (n = 6; age range: 5 to 15 years). Some experts have suggested 0.5 to 2.5 mg/day PO given in 2 to 4 divided doses for patients 5 to 16 years of age. Max dosing is based on weight: less than 20 kg = 1 mg/day; 20 to 45 kg = 2.5 mg/day; more than 45 kg = 3 mg/day. In a review of data from 110 seriously-ill patients with delirium who were treated with atypical antipsychotics, a limited number of the same or lower doses were used as needed to control persistent symptoms and a routine daily dose was established based on the total amount needed to gain control of symptoms. Of those receiving risperidone (n = 13; mean age: 8.6 years; range: 1 to 16 years), a mean starting dose of 0.6 mg/day (range: 0.25 to 1 mg/day), mean ending dose of 0.7 mg/day (range: 0.25 to 2 mg/day), mean maximum dose of 1 mg/day (range: 0.25 to 2 mg/day), and average dose of 1.3 mg/day (range: 0.375 to 4 mg/day) was used. Antipsychotic was discontinued as soon as possible; mean length of therapy was 17.5 days (range: 2 to 54 days). Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Children
1 to 4 years: Safety and efficacy have not been established.
5 to 9 years: 3 mg/day PO for autistic disorder; 0.06 mg/kg/day PO has been suggested in developmental disability with severe disruptive behaviors; safety and efficacy of injectable administration are not established.
10 to 12 years: 6 mg/day PO for bipolar I disorder; 3 mg/day PO for autistic disorder; 0.06 mg/kg/day PO has been suggested in developmental disability with severe disruptive behaviors; safety and efficacy of injectable administration are not established.
-Adolescents
6 mg/day PO for schizophrenia or bipolar I disorder; 3 mg/day PO for autistic disorder; 0.06 mg/kg/day PO has been suggested for the treatment of tics or severe behavior disorders associated with Tourette's or ADHD; safety and efficacy of injectable administration are not established.

Patients with Hepatic Impairment Dosing
Specific guidelines for pediatric patients are not available. In adult patients with a Child Pugh score of 10 to 15, the recommended initial starting dose is 0.5 mg PO twice daily; titrate in increments of 0.5 mg or less. For doses more than 1.5 mg PO twice daily, titrate in weekly intervals.

Patients with Renal Impairment Dosing
Specific guidelines for pediatric patients are not available. In adult patients with a CrCl less than 30 mL/minute, the recommended initial starting dose is 0.5 mg PO twice daily; titrate in increments of 0.5 mg or less. For doses more than 1.5 mg PO twice daily, titrate in weekly intervals.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Although the exact mechanism of action of antipsychotics is unknown, it has been proposed that central blockade of dopamine D-2 in the mesolimbic pathway targets the positive symptoms of schizophrenia (e.g., hallucinations, delusions). Optimal blockade is within the range of 65% to 75% of D-2 receptors, leading to effectiveness while preserving safety. The receptor binding profile of many conventional antipsychotics (e.g., haloperidol, fluphenazine) involves a preferred affinity for D-2 receptors over serotonin receptors, whereas the receptor binding profile of some atypical antipsychotics (such as risperidone) involves a high affinity for 5-HT2A receptor blockade. It has been theorized that antagonism of serotonin in the prefrontal cortex leads to an increase in dopamine release thereby creating the potential for improvement in the negative symptoms (e.g., blunted affect, social withdrawal) and cognitive deficits observed in schizophrenia. It should be noted that modulation of serotonin receptors alone does not have an antipsychotic effect. Antipsychotic drugs appear to have neuroplastic effects, including synaptic plasticity (remodeling of synapses and development of new neuron connections) and neurogenesis (new neuron development), which may partially explain the delay in some of the therapeutic effects of antipsychotics.

Dopamine blockade by antipsychotics in the nigrostriatal pathway of the brain is thought to cause extrapyramidal symptoms (EPS) such as pseudoparkinsonism, dystonic reactions, and akathisia. It has been suggested that blockade of 5-HT2A receptors leads to increased output of dopaminergic neurons into the striatum, decreasing the likelihood of extrapyramidal reactions. Dopamine receptor blockade in the tuberoinfundibular tract results in prolactin release, with the potential for hyperprolactinemia and its adverse clinical effects. The likelihood of developing hyperprolactinemia is generally related to the potency of the individual antipsychotic to block D-2 receptors. Thus, based on its D-2 receptor binding profile, risperidone has a higher propensity for causing prolactin elevations than most other atypical antipsychotics.

Risperidone exhibits strong antagonist activity at alpha-1 receptors, which likely contributes to adverse cardiovascular effects such as orthostatic hypotension, which may be associated with dizziness, syncope, and reflex tachycardia. The alpha-1 blocking effect is also thought to be responsible for priapism, a potentially severe adverse reaction which has occurred during post-marketing use of the drug. High affinity at H-1 histamine receptors has also been demonstrated, which partially accounts for adverse effects such as sedation and weight gain. Risperidone has low to moderate affinity for serotonin 5-HT1A, 5-HT1C, and 5-HT1D receptors and a weak affinity for dopamine D-1 receptors and haloperidol-sensitive sigma binding sites. There is no affinity for cholinergic or beta-adrenergic receptors.

Pharmacokinetics: Risperidone is administered orally or parenterally as a long-acting intramuscular injection (Risperdal Consta) or subcutaneous injection (Perseris). Risperidone is rapidly distributed with a Vd of 1 to 2 L/kg. Plasma protein binding to albumin and alpha1-acid glycoprotein is 90% (risperidone) and 77% (active metabolite). Risperidone is primarily metabolized via hydroxylation to 9-hydroxyrisperidone by CYP2D6 with minor contribution by CYP3A4. N-dealkylation is a minor metabolic route. Risperidone and the principal active metabolite, 9-hydroxyrisperidone, have similar pharmacologic activity; consequently, clinical effect is a result from combined concentrations of risperidone and 9-hydroxyrisperidone. Risperidone and its active metabolites are eliminated primarily via the urine (70%), and to a lesser extent, via feces (14%). Combined pharmacokinetics of risperidone and 9-hydroxyrisperidone are similar in extensive and poor metabolizers of CYP2D6, with an overall mean elimination half-life of approximately 20 hours in adults after oral dosing.

Affected cytochrome P450 isoenzymes and drug transporters: CYP2D6, CYP3A4, P-gp
Risperidone is primarily metabolized by CYP2D6 to an equally active metabolite, 9-hydroxyrisperidone. Risperidone is also metabolized by CYP3A4, but to a lesser extent. Extensive metabolizers of CYP2D6 convert risperidone rapidly into 9-hydroxyrisperidone, while poor metabolizers convert it much more slowly. Although extensive metabolizers have lower risperidone and higher 9-hydroxyrisperidone concentrations than poor metabolizers, the pharmacokinetics of both risperidone and 9-hydroxyrisperidone combined are similar in both populations after single and multiple doses. Drugs that are inhibitors of CYP2D6 interfere with the conversion of risperidone to 9-hydroxyrisperidone, potentially increasing plasma concentrations of risperidone and decreasing plasma concentrations of 9-hydroxyrisperidone. Enzyme inducers may decrease the combined plasma concentrations of risperidone and 9-hydroxyrisperidone, which may result in decreased therapeutic efficacy. Risperidone is also a weak inhibitor of CYP2D6 in vitro; however, it is not expected to significantly affect the pharmacokinetics of CYP2D6 substrates. In vitro studies have demonstrated that drugs metabolized by 1A1, 1A2, 2C9, 2C19, and 3A4 are only weak inhibitors of risperidone metabolism. Risperidone has a strong affinity for P-glycoprotein (P-gp).


-Route-Specific Pharmacokinetics
Oral Route
Risperidone is well-absorbed, with an absolute bioavailability of 70%. The orally disintegrating tablets and solution are bioequivalent to the tablets. Peak plasma concentrations of risperidone occur 1 hour after administration; peak concentrations of 9-hydroxyrisperidone occur at 3 hours in extensive metabolizers and 17 hours in poor metabolizers. Steady-state concentrations of risperidone are reached in 1 day in extensive metabolizers and in an estimated 5 days in poor metabolizers. Steady-state concentrations of 9-hydroxyrisperidone are reached in 5 to 6 days in extensive metabolizers. Food does not affect the rate or extent of absorption.

Intramuscular Route
After a single dose of long-acting risperidone injection (Risperdal Consta), there is a small initial release of the drug (less than 1% of the dose), followed by a lag time of 3 weeks. The main release of the drug starts at 3 weeks, is maintained from 4 to 6 weeks, and subsides by 7 weeks after intramuscular injection. Steady-state plasma concentrations are attained after 4 injections (given every 2 weeks). Deltoid and gluteal administration are bioequivalent and interchangeable. Apparent half-life of risperidone plus 9-hydroxyrisperidone is 3 to 6 days after intramuscular depot injection and is associated with a monoexponential decline in plasma concentrations. This half-life is related to the erosion of the microspheres and subsequent absorption of risperidone. No accumulation is seen during long-term use; the elimination phase is complete approximately 7 to 8 weeks after the last injection.

Subcutaneous Route
After subcutaneous injection, the extended-release injectable suspension (Perseris) forms a depot that provides sustained plasma concentrations of risperidone over the monthly dosing interval. There are 2 absorption peaks, the first 4 to 6 hours post-injection and the second 10 to 14 days post-injection. These peaks represent the initial release of the drug during the depot formation process and the slow release of risperidone from the depot. Both peaks are of similar magnitude. For both 9-hydroxyrisperidone and total active moiety, the median Tmax of the first peak ranges from 4 to 48 hours and the second peak ranges from 7 to 11 days. Risperidone plasma concentrations have a Tmax of 4 to 6 hours and approach steady state concentration after the first subcutaneous injection. Steady-state plasma concentrations are attained by the end of the second injection for risperidone, 9-hydroxyrisperidone, and total active moiety and are maintained for 4 weeks after the last injection. Total active moiety concentrations reach clinically relevant concentrations after the first injection without use of a loading dose or supplemental oral risperidone. Based on average plasma concentrations of risperidone and total active moiety, 90 mg of the subcutaneous depot injection corresponds to 3 mg/day of oral risperidone and 120 mg of the subcutaneous depot injection corresponds to 4 mg/day of oral risperidone.


-Special Populations
Pediatrics
Children and Adolescents
The pharmacokinetics of risperidone and 9-hydroxyrisperidone in pediatric patients are similar to those in adults after correcting for differences in body weight.

Hepatic Impairment
The mean free fraction of risperidone in plasma is increased by about 35% in patients with hepatic disease, due to diminished concentration of both albumin and alpha1-acid glycoprotein.

Renal Impairment
The clearance of risperidone and its active metabolite is decreased by 60% in patients with moderate to severe renal impairment (CrCl 15 to 59 mL/minute) compared to healthy subjects.