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Pharmaceuticals -> Nervous system -> Antipsychotics

Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals -> Antipsychotics

Pharmaceuticals

White to slightly beige powder

Crystals from dimethylformamide + propanol

Soluble in methylene chloride; sparingly soluble in alcohol; practically insoluble in water

Practically insoluble in water, freely soluble in methylene chloride and soluble in methanol and 0.1N hydrochloric acid

Breast Feeding; Lactation; Milk, Human; Antipsychotic Agents

FDA approved drugs -> Active ingredient

EMA approved medicines: Human medicine

FDA approved drugs -> Active ingredient

Pharmaceuticals

Medicines for psychotic disorders

170 °C

170 °C

205.5 Ų [M+H]+ [CCS Type: TW; Method: Major Mix IMS/Tof Calibration Kit (Waters)]

205.77 Ų [M+H]+

Danger

H301 (99.3%): Toxic if swallowed [Danger Acute toxicity, oral]

P203, P261, P264, P270, P271, P273, P280, P301+P316, P304+P340, P316, P318, P321, P330, P391, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 146 reports by companies from 18 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including risperidone, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

Risperdal Tablets should be stored at controlled room temperature 15 deg - 25 °C (59 deg -77 °F). Protect from light and moisture. Risperdal 1 mg/mL Oral Solution should be stored at controlled room temperature 15 deg - 25 °C (59 deg - 77 °F). Protect from light and freezing. Risperdal M-TAB Orally Disintegrating Tablets should be stored at controlled room temperature 15 deg - 25 °C (59 deg - 77 °F).

Keep container tightly closed in a dry and well-ventilated place. Keep in a dry place.

The entire dose pack should be stored in the refrigerator (36 deg - 46 dg F; 2 deg - 8 °C) and protected from light. If refrigeration is unavailable, Risperdal Consta can be stored at temperatures not exceeding 77 °F (25 °C) for no more than 7 days prior to administration. Do not expose unrefrigerated product to temperatures above 77 °F (25 °C).

Personal precautions: Wear respiratory protection. Avoid dust formation. Avoid breathing vapours, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal.

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.

Avoid contact with skin, eyes and clothing. Wash hands before breaks and immediately after handling the product.

Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed. Normal measures for preventive fire protection.

Respiratory protection: Where risk assessment shows air-purifying respirators are appropriate use a full-face particle respirator type N99 (US) or type P2 (EN 143) respirator cartridges as a backup to engineering controls. If the respirator is the sole means of protection, use a full-face supplied air respirator. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU). Hand protection: Handle with gloves. Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands. Full contact Material: Nitrile rubber (Minimum layer thickness: 0.11 mm Break through time: 480 min). Splash contact Material: Nitrile rubber (Minimum layer thickness: 0.11 mm Break through time: 480 min). Eye protection: Face shield and safety glasses Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU). Skin and body protection: Complete suit protecting against chemicals, The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.

In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation and ventilation. Gastric lavage (after intubation, if patient is unconscious) and administration of activated charcoal together with a laxative should be considered. The possibility of obtundation, seizures, or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide, and quinidine carry a theoretical hazard of QT-prolonging effects that might be additive to those of risperidone. Similarly, it is reasonable to expect that the alpha-blocking properties of bretylium might be additive to those of risperidone, resulting in problematic hypotension. There is no specific antidote to Risperidone. (L1712)

Given the primary CNS effects of risperidone, caution should be used when Risperdal is taken in combination with other centrally-acting drugs and alcohol.

Risperdal may antagonize the effects of levodopa and dopamine agonists.

When Risperdal is co-administered with enzyme inducers (e.g., carbamazepine), the dose of Risperdal should be increased up to double the patient's usual dose. It may be necessary to decrease the Risperdal dose when enzyme inducers such as carbamazepine are discontinued [see Drug Interactions (7.1)]. Similar effect may be expected with co-administration of Risperdal with other enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital).

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

For more Interactions (Complete) data for RISPERIDONE (10 total), please visit the HSDB record page.

Liver test abnormalities may occur in up to 30% of patients on long term therapy with risperidone, usually arising within the first 8 weeks of treatment. The ALT elevations are usually mild, transient and may resolve even with continuation of medication. Instances of more marked ALT and alkaline phosphatase elevations, with or without symptoms and with or without jaundice, have also been reported. The onset of injury typically occurs within a few days of starting risperidone and resolves rapidly with stopping. Instances of acute liver injury with jaundice arising several months and even years after starting risperidone have also been reported. The pattern of serum enzyme elevations is typically cholestatic, but cases with hepatocellular and mixed patterns have also been described. Immunoallergic manifestations (rash, fever, eosinophilia) are rare; a case of autoimmune hepatitis apparently triggered by risperidone therapy has been published, but most cases do not have autoimmune features.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1.3X10+6(SRC), determined from a structure estimation method(2), indicates that risperidone is expected to be immobile in soil(SRC). The estimated pKa of risperidone is 8.76(3), indicating that this compound will exist partially in cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization of neutral risperidone from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 2.2X10-16 atm-cu m/mole(SRC), using a fragment constant estimation method(5). The cation form of risperidone will not volatilize(SRC). Risperidone is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 4.6X10-11 mm Hg at 25 °C(SRC), determined from a fragment constant method(6). Biodegradation data in soil were not available(SRC, 2013).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 1.3X10+6(SRC), determined from a structure estimation method(2), indicates that risperidone is expected to adsorb to suspended solids and sediment(SRC). An estimated pKa of 8.76(3) indicates risperidone will partially exist in the cation form at pH values of 5 to 9 and, therefore, volatilization from water surfaces of the ion form is not expected to be an important fate process(SRC). Volatilization of the neutral form from water surfaces is not expected(4) based upon an estimated Henry's Law constant of 2.2X10-16 atm-cu m/mole(SRC), developed using a fragment constant estimation method(5). According to a classification scheme(6), an estimated BCF of 93(SRC), from an estimated log Kow of 3.49(7) and a regression-derived equation(8), suggests the potential for bioconcentration in aquatic organisms is moderate(SRC). Risperidone is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(4). Biodegradation data in water were not available(SRC, 2013).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), risperidone, which has an estimated vapor pressure of 4.6X10-11 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase risperidone may be removed from the air by wet or dry deposition(SRC). Risperidone does not contain chromophores that absorb at wavelengths >290 nm(3) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC).

Patients receiving risperidone may experience significant weight changes, metabolic changes, and sedation. Risperidone may produce extrapyramidal symptoms (EPS), including acute dystonia, akathisia, tardive dyskinesia (TD), and parkinsonism. Acute/early EPS can occur at the beginning of treatment or when the dose is adjusted. Late-onset EPS (tardive dyskinesia) typically results from chronic treatment. Akathisia is a feeling of restlessness and may manifest as the patient pacing. Acute dystonia includes muscle spasms that result in abnormal postures and typically affect the head and neck. Parkinsonian features include skeletal muscle rigidity (often described as "cogwheel rigidity"), tremor, shuffling gait, and bradykinesia. Movements of the limbs, torso, neck, and head (commonly involving the tongue and lips) characterize tardive dyskinesia. This may also appear as facial grimacing or oculogyric crisis. EPS is thought to be caused by D2 blockade in the nigrostriatal pathway. Since acute EPS symptoms often improve after discontinuing the medication, these adverse effects are a significant cause of noncompliance with treatment.

Signs and Symptoms of Overdose

Blockade of dopaminergic D2 receptors in the limbic system alleviates positive symptoms of schizophrenia such as hallucinations, delusions, and erratic behavior and speech. Blockade of serotonergic 5-HT₂ receptors in the mesocortical tract, causes an excess of dopamine and an increase in dopamine transmission, resulting in an increase in dopamine transmission and an elimination of core negative symptoms. Dopamine receptors in the nigrostriatal pathway are not affected by risperidone and extrapyramidal effects are avoided. Like other 5-HT₂ antagonists, risperidone also binds at alpha(1)-adrenergic receptors and, to a lesser extent, at histamine H1 and alpha(2)-adrenergic receptors.

Using a structure estimation method based on molecular connectivity indices(1), the Koc of risperidone can be estimated to be 1.3X10+6(SRC). According to a classification scheme(2), this estimated Koc value suggests that risperidone is expected to be immobile in soil. The pKa of risperidone is estimated as 8.76(3), indicating that this compound will partially exist in cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Reported log Kd values were 2.8 to 3.8(5).

/HUMAN EXPOSURE STUDIES/ The aim of this study was to evaluate the role of the main compound risperidone and its active 9-hydroxy metabolite on elevating prolactin levels. Twenty patients with psychotic disorders, on therapy with risperidone, were studied. All patients had been receiving risperidone for at least 2.5 months, and the median daily dose of risperidone was 3 mg (range 1-10). Morning serum samples for prolactin were analyzed and investigated in relation to the serum concentrations of risperidone and 9-hydroxyrisperidone. Elevated prolactin levels were found in 17 (85%) of the patients. Levels of prolactin were positively correlated to the 9-hydroxyrisperidone serum concentration (r(s) = 0.48, p = 0.03) and to the daily dose of risperidone (r(s) = 0.51, p = 0.03), but did not correlate to the risperidone serum concentration. The present results suggest that 9-hydroxyrisperidone and not risperidone is the main contributor to the increased serum levels of prolactin observed in many risperidone-treated patients.

/HUMAN EXPOSURE STUDIES/ Sixty-seven outpatients with schizophrenia receiving stable doses of risperidone or haloperidol were evaluated for akathisia and other extrapyramidal side effects. Subjective cognitive dysfunction was comprehensively assessed using the Frankfurt Complaint Questionnaire (FCQ). The severity of subjective cognitive deficits was compared between the groups with and without akathisia using analysis of covariance with relevant variables as covariates. The akathisia group (n = 25) scored significantly higher on the total FCQ score than the non-akathisia group (n = 42) (P < 0.05). In phenomenological subscale scores, the akathisia group had significantly higher scores on various subscales, i.e. 'anxiety', 'disorder of selective attention', 'deterioration of discrimination', 'perceptual disorder' and 'disorder of coping responses' than the non-akathisia group (P < 0.05). These results suggest that akathisia is significantly associated with a variety of subjective cognitive-perceptual deficits. Early therapeutic interventions for akathisia should be performed considering its significant association with the subjective cognitive dysfunction and the impairment of coping responses.

/HUMAN EXPOSURE STUDIES/ Prolactin elevation has been proposed as a risk factor for low bone density and potentially osteoporosis in patients on long-term treatment with prolactin-elevating antipsychotics. /The/ objective was to study the acute effects of prolactin elevation on serum markers of bone formation and resorption in patients treated with risperidone. Thirty participants meeting Diagnostic and Statistical Manual of Mental Disorders fourth edition criteria for schizophrenia, major depressive disorder with psychotic features, or bipolar disorder with psychosis were enrolled. At baseline, subjects were antipsychotic free. Subjects were evaluated before and after 4 weeks of risperidone treatment. Assessments included symptom ratings along with testosterone, estradiol, prolactin, osteocalcin (marker of bone formation), and n-telopeptide crosslinks (NTx marker of bone resorption). Primary analysis examined the impact of risperidone treatment on change in the bone markers and hormone levels from pre to post treatment. Prolactin levels significantly increased from 12.1 +or - 1.9 ng/ml to 65.7 + or - 12.2 ng/mL after treatment (p < 0.001). NTx markers of bone resorption significantly decreased from 18.31 + or - 1.49 nM bone collagen equivalent (BCE) before treatment to 15.50 + or - 1.22 nM BCE after treatment in the study sample as a whole (p < 0.05). A trend was observed indicating that NTx may increase in individuals who have the greatest increases in prolactin after treatment r = 0.33, p = 0.07). These findings suggest that prolactin elevation is associated with changes in bone physiology very early in the course of treatment with risperidone. Bone resorption decreased in many subjects but higher levels of bone resorption occurred in patients with the greatest increases in prolactin. This may have important implications for prolactin monitoring or the periodic assessment of osteoporosis-related outcomes in patients requiring extended treatment.

/HUMAN EXPOSURE STUDIES/ Twenty-five children (aged 5-15 years) with pervasive developmental disorders were genotyped for CYP2D6 polymorphisms. Serum prolactin, risperidone, and 9-hydroxyrisperidone were assessed at baseline and after 8 weeks of risperidone treatment (mean dosage, 0.06 +/- 0.03 mg/kg/d). After 24 weeks of treatment, prolactin was measured in a subsample of 15 children. Adverse effects were evaluated using a clinician-rated survey. Mean +/- SD prolactin levels increased from 7.8 +/- 8.0 ng/mL at baseline to 33.2 +/- 12.8 ng/mL at week 8 (P < 0.001), with a slight decrease to 28.8 +/- 13.6 ng/mL at week 24. At week 8, serum prolactin level was positively correlated with dose per kilogram (r = 0.648, P < 0.001), number of functional CYP2D6 genes (J = 2.117, P = 0.034), and serum 9-hydroxyrisperidone concentration (r = 0.664, P = 0.001) and was negatively correlated with the risperidone/9-hydroxyrisperidone ratio (r = -0.571, P = 0.004) but not with risperidone concentration (r = -0.243, P = 0.264) nor age (r = 0.072, P = 0.733). Prolactin elevation was not associated with adverse effects. Low-to-intermediate doses of risperidone induced a 4-fold prolactin increase in children without a clear development of tolerance up to 6 months. CYP2D6 ultrarapid metabolism may be a risk factor for more pronounced prolactin elevation.

For more Human Toxicity Excerpts (Complete) data for RISPERIDONE (28 total), please visit the HSDB record page.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including risperidone, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

N05AX08

N - Nervous system

QN - Nervous system

N05AX08

The primary action of risperidone is to decrease dopaminergic and serotonergic pathway activity in the brain, therefore decreasing symptoms of schizophrenia and mood disorders. Risperidone has a high binding affinity for serotonergic 5-HT2A receptors when compared to dopaminergic D2 receptors in the brain. Risperidone binds to D2 receptors with a lower affinity than first-generation antipsychotic drugs, which bind with very high affinity. A reduction in extrapyramidal symptoms with risperidone, when compared to its predecessors, is likely a result of its moderate affinity for dopaminergic D2 receptors.

Though its precise mechanism of action is not fully understood, current focus is on the ability of risperidone to inhibit the D2 dopaminergic receptors and 5-HT2A serotonergic receptors in the brain. Schizophrenia is thought to result from an excess of dopaminergic D2 and serotonergic 5-HT2A activity, resulting in overactivity of central mesolimbic pathways and mesocortical pathways, respectively. D2 dopaminergic receptors are transiently inhibited by risperidone, reducing dopaminergic neurotransmission, therefore decreasing positive symptoms of schizophrenia, such as delusions and hallucinations. Risperidone binds transiently and with loose affinity to the dopaminergic D2 receptor, with an ideal receptor occupancy of 60-70% for optimal effect. Rapid dissociation of risperidone from the D2 receptors contributes to decreased risk of extrapyramidal symptoms (EPS), which occur with permanent and high occupancy blockade of D2 dopaminergic receptors. Low-affinity binding and rapid dissociation from the D2 receptor distinguish risperidone from the traditional antipsychotic drugs. A higher occupancy rate of D2 receptors is said to increase the risk of extrapyramidal symptoms and is therefore to be avoided. Increased serotonergic mesocortical activity in schizophrenia results in negative symptoms, such as depression and decreased motivation. The high-affinity binding of risperidone to 5-HT2A receptors leads to a decrease in serotonergic activity. In addition, 5-HT2A receptor blockade results in decreased risk of extrapyramidal symptoms, likely by increasing dopamine release from the frontal cortex, and not the nigrostriatal tract. Dopamine level is therefore not completely inhibited. Through the above mechanisms, both serotonergic and D2 blockade by risperidone are thought to synergistically work to decrease the risk of extrapyramidal symptoms. Risperidone has also been said to be an antagonist of alpha-1 (α1), alpha-2 (α2), and histamine (H1) receptors. Blockade of these receptors is thought to improve symptoms of schizophrenia, however the exact mechanism of action on these receptors is not fully understood at this time.

Risperidone has high affinity for several receptors, including serotonin receptors (5-HT 2A/2C), D2 dopamine receptors and alpha1 and H1 receptors. It has no appreciable activity at M1 receptors. Its primary metabolite (9-hydroxyrisperidone) is nearly equipotent compared with the parent compound at D2 and 5-HT 2A receptors.

The exact mechanism of antipsychotic action of risperidone has not been fully elucidated but, like that of clozapine, appears to be more complex than that of most other antipsychotic agents and may involve antagonism of central type 2 serotonergic (5-HT2) receptors and central dopamine D2 receptors.

Risperidone is an atypical antipsychotic drug that is widely prescribed to young patients with different psychotic disorders. The long-term effects of this antipsychotic agent on neuronal receptors in developing brain remain unclear and require further investigation. In this study, we examined the effects of long-term treatment of risperidone on two serotonin receptor subtypes in brain regions of juvenile rat. Levels of 5-HT(1A) and 5-HT(2A) receptors in forebrain regions of juvenile rats were quantified after 3 weeks of treatment with three different doses of risperidone (0.3, 1.0 and 3.0mg/kg). Findings were compared to previously reported changes in 5-HT receptors after risperidone treatment (3.0mg/kg) in adult rat brain. The three doses of risperidone selectively and dose-dependently increased levels of 5-HT(1A) receptors in medial-prefrontal and dorsolateral-frontal cortices of juvenile animals. The higher doses (1.0 and 3.0mg/kg) of risperidone also increased 5-HT(1A) receptor binding in hippocampal CA(1) region of juvenile but not adult rats. In contrast, the three doses of risperidone significantly reduced 5-HT(2A) labeling in medial-prefrontal and dorsolateral-frontal cortices in juvenile as well as in adult animals in an equipotent fashion. 5-HT(1A) and 5-HT(2A) receptors in other forebrain regions were not altered by repeated risperidone treatment. These findings indicate that there are differential effects of risperidone on 5-HT(1A) and 5-HT(2A) receptors in juvenile animals, and that the 5-HT system in developing animals is more sensitive than adults to the long-term effects of risperidone.

The main class of atypical antipsychotic drugs (APDs) in current use includes the protypical atypical APD, clozapine, as well as aripiprazole, asenapine, iloperidone, lurasidone, olanzapine, quetiapine, risperidone, and ziprasidone. At clinically effective doses, these agents produce extensive blockade of serotonin (5-HT)(2A) receptors, direct or indirect stimulation of 5-HT(1A) receptors, and to a lesser extent, reduction in dopamine (DA) D(2) receptor-mediated neurotransmission. This contrasts with typical APDs, for example haloperidol and perphenazine, which are mainly DA D(2/)D(3) receptor antagonists and have weaker, if any, potency as 5-HT(2A) receptor antagonists. Some, but not all, atypical APDs are also effective 5-HT(2C) receptor inverse agonists or neutral antagonists, 5-HT(6) or 5-HT(7) receptor antagonists. This diverse action on 5-HT receptors may contribute to significant differences in efficacy and tolerability among the atypical APDs. There is considerable preclinical and some clinical evidence that effects on 5-HT receptors contribute to the low risk of producing extrapyramidal side effects, which is the defining characteristic of an atypical APD, the lack of elevation in plasma prolactin levels (with risperidone and 9-hydroxyrisperidone being exceptions), antipsychotic action, and ability to improve some domains of cognition in patients with schizophrenia. The serotonergic actions of the atypical APDs, especially 5-HT(2A) receptor antagonism, are particularly important to the differential effects of typical and atypical APDs to overcome the effects of acute or subchronic administration of N-methyl-d-aspartate (NMDA) receptor antagonists, such as phencyclidine, ketamine, and dizocipline (MK-801). 5-HT(1A) receptor stimulation and 5-HT(6) and 5-HT(7) receptor antagonism may contribute to beneficial effects of these agents on cognition. In particular, 5-HT(7) receptor antagonism may be the basis for the pro-cognitive effects of the atypical APD, amisulpride, a D(2)/D(3) receptor antagonist, which has no effect on other 5-HT receptor. 5-HT(2C) receptor antagonism appears to contribute to the weight gain produced by some atypical APDs and may also affect cognition and psychosis via its influence on cortical and limbic dopaminergic activity.

Paliperidone is an active metabolite of the second-generation atypical antipsychotic, risperidone recently approved for the treatment of schizophrenia and schizoaffective disorder. Because paliperidone differs from risperidone by only a single hydroxyl group, questions have been raised as to whether there are significant differences in the effects elicited between these two drugs. /The researchers/ compared the relative efficacies of paliperidone versus risperidone to regulate several cellular signalling pathways coupled to four selected GPCR targets that are important for either therapeutic or adverse effects: human dopamine D2 , human serotonin 2A receptor subtype (5-HT2A ), human serotonin 2C receptor subtype and human histamine H1 receptors. Whereas the relative efficacies of paliperidone and risperidone were the same for some responses, significant differences were found for several receptor-signalling systems, with paliperidone having greater or less relative efficacy than risperidone depending upon the receptor-response pair. Interestingly, for 5-HT2A -mediated recruitment of beta-arrestin, 5-HT2A -mediated sensitization of ERK, and dopamine D2 -mediated sensitization of adenylyl cyclase signalling, both paliperidone and risperidone behaved as agonists. These results suggest that the single hydroxyl group of paliperidone promotes receptor conformations that can differ from those of risperidone leading to differences in the spectrum of regulation of cellular signal transduction cascades. Such differences in signalling at the cellular level could lead to differences between paliperidone and risperidone in therapeutic efficacy or in the generation of adverse effects.

3 hours in extensive metabolizers Up to 20 hours in poor metabolizers

The apparent half-life of risperidone plus 9-hydroxyrisperidone following Risperdal Consta administration is 3 to 6 days, and is associated with a monoexponential decline in plasma concentrations. This half-life of 3-6 days is related to the erosion of the microspheres and subsequent absorption of risperidone.

The apparent half-life of risperidone was 3 hours (CV=30%) in extensive metabolizers and 20 hours (CV=40%) in poor metabolizers. The apparent half-life of 9-hydroxyrisperidone was about 21 hours (CV=20%) in extensive metabolizers and 30 hours (CV=25%) in poor metabolizers. The pharmacokinetics of risperidone and 9-hydroxyrisperidone combined, after single and multiple doses, were similar in extensive and poor metabolizers, with an overall mean elimination half-life of about 20 hours.

Extensively metabolized by hepatic cytochrome P450 2D6 isozyme to 9-hydroxyrisperidone (i.e. [paliperidone]), which has approximately the same receptor binding affinity as risperidone. Hydroxylation is dependent on debrisoquine 4-hydroxylase and metabolism is sensitive to genetic polymorphisms in debrisoquine 4-hydroxylase. Risperidone also undergoes N-dealkylation to a lesser extent.

Risperidone is extensively metabolized in the liver. The main metabolic pathway is through hydroxylation of risperidone to 9-hydroxyrisperidone by the enzyme, CYP 2D6. A minor metabolic pathway is through N-dealkylation. The main metabolite, 9-hydroxyrisperidone, has similar pharmacological activity as risperidone. Consequently, the clinical effect of the drug results from the combined concentrations of risperidone plus 9-hydroxyrisperidone. CYP 2D6, also called debrisoquin hydroxylase, is the enzyme responsible for metabolism of many neuroleptics, antidepressants, antiarrhythmics, and other drugs. CYP 2D6 is subject to genetic polymorphism (about 6%-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 CYP 2D6 metabolizers convert risperidone rapidly into 9-hydroxyrisperidone, whereas poor CYP 2D6 metabolizers convert it much more slowly. Although extensive metabolizers have lower risperidone and higher 9-hydroxyrisperidone concentrations than poor metabolizers, the pharmacokinetics of risperidone and 9-hydroxyrisperidone combined, after single and multiple doses, are similar in extensive and poor metabolizers.

Risperidone has known human metabolites that include Paliperidone, 3-ethyl-2,9-dimethyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one, 6-Fluoro-3-(4-piperidinyl)-1,2-benzisoxazole, 3-[2-[4-(6-fluoro-2-hydroxy-1,2-benzoxazol-2-ium-3-yl)piperidin-1-yl]ethyl]-2,9-dimethyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one, and 9-Hydroxy-risperidone.

Extensively metabolized by hepatic cytochrome P450 2D6 isozyme to 9-hydroxyrisperidone, which has approximately the same receptor binding affinity as risperidone. Hydroxylation is dependent on debrisoquine 4-hydroxylase and metabolism is sensitive to genetic polymorphisms in debrisoquine 4-hydroxylase. Risperidone also undergoes N-dealkylation to a lesser extent. Route of Elimination: Risperidone is extensively metabolized in the liver.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. Half Life: 20-24 hours

L6UH7ZF8HC

RISPERIDONE

Established Pharmacologic Class [EPC] - Atypical Antipsychotic

Risperidone is an Atypical Antipsychotic.

RISPERIDONE

Atypical Antipsychotic [EPC]

Drugs that bind to but do not activate serotonin receptors, thereby blocking the actions of serotonin or SEROTONIN RECEPTOR AGONISTS.

Agents that control agitated psychotic behavior, alleviate acute psychotic states, reduce psychotic symptoms, and exert a quieting effect. They are used in SCHIZOPHRENIA; senile dementia; transient psychosis following surgery; or MYOCARDIAL INFARCTION; etc. These drugs are often referred to as neuroleptics alluding to the tendency to produce neurological side effects, but not all antipsychotics are likely to produce such effects. Many of these drugs may also be effective against nausea, emesis, and pruritus.

Drugs that bind to but do not activate DOPAMINE RECEPTORS, thereby blocking the actions of dopamine or exogenous agonists. Many drugs used in the treatment of psychotic disorders (ANTIPSYCHOTIC AGENTS) are dopamine antagonists, although their therapeutic effects may be due to long-term adjustments of the brain rather than to the acute effects of blocking dopamine receptors. Dopamine antagonists have been used for several other clinical purposes including as ANTIEMETICS, in the treatment of Tourette syndrome, and for hiccup. Dopamine receptor blockade is associated with NEUROLEPTIC MALIGNANT SYNDROME.

Well absorbed. The absolute oral bioavailability of risperidone is 70% (CV=25%). The relative oral bioavailability of risperidone from a tablet is 94% (CV=10%) when compared to a solution.

Risperidone is extensively metabolized in the liver. In healthy elderly subjects, renal clearance of both risperidone and 9-hydroxyrisperidone was decreased, and elimination half-lives are prolonged compared to young healthy subjects.

The volume of distribution of risperidone is approximately 1 to 2 L/kg.

Risperidone is cleared by the kidneys. Clearance is decreased in the elderly and those with a creatinine clearance (ClCr) between 15-59 mL/min, in whom clearance is decreased by approximately 60%.

Risperidone is well absorbed. The absolute oral bioavailability of risperidone is 70% (CV=25%). The relative oral bioavailability of risperidone from a tablet is 94% (CV=10%) when compared to a solution.

Risperidone is rapidly distributed. The volume of distribution is 1-2 L/kg. In plasma, risperidone is bound to albumin and a1-acid glycoprotein. The plasma protein binding of risperidone is 90%, and that of its major metabolite, 9-hydroxyrisperidone, is 77%. Neither risperidone nor 9-hydroxyrisperidone displaces each other from plasma binding sites. High therapeutic concentrations of sulfamethazine (100 ug/mL), warfarin (10 ug/mL), and carbamazepine (10 ug/mL) caused only a slight increase in the free fraction of risperidone at 10 ng/mL and 9-hydroxyrisperidone at 50 ng/mL, changes of unknown clinical significance.

Antipsychotic Agents; Dopamine Antagonists; Serotonin Antagonists

MEDICATION

Use (kg; approx.) in Germany (2009): >100

For the treatment of schizophrenia in adults and in adolescents, ages 13 to 17, and for the short-term treatment of manic or mixed episodes of bipolar I disorder in children and adolescents ages 10 to 17. May also be used to manage symptoms of inappropriate behavior due to aggression and/or psychosis in patients with severe dementia.

3-[2-[4-[(E)-(2,4-difluorophenyl)(hydroxyimino)methyl]piperidin-1-yl]ethyl]-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one; 3-[2-[4-[(Z)-(2,4-difluorophenyl)(hydroxyimino)methyl]piperidin-1-yl]ethyl]-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one; (9RS)-3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl]-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one; 3-[2-[4-(5-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl]-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one; (6RS)-3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl]-2,6-dimethyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one; 2-[2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-3-yl]ethyl 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine-1-carboxylate; 3-[2-[4-(2,4-difluorobenzoyl)piperidin-1-yl]ethyl]-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one; 3-[2-[4-[4-fluoro-2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine-1-yl]benzoyl]piperidin-1-yl]ethyl]-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one

A Friedel-Crafts condensation of 1-acetylpiperidone-4-carbonyl chloride and 2,4-difluorobenzene, followed by hydrolysis of the N-acetyl group yields 4-(2,4-difluorobenzoyl)piperidone and the benzoyl carbonyl is converted to the oxime. With alkali, the fluorine atom in the 2-position is displaced through ring closure to form the isoxazole moiety. The secondary amine of the piperidine ring is alkylated with 3-(2-chloroethyl)pyridol[1,2-a]pyrimidin-4-one to yield the product.

Preparation: L. E. J. Kennis, J. Vandenberk, European Patent Office 196132; eidem, United States of America patent 4804663 (1986, 1989 both to Janssen)

Table: Risperidone Preparations [Table#7275]

Table: Risperidone Preparations [Table#7276]