Risperidone

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.

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.

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]