Paliperidone

426.48

426.48

1806241-263-5

DTXSID7049059

Crystals from 2-propanol

N05AX13|N - Nervous system

29349990

82.2

2.2

white to brown

1.45±0.1 g/cm3(Predicted)

158-160°C

612.3±65.0 °C(Predicted)

9℃

1.692

Practically insoluble in water;DMSO: soluble 2mg/mL, clear (warmed)

room temp

1.3X10-15 mm Hg at 25 deg C (est)

Henry's Law constant = 7.92X10-21 atm-cu m/mol at 25 °C (est)

pKa = 8.76 (est)

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

Crystals from isopropanol /Paliperidone palmitate/

III

6.1

UN28116.1/PG3

3

25-39/23/24/25-23/24/25-11

45-36/37-16

UV1164720

T,F

Stable under recommended storage conditions.

P301 + P310

H301

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.

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

|Danger|H301 (100%): Toxic if swallowed [Danger Acute toxicity, oral]|P264, P270, P301+P310, P321, P330, P405, and P501|Aggregated GHS information provided by 50 companies from 6 notifications to the ECHA C&L Inventory.

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.

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide. Special protective equipment for firefighters: Wear self contained breathing apparatus for fire fighting if necessary.

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.

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.

The possibility of obtundation, seizures, or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis.

Liver test abnormalities occur in up to 1% of patients receiving paliperidone, but similar rates have been reported with placebo therapy and with comparator agents. The ALT elevations are usually mild, transient and often resolve even without dose modification or drug discontinuation. There have been no published reports of clinically apparent liver injury with symptoms or jaundice attributed solely to paliperidone therapy, even with the long acting parenteral formulations.|In preregistration controlled trials, ALT elevations arose in 2% of patients receiving lumateperone compared to less than 1% of placebo controls. The elevations, however, were usually mild, transient and typically resolved without dose modification or drug discontinuation. In preregistration trials, there were no instances of severe hepatic adverse events, discontinuations because of liver related events or episodes of clinically apparent liver injury with jaundice. Since its approval and more widescale use, there have been no published reports of liver injury with symptoms or jaundice attributed to lumateperone therapy, but clinical experience with its use has been limited.

Concurrent administration of carbamazepine and paliperidone decreased mean steady-state peak plasma concentrations and area under the concentration-time curves (AUCs) of paliperidone by approximately 37%. The manufacturer recommends reevaluating the dosage of paliperidone upon initiation of carbamazepine and increasing it, if necessary, based on clinical assessment. Upon discontinuance of carbamazepine, the dosage of paliperidone should also be reevaluated and decreased, if necessary.|Potential pharmacologic interaction (possible disruption of body temperature regulation); use paliperidone with caution in patients concurrently receiving drugs with anticholinergic activity.|Potential pharmacologic interaction /when used with othe CNS agents/ (additive CNS effects).Use with caution.|Potential pharmacologic interaction (additive CNS effects). Avoid alcoholic beverages during paliperidone therapy.|For more Interactions (Complete) data for Paliperidone (10 total), please visit the HSDB record page.

An increased incidence of adverse cerebrovascular events (cerebrovascular accidents and transient ischemic attacks), including fatalities, has been observed in geriatric patients with dementia-related psychosis treated with certain atypical antipsychotic agents (aripiprazole, olanzapine, risperidone) in placebo-controlled studies. The manufacturer states that paliperidone is not approved for the treatment of patients with dementia-related psychosis.|Patients with parkinsonian syndrome or dementia with Lewy bodies who receive antipsychotics reportedly have an increased sensitivity to antipsychotic agents. Clinical manifestations of this increased sensitivity have been reported to include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and features consistent with NMS.|Paliperidone has not been adequately evaluated in patients with a recent history of myocardial infarction or unstable cardiovascular disease to date and patients with these conditions were excluded from premarketing clinical trials. Because of the risk of orthostatic hypotension associated with paliperidone, the manufacturer states that the drug should be used with caution in patients with known cardiovascular disease.|Paliperidone causes a modest increase in the corrected QT (QTc) interval. The risk of torsades de pointes in association with drugs that prolong the QTc interval may be increased in patients with bradycardia, hypokalemia, or hypomagnesemia; patients receiving other drugs that prolong the QTc interval; and in those with congenital prolongation of the QT interval. Therefore, the manufacturer states that paliperidone should be avoided in patients concurrently receiving other drugs known to prolong the QTc interval, patients with congenital long QT syndrome, and those with a history of cardiac arrhythmias.

The plasma protein binding of racemic paliperidone is 74%.

Paliperidone's production and use as an antipsychotic(1) may result in its release to the environment through various waste streams(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1.0X10+5(SRC), determined from a structure estimation method(2), indicates that paliperidone is expected to be immobile in soil(SRC). The estimated pKa of paliperidone 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 paliperidone from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 7.9X10-21 atm-cu m/mole(SRC), using a fragment constant estimation method(5). The cation form of paliperidone will not volatilize(SRC). Paliperidone is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.3X10-15 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 1.0X10+5(SRC), determined from a structure estimation method(2), indicates that paliperidone is expected to adsorb to suspended solids and sediment(SRC). An estimated pKa of 8.76(3) indicates paliperidone 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 7.9X10-21 atm-cu m/mole(SRC), developed using a fragment constant estimation method(5). According to a classification scheme(6), an estimated BCF of 9(SRC), from an estimated log Kow of 1.95(2) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Paliperidone 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), paliperidone, which has an estimated vapor pressure of 1.3X10-15 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 paliperidone may be removed from the air by wet or dry deposition(SRC). Paliperidone 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).

Paliperidone is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(1). Paliperidone does not contain chromophores that absorb at wavelengths >290 nm(1) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC).

An estimated BCF of 9 was calculated in fish for paliperidone(SRC), using an estimated log Kow of 1.95(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of paliperidone can be estimated to be 1.0X10+5(SRC). According to a classification scheme(2), this estimated Koc value suggests that paliperidone is expected to be immobile in soil. The estimated pKa of paliperidone is 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).

An estimated pKa of 8.76(1) indicates paliperidone will partially exist in the cation form at pH values of 5 to 9 and, therefore, volatilization from water and moist soil surfaces of the ion form is not expected to be an important fate process(SRC). The Henry's Law constant for paliperidone is estimated as 7.9X10-21 atm-cu m/mole(SRC) using a fragment constant estimation method(2). This Henry's Law constant indicates that the neutral form of paliperidone is expected to be essentially nonvolatile from water surfaces(3). Paliperidone is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.3X10-15 mm Hg(SRC), determined from a fragment constant method(4).

While data specific to paliperidone were not located(2013, SRC), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2).

Occupational exposure to paliperidone may occur through inhalation of dust and dermal contact with this compound at workplaces where paliperidone is produced or used. Use data indicate that the general population may be exposed to paliperidone via medical administration of this compound for its use as an antipsychotic. (SRC)

For the treatment of schizophrenia.|Trevicta, a 3 monthly injection, is indicated for the maintenance treatment of schizophrenia in adult patients who are clinically stable on 1 monthly paliperidone palmitate injectable product.|Xeplion is indicated for maintenance treatment of schizophrenia in adult patients stabilised with paliperidone or risperidone.In selected adult patients with schizophrenia and previous responsiveness to oral paliperidone or risperidone, Xeplion may be used without prior stabilisation with oral treatment if psychotic symptoms are mild to moderate and a long-acting injectable treatment is needed.|Invega is indicated for the treatment of schizophrenia in adults and in adolescents 15 years and older.Invega is indicated for the treatment of schizoaffective disorder in adults.|Schizoaffective disorder, Schizophrenia|Paliperidone Janssen-Cilag International is indicated for maintenance treatment of schizophrenia in adult patients stabilised with paliperidone or risperidone.In selected adult patients with schizophrenia and previous responsiveness to oral paliperidone or risperidone, Paliperidone Janssen-Cilag International may be used without prior stabilisation with oral treatment if psychotic symptoms are mild to moderate and a long acting injectable treatment is needed.

Paliperidone is a second generation (atypical) antipsychotic agent that is available in both oral and long acting parenteral forms and is used in the treatment of schizophrenia and schizoaffective disorder. Paliperidone is associated with a low rate of serum aminotransferase elevations during therapy, but has not been linked to instances of clinically apparent acute liver injury.|Lumateperone is a second generation (atypical) antipsychotic agent that is used in the treatment of schizophrenia. Lumateperone is associated with a low rate of serum aminotransferase elevations during therapy, but has not been linked to instances of clinically apparent acute liver injury.

Antipsychotic Agents

Antipsychotic Agent|Invega (paliperidone) Extended-Release Tablets are indicated for the treatment of schizophrenia. The efficacy of Invega in schizophrenia was established in three 6-week trials in adults and one 6-week trial in adolescents, as well as one maintenance trial in adults. /Included in US product label/|Invega (paliperidone) Extended-Release Tablets are indicated for the treatment of schizoaffective disorder as monotherapy and an adjunct to mood stabilizers and/or antidepressant therap. The efficacy of Invega in schizoaffective disorder was established in two 6-week trials in adults. /Included in US product label/|Invega Sustenna (paliperidone palmitate) is indicated for the treatment of schizophrenia. Efficacy was established in four short-term studies and one longer-term study in adults. /Paliperidone palmitate; Included in US product label/

/BOXED WARNING/ WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS. Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Invega (paliperidone) Extended-Release Tablets is not approved for the treatment of patients with dementia-related psychosis.|/BOXED WARNING/ WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS: Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Invega Sustenna is not approved for use in patients with dementia-related psychosis. /Paliperidone palmitate/|Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been observed in patients receiving risperidone or paliperidone. Paliperidone is therefore contraindicated in patients with a known hypersensitivity to paliperidone, risperidone, or any ingredient in the paliperidone formulation.|An increased incidence of adverse cerebrovascular events (cerebrovascular accidents and transient ischemic attacks), including fatalities, has been observed in geriatric patients with dementia-related psychosis treated with certain atypical antipsychotic agents (aripiprazole, olanzapine, risperidone) in placebo-controlled studies. The manufacturer states that paliperidone is not approved for the treatment of patients with dementia-related psychosis.|For more Drug Warnings (Complete) data for Paliperidone (32 total), please visit the HSDB record page.

Paliperidone is an atypical antipsychotic developed by Janssen Pharmaceutica. Chemically, paliperidone is primary active metabolite of the older antipsychotic risperidone (paliperidone is 9-hydroxyrisperidone). The mechanism of action is unknown but it is likely to act via a similar pathway to risperidone.

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. (See all compounds classified as Antipsychotic Agents.)|Compounds and drugs that bind to and inhibit or block the activation of DOPAMINE D2 RECEPTORS. (See all compounds classified as Dopamine D2 Receptor Antagonists.)|Drugs that bind to but do not activate SEROTONIN 5-HT2 RECEPTORS, thereby blocking the actions of SEROTONIN or SEROTONIN 5-HT2 RECEPTOR AGONISTS. Included under this heading are antagonists for one or more specific 5-HT2 receptor subtypes. (See all compounds classified as Serotonin 5-HT2 Receptor Antagonists.)

The absolute oral bioavailability of paliperidone following paliperidone administration is 28%.|One week following administration of a single oral dose of 1 mg immediate-release 14C-paliperidone to 5 healthy volunteers, 59% (range 51% – 67%) of the dose was excreted unchanged into urine, 32% (26% – 41%) of the dose was recovered as metabolites, and 6% – 12% of the dose was not recovered.|487 L|The absolute oral bioavailability of paliperidone following Invega administration is 28%. Administration of a 12 mg paliperidone extended-release tablet to healthy ambulatory subjects with a standard high-fat/high-caloric meal gave mean Cmax and AUC values of paliperidone that were increased by 60% and 54%, respectively, compared with administration under fasting conditions. Clinical trials establishing the safety and efficacy of Invega were carried out in subjects without regard to the timing of meals. While Invega can be taken without regard to food, the presence of food at the time of Invega administration may increase exposure to paliperidone. Based on a population analysis, the apparent volume of distribution of paliperidone is 487 L. The plasma protein binding of racemic paliperidone is 74%.|Following a single dose, the plasma concentrations of paliperidone gradually rise to reach peak plasma concentration (Cmax) approximately 24 hours after dosing. The pharmacokinetics of paliperidone following Invega administration are dose-proportional within the available dose range. The terminal elimination half-life of paliperidone is approximately 23 hours. Steady-state concentrations of paliperidone are attained within 4-5 days of dosing with Invega in most subjects. The mean steady-state peak:trough ratio for an Invega dose of 9 mg was 1.7 with a range of 1.2-3.1.|One week following administration of a single oral dose of 1 mg immediate-release (14)C-paliperidone to 5 healthy volunteers, 59% (range 51% - 67%) of the dose was excreted unchanged into urine, 32% (26% - 41%) of the dose was recovered as metabolites, and 6% - 12% of the dose was not recovered. Approximately 80% of the administered radioactivity was recovered in urine and 11% in the feces.|Paliperidone is excreted in human breast milk.|For more Absorption, Distribution and Excretion (Complete) data for Paliperidone (7 total), please visit the HSDB record page.

Although in vitro studies suggested a role for CYP2D6 and CYP3A4 in the metabolism of paliperidone, in vivo results indicate that these isozymes play a limited role in the overall elimination of paliperidone. Four primary metabolic pathways have been identified in vivo, none of which could be shown to account for more than 10% of the dose: dealkylation, hydroxylation, dehydrogenation, and benzisoxazole scission. Paliperidone does not undergo extensive metabolism and a significant portion of its metabolism occurs in the kidneys.|Four primary metabolic pathways have been identified in vivo, none of which could be shown to account for more than 10% of the dose: dealkylation, hydroxylation, dehydrogenation, and benzisoxazole scission.|Although in vitro studies suggested a role for CYP2D6 and CYP3A4 in the metabolism of paliperidone, in vivo results indicate that these isozymes play a limited role in the overall elimination of paliperidone.|Paliperidone is a known human metabolite of risperidone.

The terminal elimination half-life of paliperidone is approximately 23 hours.|The median apparent half-life of paliperidone following Invega Sustenna single-dose administration over the dose range of 39 mg - 234 mg ranged from 25 days - 49 days. /Paliperidone palmitate/

Paliperidone is the major active metabolite of risperidone. The mechanism of action of paliperidone, as with other drugs having efficacy in schizophrenia, is unknown, but it has been proposed that the drug's therapeutic activity in schizophrenia is mediated through a combination of central dopamine Type 2 (D2) and serotonin Type 2 (5HT2A) receptor antagonism.|The exact mechanism of paliperidone's antipsychotic action, like that of other antipsychotic agents, has not been fully elucidated, but may involve antagonism of central dopamine type 2 (D2) and serotonin type 2 (5-hydroxytryptamine [5-HT2A]) receptors.1 39 41 Antagonism at a1- and a2-adrenergic and histamine (H1) receptors may contribute to other therapeutic and adverse effects observed with the drug.1 2 39 Paliperidone possesses no affinity for cholinergic muscarinic and beta1- and beta2-adrenergic receptors.|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.

There is no specific antidote to paliperidone, therefore, appropriate supportive measures should be instituted and close medical supervision and monitoring should continue until the patient recovers. Consideration should be given to the extended-release nature of the product when assessing treatment needs and recovery. Multiple drug involvement should also be considered. In case of acute overdose, 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, including continuous electrocardiographic monitoring for possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide, and quinidine carry a theoretical hazard of additive QT-prolonging effects when administered in patients with an acute overdose of paliperidone. Similarly the alpha-blocking properties of bretylium might be additive to those of paliperidone, resulting in problematic hypotension. Hypotension and circulatory collapse should be treated with appropriate measures, such as intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should not be used, since beta stimulation may worsen hypotension in the setting of paliperidone-induced alpha blockade). In cases of severe extrapyramidal symptoms, anticholinergic medication should be administered.|Maintain an open airway and assist ventilation if necessary. Administer supplemental oxygen. Treat coma, seizures, hypotension, and hyperthermia if they occur. Monitor vital signs ECG for at least 6 hours and admit the patient for at least 24 hours if there are signs of significant intoxication. Children with antipsychotic intoxication should be evaluated for possible intentional abuse. There is no specific antidote. /For/ dystonic reactions give diphenhydramine ... or benztropine ... . QRS interval prolongation: treat quinidine-like cardiotoxic effects with bicarbonate ... . Hypotension from /risperidone/ probably involves vasodilation caused by alpha-1 receptor blockade. Treat with iv fluids and, if needed a vasoconstrictor such as norepinephrine or phenylephrine. Theoretically, drugs with beta-2 activity (eg, epinephrine, isoproterenol) may worsen hypotension. QT prolongation and torsade may respond to magnesium infusion or overdrive pacing. Administer activated charcoal orally if conditions are appropriate. Gastric lavage is not necessary after small to moderate ingestions if activated charcoal can be given promptly. Owing to extensive tissue distribution, these drugs are not effectively removed by hemodialysis or hemoperfusion. Repeat-dose activated charcoal has not been evaluated. /Antipsychotic drugs/|/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/SIGNS AND SYMPTOMS/ While experience with paliperidone overdose is limited, among the few cases of overdose reported in pre-marketing trials, the highest estimated ingestion of Invega was 405 mg. Observed signs and symptoms included extrapyramidal symptoms and gait unsteadiness. Other potential signs and symptoms include those resulting from an exaggeration of paliperidone's known pharmacological effects, i.e., drowsiness and somnolence, tachycardia and hypotension, and QT prolongation. Torsade de pointes and ventricular fibrillation have been reported in a patient in the setting of overdose.|/SIGNS AND SYMPTOMS/ Hyperglycemia and diabetes mellitus, sometimes severe and associated with ketoacidosis, hyperosmolar coma, or death, have been reported in patients treated with all atypical antipsychotic agents. These cases were mainly seen in postmarketing clinical use and epidemiologic studies, not in clinical trials, and there have been few reports of hyperglycemia or diabetes mellitus in paliperidone-treated patients to date. While confounding factors such as an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population make it difficult to establish with certainty the relationship between use of agents in this drug class and glucose abnormalities, epidemiologic studies (which did not include paliperidone) suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with atypical antipsychotic agents. It remains to be determined whether paliperidone also is associated with this increased risk.|/SIGNS AND SYMPTOMS/ Esophageal dysmotility and aspiration have been associated with the use of antipsychotic agents. Aspiration pneumonia is a common cause of morbidity and mortality in geriatric patients, particularly in those with advanced Alzheimer's dementia. Paliperidone is not approved for the treatment of patients with dementia-related psychosis and should be used with caution in patients at risk for aspiration pneumonia.|/CASE REPORTS/ The case of a 49-year-old woman with paranoid schizophrenia who developed orofacial dyskinesia some 4 months after the commencement of paliperidone long-acting injection /is reported/.|For more Human Toxicity Excerpts (Complete) data for Paliperidone (8 total), please visit the HSDB record page.

3-(2-(4-(6-fluoro-3-(1,2-benzisoxazolyl))-1-piperidinyl)ethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido(1,2-a)pyrimidin-4-one

Table: Paliperidone Palmitate [Table#8122]|Table: Paliperidone Preparations [Table#8123]

Two liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) methods are described, one for the quantitative determination of risperidone and the enantiomers of its active metabolite 9-hydroxyrisperidone (paliperidone) in human plasma and the other for the determination of the enantiomers of 9-hydroxyrisperidone in human urine. The plasma method is based on solid-phase extraction of 200 microl of sample on a mixed-mode sorbent, followed by separation on a cellulose-based LC column with a 13.5-min mobile phase gradient of hexane, isopropanol and ethanol. After post-column addition of 10 mM ammonium acetate in ethanol/water, detection takes place by ion-spray tandem mass spectrometry in the positive ion mode. Method validation results show that the method is sufficiently selective towards the enantiomers of 7-hydroxyrisperidone and capable of quantifying the analytes with good precision and accuracy in the concentration range of 0.2-100 ng/ml. An accelerated (run time of 4.3 min) and equally valid method for the enantiomers of 9-hydroxyrisperidone alone in plasma is obtained by increasing the mobile phase flow-rate from 1.0 to 2.0 ml/min and slightly adapting the gradient conditions. The urine method is based on the same solid-phase extraction and chromatographic approach as the accelerated plasma method. Using 100 microl of sample, (+)- and (-)-9-hydroxyrisperidone can be quantified in the concentration range 1-2000 ng/ml. The accelerated method for plasma and the method for urine can be used only when paliperidone is administered instead of risperidone, as there is insufficient separation of the 9-hydroxy enantiomers from the 7-hydroxy enantiomers, the latter ones being present only after risperidone administration. PMID:18571483|LC/MS/MS determination with risperidone in plasma.

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