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PALIPERIDONE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Paliperidone, an atypical antipsychotic agent, is the major active metabolite of risperidone. While the mechanism of action is unknown, its proposed therapeutic activity is antagonism of both the central dopamine Type 2 (D(2)) and serotonin Type 2 (5HT(2A)) receptors.

Specific Substances

    1) Paliperidone palmitate
    2) 9-Hydroxyrisperidone
    3) CAS 144598-75-4
    1.2.1) MOLECULAR FORMULA
    1) PALIPERIDONE: C23-H27-F-N4-O3 (Prod Info INVEGA(R) extended-release oral tablets, 2009)
    2) PALIPERIDONE PALMITATE: C39-H57-F-N4-O4 (Prod Info INVEGA(R) SUSTENNA(TM) injectable extended-release suspension , 2009)

Available Forms Sources

    A) FORMS
    1) Paliperidone is available as 1.5 mg, 3 mg, 6 mg, and 9 mg extended-release tablets (Prod Info INVEGA(R) extended-release oral tablets, 2009).
    2) Paliperidone is also available as 39 mg, 78 mg, 117 mg, 156 mg, and 234 mg of paliperidone palmitate in prefilled syringes for intramuscular injection (Prod Info INVEGA(R) SUSTENNA(TM) injectable extended-release suspension , 2009).
    B) USES
    1) Paliperidone is indicated for the acute and maintenance therapy of schizophrenia. It is also used to treat schizoaffective disorder acutely as monotherapy and as adjunct therapy to antidepressants and/or mood stabilizers (Prod Info INVEGA(R) extended-release oral tablets, 2009; Prod Info INVEGA(R) SUSTENNA(TM) injectable extended-release suspension , 2009).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Paliperidone is indicated for the acute and maintenance therapy of schizophrenia. It is also used to treat schizoaffective disorder acutely as monotherapy and as adjunct therapy to antidepressants and/or mood stabilizers.
    B) PHARMACOLOGY: Paliperidone is the major active metabolite of risperidone. Although the specific mechanism of action of paliperidone is unknown, its proposed therapeutic activity is antagonism of both the central dopamine Type 2 (D(2)) and serotonin Type 2 (5HT(2A)) receptors. It also has antagonistic effects on the alpha-1 adrenergic, alpha-2 adrenergic, and H1 histaminergic receptors; however, the degree of affinity is unclear.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: Weight gain, constipation, dizziness, somnolence, tachycardia, orthostatic hypotension, and extrapyramidal symptoms (ie, dystonia, dyskinesia, akathisia).
    E) WITH POISONING/EXPOSURE
    1) Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses. Drowsiness/lethargy, tachycardia, dystonia, agitation/irritability, tremor, hypertension, hypotension, confusion, dizziness/vertigo, and muscle rigidity have been reported following paliperidone overdose. Severe toxicity following overdose has not been reported.
    0.2.20) REPRODUCTIVE
    A) Third-trimester antipsychotic drug exposure has been associated with extrapyramidal and/or withdrawal symptoms in neonates. In animal studies, there were no fetal abnormalities following administration of paliperidone, up to 8 times the maximum recommended human dose, to pregnant rats and rabbits during organogenesis. However, there was an increase in pup deaths when risperidone, the parent compound of paliperidone, was given to rats at oral doses less than the maximum recommended human dose.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, human carcinogenicity studies with paliperidone have not been conducted.

Laboratory Monitoring

    A) Monitor vital signs and mental status.
    B) Monitor fluid and electrolyte status in patients with significant vomiting and/or diarrhea.
    C) Monitor CBC.
    D) Institute continuous cardiac monitoring and obtain serial ECGs to evaluate for evidence of QT prolongation.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Management will primarily be symptomatic and supportive. Manage mild hypotension with IV fluids.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Manage hypotension with IV fluids and pressors if needed (norepinephrine is preferred). Manage severe extrapyramidal symptoms with anticholinergics and/or benzodiazepines. Treat neuroleptic malignant syndrome with benzodiazepines, as well as cooling and supportive measures; consider bromocriptine and dantrolene in severe cases.
    C) DECONTAMINATION
    1) PREHOSPITAL: Activated charcoal is not recommended due to the potential for somnolence and dystonic reaction.
    2) HOSPITAL: Consider activated charcoal in a patient with a recent, substantial overdose who is alert or in whom airway is protected.
    D) AIRWAY MANAGEMENT
    1) Insure adequate ventilation and perform endotracheal intubation early in patients with serious cardiac toxicity or significant CNS depression.
    E) ANTIDOTE
    1) None
    F) HYPOTENSIVE EPISODES
    1) Treat hypotension with intravenous fluids, add vasopressors if unresponsive to fluids. Norepinephrine is preferred; the manufacturer recommends avoidance of epinephrine and dopamine since beta stimulation may worsen hypotension in the setting of paliperidone-induced alpha blockade.
    G) NEUROLEPTIC MALIGNANT SYNDROME
    1) Oral bromocriptine, benzodiazepines or oral or IV dantrolene in conjunction with cooling and other supportive measures.
    H) ENHANCED ELIMINATION
    1) Hemodialysis and hemoperfusion are UNLIKELY to be of value because of the high degree of protein binding and large volume of distribution.
    I) PATIENT DISPOSITION
    1) HOME CRITERIA: Asymptomatic adults who inadvertently ingest an extra dose or two can be monitored at home.
    2) OBSERVATION CRITERIA: All patients with deliberate self-harm ingestions should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with unintentional ingestions should be observed in a healthcare facility. Patients ingesting sustained release formulations should be observed for at least 24 hours as delayed toxicity has been reported. Patients with overdose of intramuscular paliperidone palmitate will require prolonged outpatient monitoring as it reaches peak concentrations at a median of 13 days.
    3) ADMISSION CRITERIA: Patients with deliberate ingestions demonstrating cardiotoxicity or persistent neurotoxicity should be admitted.
    4) CONSULT CRITERIA: Consult a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity (ie, dysrhythmias) or in whom the diagnosis is unclear.
    J) PITFALLS
    1) When managing a suspected paliperidone overdose, the possibility of coingestion of other CNS depressant or cardiotoxic agents should be considered.
    K) PHARMACOKINETICS
    1) The absolute oral bioavailability of the extended-release tablet is 28%. Protein binding is 74% and volume of distribution ranges from 391 to 487 liters. Four metabolic pathways have been identified with each pathway accounting for no more than 10% of the dose: dealkylation, hydroxylation, dehydrogenation, and benzisoxazole scission. The terminal elimination half-life of oral paliperidone is approximately 23 hours. The median apparent half-life of paliperidone palmitate, following IM administration of a single 39 mg to 234 mg dose, ranged from 25 days to 49 days and peak plasma concentrations were reached at a median of 13 days.
    L) TOXICOKINETICS
    1) Delayed toxicity (becoming most severe more than 20 hours after ingestion) has been reported after ingestion of sustained release formulations.
    M) DIFFERENTIAL DIAGNOSIS
    1) Includes overdose ingestions of other centrally acting agents (tricyclic antidepressants, skeletal muscle relaxants, etc).

Range Of Toxicity

    A) TOXICITY: Agitation, tachycardia, and hypertension were reported following an overdose ingestion of 81 mg over a three-day period. During clinical trials, the highest estimated ingested dose was 405 mg with extrapyramidal symptoms and gait unsteadiness reported. One study reported the following paliperidone doses and medical outcomes: In children younger than 6 years: no effects (median dose: 6 mg; range: 1.5 to 168 mg), minor effects (median dose: 12 mg; range: 3 to 90 mg), moderate effects (median dose: 12 mg; range, 3 to 63 mg). In children aged 6 to 12 years: no effects (median dose: 6 mg; range: 3 to 36 mg), minor effects (median dose: 6 mg; range: 6 to 180 mg), moderate effects (median dose: 6 mg; range: 1 to 108 mg). In patients 13 years and older: no effects (median dose: 36 mg; range: 1.5 to 300 mg), minor effects (median dose: 39 mg; range: 1.5 to 390 mg), moderate effects (median dose: 25.5 mg; range: 1.5 to 4600 mg).
    B) THERAPEUTIC DOSE: PALIPERIDONE: Extended release tablets: Initially 6 mg/day orally; may increase by 3 mg/day increments at intervals of more than 5 days, to a maximum of 12 mg/day. PALIPERIDONE PALMITATE: IM injection: INVEGA(R) SUSTENNA(R): Initiate with 234 mg IM on day 1 and 156 mg IM one week later; monthly maintenance dose for schizophrenia is 117 mg IM (range varies by indication, 39 to 234 mg). IM injection: INVEGA(R) TRINZA(TM): After 4 doses of monthly injections with Invega(R) Sustenna(R) (last 2 doses of same strength), the Invega Trinza(TM) dose equals 3.5 times the 1-month dose. PEDIATRIC: Extended release tablets: Safety and efficacy have not been established in children younger than 12 years of age. Age 12 to 17 years; weight 51 kg or greater: Initial 3 mg/day orally; may increase by 3 mg/day increments at intervals of more than 5 days, to a maximum of 12 mg/day. Age 12 to 17 years; weight less than 51 kg: Initial 3 mg/day orally; may increase by 3 mg/day increments at intervals of more than 5 days, to a maximum of 6 mg/day. IM injection: Safety and effectiveness not established in pediatric patients.

Clinical Effects

Summary Of Exposure

    A) USES: Paliperidone is indicated for the acute and maintenance therapy of schizophrenia. It is also used to treat schizoaffective disorder acutely as monotherapy and as adjunct therapy to antidepressants and/or mood stabilizers.
    B) PHARMACOLOGY: Paliperidone is the major active metabolite of risperidone. Although the specific mechanism of action of paliperidone is unknown, its proposed therapeutic activity is antagonism of both the central dopamine Type 2 (D(2)) and serotonin Type 2 (5HT(2A)) receptors. It also has antagonistic effects on the alpha-1 adrenergic, alpha-2 adrenergic, and H1 histaminergic receptors; however, the degree of affinity is unclear.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: Weight gain, constipation, dizziness, somnolence, tachycardia, orthostatic hypotension, and extrapyramidal symptoms (ie, dystonia, dyskinesia, akathisia).
    E) WITH POISONING/EXPOSURE
    1) Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses. Drowsiness/lethargy, tachycardia, dystonia, agitation/irritability, tremor, hypertension, hypotension, confusion, dizziness/vertigo, and muscle rigidity have been reported following paliperidone overdose. Severe toxicity following overdose has not been reported.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) TACHYCARDIA
    1) WITH THERAPEUTIC USE
    a) In 3 short-term (6-week), fixed-dose, placebo-controlled trials, tachycardia occurred in 12% to 14% of patients treated with paliperidone doses ranging from 3 mg to 12 mg orally once daily (n=850) compared with 7% in placebo-treated patients (n=355). Additional cardiac disorders occurring at a higher incidence than placebo included first-degree atrioventricular block, bundle branch block, and sinus arrhythmia (Prod Info INVEGA(R) extended-release oral tablets, 2009).
    b) In another safety trial, the incidence of tachycardia was 10% to 16% in paliperidone-treated patients (Tzimos et al, 2008).
    2) WITH POISONING/EXPOSURE
    a) CASE SERIES: In a retrospective, observational case series of 801 paliperidone overdoses (ages, 592 patients 13 years or older; 67 patients 6 to 12 years, 140 patients less than 6 years; 2 unknown ages), tachycardia developed in 23.3% of patients (Tsay et al, 2014).
    b) CASE REPORT: A 28-year-old man with schizophrenia was prescribed paliperidone following a poor response with risperidone therapy. His initial paliperidone dose was 3 mg/day and titrated to 9 mg/day. On presentation to the emergency department, the patient was agitated, tachycardic (100 beats per minute), and hypertensive (150/98 mmHg) after tripling his prescribed paliperidone dose 3 days prior to presentation (total ingested dose was 81 mg). Neurologic examination was normal, with a full Glasgow Coma Scale score. An ECG indicated normal sinus rhythm with a normal QTc interval of 350 ms. With supportive care and a gradual tapering off of paliperidone, the patient recovered without sequelae (Chang et al, 2010).
    c) CASE REPORT: A 2-year-old boy who was initially asymptomatic after being found with several 6 mg paliperidone extended-release tablets, presented 26 hours later with unusual behavior, disconjugate gaze, and nuchal rigidity. A pill count showed a missing paliperidone tablet. His vital signs included a pulse of 185 beats/min, a blood pressure of 108/68 mmHg, and a temperature of 37.2 degrees C. All laboratory results were normal. His dystonic reaction improved after receiving 15 mg of IV diphenhydramine. After he was transferred to a children's hospital, he received oral diphenhydramine (initially, 6.25 mg and then 5 mg every 6 hours) and an ECG revealed a heart rate of 114 beats/min and QTc interval of 443 msec. Although paliperidone was not detected in the urine screen using a gas chromatography-mass spectrometry, confirmatory tests on samples obtained 30 hours post-exposure revealed a paliperidone serum concentration of 120 ng/mL (normal 4.8 to 16.5 ng/mL) and a urine concentration of greater than 2000 ng/mL (no normal range). He was discharged 36 hours after presentation and continued to take diphenhydramine (5 mg every 6 hours) for 2 days (Thornton & Christian, 2015).
    B) PROLONGED QT INTERVAL
    1) WITH THERAPEUTIC USE
    a) In a double-blind multicenter QT study (n=141), a mean placebo-subtracted increase of linear-derived QTc interval (QTcLD) from baseline was 12.3 msec (90% confidence interval (CI), 8.9 to 15.6) on day 8, approximately 1.5 hours after a dose of immediate-release oral paliperidone 8 mg (n=50). A 4 mg dose of immediate-release oral paliperidone demonstrated a placebo-substracted QTcLD increase of 6.8 msec (90% CI, 3.6 to 10.1) on day 2 at 1.5 hours postdose. Overall, none of the subjects had a QTcLD exceeding 500 msec or a change exceeding 60 msec at any time point (Prod Info INVEGA(R) extended-release oral tablets, 2009).
    b) In another safety trial, between 3% and 10% of paliperidone treated patients developed QTc prolongation, although prolongation of 500 msec or more was rare (Tzimos et al, 2008).
    c) In a paliperidone maintenance trial (n=849), a schizophrenia patient who received paliperidone palmitate intramuscularly experienced a linear-derived corrected QT (QTcLD) value of 507 msec (Bazett QT corrected interval of 483 msec) and a heart rate of 45 beats per minute. No patient experienced a QTcLD change greater than 60 msec (Prod Info INVEGA(R) SUSTENNA(TM) injectable extended-release suspension , 2009).
    C) ORTHOSTATIC HYPOTENSION
    1) WITH THERAPEUTIC USE
    a) In 3 short-term (6-week), fixed-dose, placebo-controlled trials, orthostatic hypotension occurred in 1% to 4% of patients treated with paliperidone doses ranging from 3 mg to 12 mg orally once daily (n=850) compared with 1% in placebo-treated patients (n=355). The incidence of orthostatic hypotension increased with the dose, occurring particularly at the 9 mg and 12 mg doses (Prod Info INVEGA(R) extended-release oral tablets, 2009).
    b) The incidence of orthostatic hypotension was 4% (3 of 76) in patients receiving paliperidone extended-release (ER), compared with none (0 of 38) of the patients receiving placebo according to a prospective, 6-week, double-blind, randomized, placebo-controlled, optional 24-week open-label extension safety trial. The study included 114 patients (mean age of 70 years), with 99% having moderate to severe schizophrenia, receiving either placebo or median mean dose of paliperidone ER 8.4 mg/day during the double-blind phase and median mean doses of 7.4 mg and 8.5 mg in the placebo/paliperidone ER and paliperidone ER/paliperidone ER groups, respectively, during the open-label phase (Tzimos et al, 2008).
    D) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) In a safety trial, hypotension developed in 2% to 5% of paliperidone-treated patients (Tzimos et al, 2008).
    2) WITH POISONING/EXPOSURE
    a) CASE SERIES: In a retrospective, observational case series of 801 paliperidone overdoses (ages, 592 patients 13 years or older; 67 patients 6 to 12 years, 140 patients less than 6 years; 2 unknown ages), hypotension developed in 3.5% of patients (Tsay et al, 2014).
    E) HYPERTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: In a retrospective, observational case series of 801 paliperidone overdoses (ages, 592 patients 13 years or older; 67 patients 6 to 12 years, 140 patients less than 6 years; 2 unknown ages), hypertension developed in 3.6% of patients (Tsay et al, 2014).
    b) CASE REPORT: A 28-year-old man with schizophrenia was prescribed paliperidone following a poor response with risperidone therapy. His initial paliperidone dose was 3 mg/day and titrated to 9 mg/day. On presentation to the emergency department, the patient was agitated, tachycardic (100 beats/min), and hypertensive (150/98 mmHg) after tripling his prescribed paliperidone dose 3 days prior to presentation (total ingested dose was 81 mg). Neurologic examination was normal, with a full Glasgow Coma Scale score. An ECG indicated normal sinus rhythm with a normal QTc interval of 350 ms. With supportive care and a gradual tapering off of paliperidone, the patient recovered without sequelae (Chang et al, 2010).
    F) TACHYARRHYTHMIA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: PEDIATRIC: A 14-year-old girl presented to the emergency department (ED) with tachycardia (119 beats/min) 1 hour after an intentional ingestion of 180 mg of extended-release paliperidone but was awake and alert. Her symptoms resolved 5 hours after presentation, and she was transferred to a psychiatric facility approximately 20 hours after ingestion. On arrival at the psychiatric facility, the patient developed tachycardia again, prompting a return to the ED. The patient developed a narrow complex tachycardia (190 beats/min) with orthostatic lightheadedness and mild hypotension (97/44 mmHg) which did not resolve with adenosine. The patient was admitted to the hospital and treated with standard medical care involving IV fluids; her tachycardia improved but did not did not resolve. A serum paliperidone concentration, obtained 40.5 hours after ingestion, was 170 nanograms/mL (therapeutic is 4.8 to 16.5 nanograms/mL). Her tachycardia persisted for 90 hours after ingestion, and she was discharged to a psychiatric facility once she was medically cleared (Levine et al, 2011).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) COUGH
    1) WITH THERAPEUTIC USE
    a) In one 9-week and three 13-week fixed-dose, double-blinded studies, cough was reported in up to 3% of schizophrenia patients who received IM paliperidone palmitate at recommended doses of 39 mg to 234 mg (n=1293) compared with 1% of patients who received placebo (n=510) (Prod Info INVEGA(R) SUSTENNA(TM) injectable extended-release suspension , 2009).
    B) PULMONARY THROMBOEMBOLISM
    1) WITH THERAPEUTIC USE
    a) CASE REPORTS: Two patients developed pulmonary thromboembolism after taking therapeutic doses of paliperidone. A 28-year-old man who was taking paliperidone 9 mg/day (increased gradually from 3 mg/day) for 8 weeks for psychotic disorder, presented with respiratory pain and hemoptysis. Laboratory analysis revealed increased concentrations of C-reactive protein (121 mg/L; reference range, less than 10 mg/L), fibrinogen (600 g/L; reference range, 2 to 4 g/L), and D-dimer (0.89 mg/L; reference range, less than 0.5 mg/L). A pulmonary embolism in the left lower lobe was observed in a spiral computed tomography. Following anticoagulant therapy, he recovered completely. A 40-year-old man who was taking paliperidone 6 mg/day for 6 months for psychotic disorder, presented with a 4-day history of fever, irritability, and mild dyspnea. Laboratory results revealed elevated concentrations of plasma D-dimer (1.2 mg/L; reference range, less than 0.5 mg/L), C-reactive protein (155 mg/L; reference range, less than 10 mg/L), and fibrinogen (970 g/L; reference range, 2 to 4 g/L). Left lobar pulmonary artery thrombosis, regional consolidation, atelectasis with infection in the left lower lobe and a small pleural effusion were observed on a computed tomographic pulmonary angiography. Following the diagnosis of pulmonary embolism, and treatment with anticoagulants, he recovered completely (Sengul et al, 2014).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DYSKINESIA
    1) WITH THERAPEUTIC USE
    a) Pooled data from 2 placebo-controlled, 6-week trials revealed dyskinesia, related to extrapyramidal symptoms, occurred in 3% of schizoaffective disorder patients treated with fixed-dose paliperidone 3 mg to 6 mg per day (n=108), in 1% treated with fixed-dose 9 mg to 12 mg per day (n=98), and in 1% treated with once daily flexible-dose 3 mg to 12 mg (n=214) compared with 1% in placebo-treated patients (n=202) (Prod Info INVEGA(R) extended-release oral tablets, 2009).
    b) In 3 short-term (6-week), fixed-dose, placebo-controlled trials, dyskinesia occurred in 3% to 9% of patients treated with paliperidone doses ranging from 3 mg to 12 mg orally once daily (n=850) compared with 3% in placebo-treated patients (n=355) (Prod Info INVEGA(R) extended-release oral tablets, 2009).
    c) Dyskinesia (combined dyskinesia, choreoathetosis, muscle twitching, myoclonus, and tardive dyskinesia) was reported in 1% to 3% of schizophrenia patients who received IM paliperidone palmitate at doses of 39 mg to 156 mg (n=581) compared with 1% of patients who received placebo (n=262), according to pooled data from two 13-week, fixed-dose, double-blinded studies. When evaluated using standard rating scales, dyskinesia occurred in 4% to 6% of patients who received paliperidone palmitate compared with 3% of patients who received placebo (Prod Info INVEGA(R) SUSTENNA(TM) injectable extended-release suspension , 2009).
    B) AKATHISIA
    1) WITH THERAPEUTIC USE
    a) Pooled data from 2 placebo-controlled, 6-week trials revealed akathisia occurred in 4% of schizoaffective disorder patients treated with fixed-dose paliperidone 3 mg to 6 mg per day (n=108), in 6% treated with fixed-dose 9 mg to 12 mg per day (n=98), and in 6% treated with once daily flexible-dose 3 mg to 12 mg (n=214) compared with 4% in placebo-treated patients (n=202) (Prod Info INVEGA(R) extended-release oral tablets, 2009).
    b) In 3 short-term (6-week), fixed-dose, placebo-controlled trials, akathisia occurred in 3% to 10% of schizophrenia patients treated with paliperidone doses ranging from 3 mg to 12 mg orally once daily (n=850) compared with 4% in placebo-treated patients (n=355). The incidence of akathisia increased with the dose, occurring particularly at the 9-mg and 12-mg doses (Prod Info INVEGA(R) extended-release oral tablets, 2009).
    c) Akathisia was reported in 5% to 6% of schizophrenia patients who received IM paliperidone palmitate at doses of 39 mg to 156 mg (n=581) compared with 5% of patients who received placebo (n=262), according to pooled data from two 13-week, fixed-dose, double-blinded studies (Prod Info INVEGA(R) SUSTENNA(TM) injectable extended-release suspension , 2009).
    d) In one 9-week and three 13-week fixed-dose, double-blinded studies, akathisia was reported in 1% to 6% of schizophrenia patients who received IM paliperidone palmitate at recommended doses of 39 mg to 234 mg (n=1293) compared with 3% of patients who received placebo (n=510) (Prod Info INVEGA(R) SUSTENNA(TM) injectable extended-release suspension , 2009).
    e) In all phases of the 9-week, fixed-dose, maintenance trial, akathisia was reported in 11% and 5% of schizophrenia patients who received IM paliperidone palmitate 156 mg and 78 mg, respectively, compared with 4% of patients who received placebo (Prod Info INVEGA(R) SUSTENNA(TM) injectable extended-release suspension , 2009).
    C) DYSTONIA
    1) WITH THERAPEUTIC USE
    a) Pooled data from 2 placebo-controlled, 6-week trials revealed dystonia, related to extrapyramidal symptoms, occurred in 2% of schizoaffective disorder patients treated with fixed-dose paliperidone 3 mg to 6 mg per day (n=108), in 3% treated with fixed-dose 9 mg to 12 mg per day (n=98), and in 2% treated with once daily flexible-dose 3 mg to 12 mg (n=214) compared with 1% in placebo-treated patients (n=202) (Prod Info INVEGA(R) extended-release oral tablets, 2009).
    b) In 3 short-term (6-week), fixed-dose, placebo-controlled trials, dystonia occurred in 1% to 5% of patients treated with paliperidone doses ranging from 3 mg to 12 mg orally once daily (n=850) compared with 1% in placebo-treated patients (n=355). Dystonic reactions included muscle spasms, oculogyration, and trismus. The incidence of dystonia increased with the dose, occurring particularly at the 9 mg and 12 mg doses (Prod Info INVEGA(R) extended-release oral tablets, 2009).
    c) Dystonia (combined dystonia and muscle spasms) was reported in 1% to 2% of schizophrenia patients who received IM paliperidone palmitate at doses of 39 mg to 156 mg (n=581) compared with none of the patients who received placebo (n=262), according to pooled data from two 13-week, fixed-dose, double-blinded studies (Prod Info INVEGA(R) SUSTENNA(TM) injectable extended-release suspension , 2009).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 2-year-old boy who was initially asymptomatic after being found with several 6 mg paliperidone extended-release tablets, presented 26 hours later with unusual behavior, disconjugate gaze, and nuchal rigidity. A pill count showed a missing paliperidone tablet. His vital signs included a pulse of 185 beats/min, a blood pressure of 108/68 mmHg, and a temperature of 37.2 degrees C. All laboratory results were normal. His dystonic reaction improved after receiving 15 mg of IV diphenhydramine. After he was transferred to a children's hospital, he received oral diphenhydramine (initially, 6.25 mg and then 5 mg every 6 hours) and an ECG revealed a heart rate of 114 beats/min and QTc interval of 443 msec. Although paliperidone was not detected in the urine screen using a gas chromatography-mass spectrometry, confirmatory tests on samples obtained 30 hours post-exposure revealed a paliperidone serum concentration of 120 ng/mL (normal 4.8 to 16.5 ng/mL) and a urine concentration of greater than 2000 ng/mL (no normal range). He was discharged 36 hours after presentation and continued to take diphenhydramine (5 mg every 6 hours) for 2 days (Thornton & Christian, 2015).
    b) CASE SERIES: In a retrospective, observational case series of 801 paliperidone overdoses (ages, 592 patients 13 years or older; 67 patients 6 to 12 years, 140 patients less than 6 years; 2 unknown ages), dystonia developed in 14.2% of patients (Tsay et al, 2014).
    c) CASE REPORT: A 22-year-old man experienced a delayed dystonic reaction after a multidrug overdose involving 42 mg paliperidone, 7500 mg bupropion extended-release, 750 mg sertraline, and 3 mg lorazepam in a suicide attempt. Upon presentation to the hospital, the patient was unconscious and subsequently intubated. The following morning, the patient tolerated extubation and appeared to be in no apparent distress. He was transferred to a psychiatric unit for further follow-up. Approximately 48 hours after the event, the patient developed sustained muscular spasm of his neck and jaw and tongue protrusion. Diphenhydramine was used for treatment and he recovered with no additional dystonic episodes (Lapid et al, 2011).
    D) HYPERACTIVE BEHAVIOR
    1) WITH THERAPEUTIC USE
    a) Pooled data from 2 placebo-controlled, 6-week trials revealed hyperkinesia, related to extrapyramidal symptoms, occurred in 5% of schizoaffective disorder patients treated with fixed-dose paliperidone 3 mg to 6 mg per day (n=108), in 8% treated with fixed-dose 9 mg to 12 mg per day (n=98), and in 7% treated with once daily flexible-dose 3 mg to 12 mg (n=214) compared with 5% in placebo-treated patients (n=202) (Prod Info INVEGA(R) extended-release oral tablets, 2009).
    b) In 3 short-term (6-week), fixed-dose, placebo-controlled trials, hyperkinesia occurred in 3% to 10% of patients treated with paliperidone doses ranging from 3 mg to 12 mg orally once daily (n=850) compared with 4% in placebo-treated patients (n=355) (Prod Info INVEGA(R) extended-release oral tablets, 2009).
    c) Hyperkinesia (combined akathisia, restless legs syndrome, and restlessness) was reported in 2% to 4% of schizophrenia patients who received IM paliperidone palmitate at doses of 39 mg to 156 mg (n=581) compared with 2% of patients who received placebo (n=262), according to pooled data from two 13-week, fixed-dose, double-blinded studies (Prod Info INVEGA(R) SUSTENNA(TM) injectable extended-release suspension , 2009).
    E) PARKINSONISM
    1) WITH THERAPEUTIC USE
    a) Pooled data from 2 placebo-controlled, 6-week trials revealed parkinsonism, related to extrapyramidal symptoms, occurred in 14% of schizoaffective disorder patients treated with fixed-dose paliperidone 3 mg to 6 mg per day (n=108), in 7% treated with fixed-dose 9 mg to 12 mg per day (n=98), and in 7% treated with once daily flexible-dose 3 mg to 12 mg (n=214) compared with 3% in placebo-treated patients (n=202) (Prod Info INVEGA(R) extended-release oral tablets, 2009).
    b) In 3 short-term (6-week), fixed-dose, placebo-controlled trials, parkinsonism occurred in 3% to 7% of patients treated with paliperidone doses ranging from 3 mg to 12 mg orally once daily (n=850) compared with 2% in placebo-treated patients (n=355) (Prod Info INVEGA(R) extended-release oral tablets, 2009).
    c) Parkinsonism (combined extrapyramidal disorder, hypertonia, musculoskeletal stiffness, parkinsonism, drooling, masked facies, muscle tightness, and hypokinesia) was reported in 4% to 6% of schizophrenia patients who received IM paliperidone palmitate at doses of 39 mg to 156 mg (n=581) compared with 5% of patients who received placebo (n=262), according to pooled data from two 13-week, fixed-dose, double-blinded studies. When evaluated using standard rating scales, parkinsonism occurred in 6% to 12% of patients who received paliperidone palmitate compared with 9% of patients who received placebo (Prod Info INVEGA(R) SUSTENNA(TM) injectable extended-release suspension , 2009).
    d) In all phases of the 9-week, fixed-dose, maintenance trial, parkinsonism was reported in 18% and 9% of schizophrenia patients who received IM paliperidone palmitate 156 mg and 78 mg, respectively, compared with 7% of patients who received placebo (Prod Info INVEGA(R) SUSTENNA(TM) injectable extended-release suspension , 2009).
    F) TREMOR
    1) WITH THERAPEUTIC USE
    a) Pooled data from 2 placebo-controlled, 6-week trials revealed tremor, related to extrapyramidal symptoms, occurred in 12% of schizoaffective disorder patients treated with fixed-dose paliperidone 3 mg to 6 mg per day (n=108), in 11% treated with fixed-dose 9 mg to 12 mg per day (n=98), and in 5% treated with once daily flexible-dose 3 mg to 12 mg (n=214) compared with 3% in placebo-treated patients (n=202) (Prod Info INVEGA(R) extended-release oral tablets, 2009).
    b) In 3 short-term (6-week), fixed-dose, placebo-controlled trials, tremor occurred in 3% to 4% of patients treated with paliperidone doses ranging from 3 mg to 12 mg orally once daily (n=850) compared with 3% in placebo-treated patients (n=355) (Prod Info INVEGA(R) extended-release oral tablets, 2009).
    2) WITH POISONING/EXPOSURE
    a) CASE SERIES: In a retrospective, observational case series of 801 paliperidone overdoses (ages, 592 patients 13 years or older; 67 patients 6 to 12 years, 140 patients less than 6 years; 2 unknown ages), tremor developed in 4.5% of patients (Tsay et al, 2014).
    G) DROWSY
    1) WITH THERAPEUTIC USE
    a) Pooled data from 2 placebo-controlled, 6-week trials revealed somnolence occurred in 12% of schizoaffective disorder patients treated with fixed-dose paliperidone 3 mg to 6 mg per day (n=108), in 12% treated with fixed-dose 9 mg to 12 mg per day (n=98), and in 8% treated with once daily flexible-dose 3 mg to 12 mg (n=214) compared with 5% in placebo-treated patients (n=202) (Prod Info INVEGA(R) extended-release oral tablets, 2009).
    b) In 3 short-term (6-week), fixed-dose, placebo-controlled trials, somnolence occurred in 6% to 11% of patients treated with paliperidone doses ranging from 3 mg to 12 mg orally once daily (n=850) compared with 7% in placebo-treated patients (n=355). The incidence of somnolence increased with the dose, particularly at the 9 mg and 12 mg doses (Prod Info INVEGA(R) extended-release oral tablets, 2009).
    c) In another safety study, somnolence was reported in 5% to 9% of patients treated with paliperidone (Tzimos et al, 2008).
    d) In one 9-week and three 13-week fixed-dose, double-blinded studies, somnolence and sedation were reported in 1% to 7% of schizophrenia patients who received IM paliperidone palmitate at recommended doses of 39 mg to 234 mg (n=1293) compared with 3% of patients who received placebo (n=510) (Prod Info INVEGA(R) SUSTENNA(TM) injectable extended-release suspension , 2009).
    2) WITH POISONING/EXPOSURE
    a) CASE SERIES: In a retrospective, observational case series of 801 paliperidone overdoses (ages, 592 patients 13 years or older; 67 patients 6 to 12 years, 140 patients less than 6 years; 2 unknown ages), drowsiness/lethargy developed in 28.7% of patients (Tsay et al, 2014).
    H) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) During the double-blind phase of a safety trial in 114 geriatric patients, the incidence of dizziness was 7% (5 of 76) in patients receiving paliperidone extended-release (ER), compared with none (0 of 38) of the patients receiving placebo according to a prospective, 6-week, double-blind, randomized, placebo-controlled, optional 24-week open-label extension safety trial. During the open-label phase, the incidence of dizziness was 3% (1 of 30) of patients switched to paliperidone ER from placebo and was 10% (6 of 58) in patients continuing with paliperidone ER treatment from the double-blind phase. The study included 114 patients (mean age of 70 years), with 99% having moderate to severe schizophrenia, receiving either placebo or median mean dose of paliperidone ER 8.4 mg/day during the double-blind phase and median mean doses of 7.4 mg and 8.5 mg in the placebo/paliperidone ER and paliperidone ER/paliperidone ER groups, respectively, during the open-label phase (Tzimos et al, 2008).
    b) In one 9-week and three 13-week fixed-dose, double-blinded studies, dizziness was reported in 1% to 6% of schizophrenia patients who received IM paliperidone palmitate at recommended doses of 39 mg to 234 mg (n=1293) compared with 1% of patients who received placebo (n=510) (Prod Info INVEGA(R) SUSTENNA(TM) injectable extended-release suspension , 2009).
    2) WITH POISONING/EXPOSURE
    a) CASE SERIES: In a retrospective, observational case series of 801 paliperidone overdoses (ages, 592 patients 13 years or older; 67 patients 6 to 12 years, 140 patients less than 6 years; 2 unknown ages), dizziness/vertigo developed in 2.5% of patients (Tsay et al, 2014).
    I) ASTHENIA
    1) WITH THERAPEUTIC USE
    a) In one 9-week and three 13-week fixed-dose, double-blinded studies, asthenia was reported in up to 2% of schizophrenia patients who received IM paliperidone palmitate at recommended doses of 39 mg to 234 mg (n=1293) compared with none of patients who received placebo (n=510) (Prod Info INVEGA(R) SUSTENNA(TM) injectable extended-release suspension , 2009).
    J) PSYCHOMOTOR AGITATION
    1) WITH THERAPEUTIC USE
    a) In one 9-week and three 13-week fixed-dose, double-blinded studies, agitation was reported in 4% to 10% of schizophrenia patients who received IM paliperidone palmitate at recommended doses of 39 mg to 234 mg (n=1293) compared with 7% of patients who received placebo (n=510) (Prod Info INVEGA(R) SUSTENNA(TM) injectable extended-release suspension , 2009).
    2) WITH POISONING/EXPOSURE
    a) CASE SERIES: In a retrospective, observational case series of 801 paliperidone overdoses (ages, 592 patients 13 years or older; 67 patients 6 to 12 years, 140 patients less than 6 years; 2 unknown ages), agitation/irritability developed in 5.5% of patients (Tsay et al, 2014).
    b) CASE REPORT: A 28-year-old man with schizophrenia was prescribed paliperidone following a poor response with risperidone therapy. His initial paliperidone dose was 3 mg/day and titrated to 9 mg/day. On presentation to the emergency department, the patient was agitated, tachycardic (100 beats per minute), and hypertensive (150/98 mmHg) after tripling his prescribed paliperidone dose 3 days prior to presentation (total ingested dose was 81 mg). Neurologic examination was normal, with a full Glasgow Coma Scale score. An ECG indicated normal sinus rhythm with a normal QTc interval of 350 ms. With supportive care and a gradual tapering off of paliperidone, the patient recovered without sequelae (Chang et al, 2010).
    K) CLOUDED CONSCIOUSNESS
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: In a retrospective, observational case series of 801 paliperidone overdoses (ages, 592 patients 13 years or older; 67 patients 6 to 12 years, 140 patients less than 6 years; 2 unknown ages), confusion developed in 3.2% of patients (Tsay et al, 2014).
    L) NEUROLEPTIC MALIGNANT SYNDROME
    1) WITH THERAPEUTIC USE
    a) During the premarketing phase, neuroleptic malignant syndrome was reported in schizophrenia patients who received at least 1 dose of paliperidone palmitate intramuscularly at recommended doses of 39 mg to 234 mg (n=2770) (Prod Info INVEGA(R) SUSTENNA(TM) injectable extended-release suspension , 2009).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) WEIGHT GAIN FINDING
    1) WITH THERAPEUTIC USE
    a) In several studies, weight gain was reported in 5% to 13% of patients treated with oral paliperidone (Prod Info INVEGA(R) extended-release oral tablets, 2009; Prod Info INVEGA(R) extended-release oral tablets, 2009; Prod Info INVEGA(R) SUSTENNA(TM) injectable extended-release suspension , 2009) and 1% to 4% of patients treated with IM paliperidone (Prod Info INVEGA(R) SUSTENNA(TM) injectable extended-release suspension , 2009).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) In one 9-week and three 13-week fixed-dose, double-blinded studies, diarrhea was reported in up to 3% of schizophrenia patients who received IM paliperidone palmitate at recommended doses of 39 mg to 234 mg (n=1293) compared with 2% of patients who received placebo (n=510) (Prod Info INVEGA(R) SUSTENNA(TM) injectable extended-release suspension , 2009).
    C) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) Pooled data from 2 placebo-controlled, 6-week trials revealed constipation occurred in 4% of schizoaffective disorder patients treated with fixed-dose paliperidone 3 mg to 6 mg per day (n=108), in 5% treated with fixed-dose 9 mg to 12 mg per day (n=98), and in 4% treated with once daily flexible-dose 3 mg to 12 mg (n=214) compared with 2% in placebo-treated patients (n=202) (Prod Info INVEGA(R) extended-release oral tablets, 2009).
    D) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) In one 9-week and three 13-week fixed-dose, double-blinded studies, nausea was reported in 2% to 4% of schizophrenia patients who received IM paliperidone palmitate at recommended doses of 39 mg to 234 mg (n=1293) compared with 3% of patients who received placebo (n=510) (Prod Info INVEGA(R) SUSTENNA(TM) injectable extended-release suspension , 2009).
    b) In one 9-week and three 13-week fixed-dose, double-blinded studies, vomiting was reported in 2% to 5% of schizophrenia patients who received IM paliperidone palmitate at recommended doses of 39 mg to 234 mg (n=1293) compared with 4% of patients who received placebo (n=510) (Prod Info INVEGA(R) SUSTENNA(TM) injectable extended-release suspension , 2009).
    E) INDIGESTION
    1) WITH THERAPEUTIC USE
    a) Pooled data from 2 placebo-controlled, 6-week trials revealed dyspepsia occurred in 5% of schizoaffective disorder patients treated with fixed-dose paliperidone 3 mg to 6 mg per day (n=108), in 6% treated with fixed-dose 9 mg to 12 mg per day (n=98), and in 6% treated with once daily flexible-dose 3 mg to 12 mg (n=214) compared with less than 2% in placebo-treated patients (n=202) (Prod Info INVEGA(R) extended-release oral tablets, 2009).
    F) INCREASED APPETITE
    1) WITH THERAPEUTIC USE
    a) Pooled data from 2 placebo-controlled, 6-week trials revealed increased appetite occurred in 3% of schizoaffective disorder patients treated with fixed-dose paliperidone 3 mg to 6 mg per day (n=108), in 2% treated with fixed-dose 9 mg to 12 mg per day (n=98), and in 2% treated with once daily flexible-dose 3 mg to 12 mg (n=214) compared with less than 1% in placebo-treated patients (n=202) (Prod Info INVEGA(R) extended-release oral tablets, 2009).
    G) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) In 3 short-term (6-week), fixed-dose, placebo-controlled trials, upper abdominal pain occurred in 1% to 3% of patients treated with paliperidone doses ranging from 3 mg to 12 mg orally once daily (n=850) compared with 1% in placebo-treated patients (n=355) (Prod Info INVEGA(R) extended-release oral tablets, 2009).
    b) In one 9-week and three 13-week fixed-dose, double-blinded studies, abdominal discomfort or upper abdominal pain were reported in up to 3% of schizophrenia patients who received IM paliperidone palmitate at recommended doses of 39 mg to 234 mg (n=1293) compared with 1% of patients who received placebo (n=510) (Prod Info INVEGA(R) SUSTENNA(TM) injectable extended-release suspension , 2009).
    H) APTYALISM
    1) WITH THERAPEUTIC USE
    a) In 3 short-term (6-week), fixed-dose, placebo-controlled trials, dry mouth occurred in 1% to 3% of patients treated with paliperidone doses ranging from 3 mg to 12 mg orally once daily (n=850) compared with 1% in placebo-treated patients (n=355) (Prod Info INVEGA(R) extended-release oral tablets, 2009).
    b) In one 9-week and three 13-week fixed-dose, double-blinded studies, dry mouth was reported in up to 3% of schizophrenia patients who received IM paliperidone palmitate at recommended doses of 39 mg to 234 mg (n=1293) compared with 1% of patients who received placebo (n=510) (Prod Info INVEGA(R) SUSTENNA(TM) injectable extended-release suspension , 2009).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) PRIAPISM
    1) WITH THERAPEUTIC USE
    a) In postmarketing surveillance, priapism has been reported in patients receiving oral paliperidone therapy (Prod Info INVEGA(R) extended-release oral tablets, 2009).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) NEUTROPENIA
    1) WITH THERAPEUTIC USE
    a) Neutropenia has been reported with the use of oral paliperidone and other antipsychotic agents, according to clinical trial and postmarketing experience (Prod Info INVEGA(R) extended-release oral tablets, 2009).
    b) CASE REPORT: A 33-year-old woman with a 1-year history of auditory and visual hallucinations, persecutory delusion, aggressive behavior, and an unstable mood, developed leukopenia and neutropenia after taking paliperidone 6 mg/day for 8 days and then 9 mg/day for 5 days. On day 14, laboratory results revealed WBC of 2.96 x 10(9)/L (6.17 x 10(9)/L on admission) and neutrophil count of 1.18 x 10(9)/L (3.97 x 10(9)/L on admission). Her WBC and neutrophil counts improved 3 days after the discontinuation of paliperidone. At this time, she was started on olanzapine and her WBC and neutrophil counts normalized on day 36 (Kim et al, 2011).
    B) AGRANULOCYTOSIS
    1) WITH THERAPEUTIC USE
    a) Agranulocytosis has been reported with the use of oral paliperidone and other antipsychotic agents, according to clinical trial and postmarketing experience (Prod Info INVEGA(R) extended-release oral tablets, 2009).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) INJECTION SITE REACTION
    1) WITH THERAPEUTIC USE
    a) In one 9-week and three 13-week fixed-dose, double-blinded studies, injection site reactions were reported in up to 10% of schizophrenia patients who received paliperidone palmitate intramuscularly at recommended doses of 39 mg to 234 mg (n=1293) compared with 2% of patients who received placebo (n=510). Injection site redness, swelling, induration, and pain were generally mild and decreased over time between the first and the last injection (Prod Info INVEGA(R) SUSTENNA(TM) injectable extended-release suspension , 2009).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCLE RIGIDITY
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: In a retrospective, observational case series of 801 paliperidone overdoses (ages, 592 patients 13 years or older; 67 patients 6 to 12 years, 140 patients less than 6 years; 2 unknown ages), muscle rigidity developed in 2.2% of patients (Tsay et al, 2014).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPERPROLACTINEMIA
    1) WITH THERAPEUTIC USE
    a) During the double-blind phase of a safety trial in 114 geriatric patients, the incidence of increased prolactin was 45% in male patients and 49% in female patients receiving paliperidone extended-release (ER), according to a prospective, 6-week, double-blind, randomized, placebo-controlled, optional 24-week open-label extension safety trial. The maximum mean change was 75.3 +/- 10.8 nanograms/mL in females and 27.2 +/- 8.7 nanograms/mL in males (Tzimos et al, 2008).

Reproductive

    3.20.1) SUMMARY
    A) Third-trimester antipsychotic drug exposure has been associated with extrapyramidal and/or withdrawal symptoms in neonates. In animal studies, there were no fetal abnormalities following administration of paliperidone, up to 8 times the maximum recommended human dose, to pregnant rats and rabbits during organogenesis. However, there was an increase in pup deaths when risperidone, the parent compound of paliperidone, was given to rats at oral doses less than the maximum recommended human dose.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) LACK OF EFFECT
    a) No increases in fetal abnormalities were reported when paliperidone was given to pregnant rats and rabbits orally, up to 8 times the maximum recommended human dose, during organogenesis (Prod Info INVEGA TRINZA(TM) intramuscular extended-release injection suspension, 2015; Prod Info INVEGA(R) oral extended-release tablets, 2011).
    b) There were also no reports of treatment-related effects in the offspring of rats who were given paliperidone intramuscularly, at doses up to 160 mg/kg (up to 10 times the maximum recommended human dose of 234 mg), during organogenesis (Prod Info INVEGA(R) SUSTENNA(R) extended-release solution for intramuscular injection, 2010).
    3.20.3) EFFECTS IN PREGNANCY
    A) RISK SUMMARY
    1) Use during pregnancy only if maternal benefit outweighs fetal risk. Monitor neonates that exhibit withdrawal or extrapyramidal symptoms, as symptoms may be self-limiting or may require long-term hospitalization in some cases (Prod Info INVEGA(R) oral extended-release tablets, 2011; Prod Info INVEGA(R) SUSTENNA(R) intramuscular extended-release injection suspension, 2012).
    B) PREGNANCY REGISTRY
    1) Physicians may register patients exposed to paliperidone during pregnancy in the National Pregnancy Registry for Atypical Antipsychotics by calling 1-866-961-2388 or by visiting http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/ (Prod Info INVEGA TRINZA(TM) intramuscular extended-release injection suspension, 2015).
    C) FETAL/NEONATAL ADVERSE REACTIONS
    1) Maternal use of antipsychotic drugs during the third trimester of pregnancy has been associated with an increased risk of neonatal extrapyramidal and/or withdrawal symptoms (eg, agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder). Severity of these adverse effects have ranged from cases that are self-limiting to cases that required prolonged periods of hospitalization and ICU care (Prod Info INVEGA TRINZA(TM) intramuscular extended-release injection suspension, 2015; Prod Info INVEGA(R) oral extended-release tablets, 2011; Prod Info INVEGA(R) SUSTENNA(R) intramuscular extended-release injection suspension, 2012).
    D) ANIMAL STUDIES
    1) RATS: An increase in pup deaths was reported following oral administration of risperidone (the parent drug of paliperidone) to pregnant rats at doses less than the maximum recommended human dose (Prod Info INVEGA TRINZA(TM) intramuscular extended-release injection suspension, 2015; Prod Info INVEGA(R) SUSTENNA(R) extended-release solution for intramuscular injection, 2010; Prod Info INVEGA(R) oral extended-release tablets, 2011).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) RISK SUMMARY
    1) Use of paliperidone is not recommended in breastfeeding women (Prod Info INVEGA(R) oral extended-release tablets, 2011; Prod Info INVEGA(R) SUSTENNA(R) intramuscular extended-release injection suspension, 2012)
    B) BREAST MILK
    1) Paliperidone is excreted in human breast milk. Low levels of paliperidone have been detected in plasma up to 18 months after single-dose administration (Prod Info INVEGA TRINZA(TM) intramuscular extended-release injection suspension, 2015)
    C) ANIMAL STUDIES
    1) Paliperidone (as the active metabolite of risperidone) was excreted in milk during animal studies (Prod Info INVEGA(R) SUSTENNA(R) extended-release solution for intramuscular injection, 2010; Prod Info INVEGA(R) extended-release oral tablets, 2010).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) Fertility did not appear to be affected in male or female rats after treatment with paliperidone (Prod Info INVEGA TRINZA(TM) intramuscular extended-release injection suspension, 2015; Prod Info INVEGA(R) oral extended-release tablets, 2011).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, human carcinogenicity studies with paliperidone have not been conducted.
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, human carcinogenicity studies with paliperidone have not been conducted (Prod Info INVEGA TRINZA(TM) intramuscular extended-release injection suspension, 2015).
    3.21.4) ANIMAL STUDIES
    A) NEOPLASMS
    1) An increase in mammary gland adenocarcinomas was reported in female rats following IM administration of paliperidone, at doses of 16, 47, and 94 mg/kg/month (0.6, 2, and 4 times, respectively, the maximum recommended human dose of 234 mg) and in male rats at IM doses of 47 and 94 mg/kg/month (Prod Info INVEGA TRINZA(TM) intramuscular extended-release injection suspension, 2015; Prod Info INVEGA(R) SUSTENNA(TM) injectable extended-release suspension , 2009).
    2) An increase in fibroadenomas and carcinomas was reported in male rats following IM administration of paliperidone at doses of 47 and 94 mg/kg/month (Prod Info INVEGA TRINZA(TM) intramuscular extended-release injection suspension, 2015; Prod Info INVEGA(R) SUSTENNA(TM) injectable extended-release suspension , 2009).

Genotoxicity

    A) There was no evidence of genotoxicity with paliperidone in the Ames reverse mutation test, the mouse lymphoma assay, or in the in vivo rat micronucleus test (Prod Info INVEGA TRINZA(TM) intramuscular extended-release injection suspension, 2015; Prod Info INVEGA(R) SUSTENNA(TM) injectable extended-release suspension , 2009; Prod Info INVEGA(R) extended-release oral tablets, 2009).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and mental status.
    B) Monitor fluid and electrolyte status in patients with significant vomiting and/or diarrhea.
    C) Monitor CBC.
    D) Institute continuous cardiac monitoring and obtain serial ECGs to evaluate for evidence of QT prolongation.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with deliberate ingestions demonstrating cardiotoxicity or persistent neurotoxicity should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Asymptomatic adults who inadvertently ingest and extra dose or two can be monitored at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Call a Poison Center for assistance in managing patients with severe toxicity (ie, dysrhythmias) or in whom the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) All patients with deliberate self-harm ingestions should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with unintentional ingestions should be observed in a healthcare facility. Patients ingesting sustained release formulations should be observed for at least 24 hours as delayed toxicity has been reported. Patients with overdose of intramuscular paliperidone palmitate will require prolonged outpatient monitoring as it reaches peak concentrations at a median of 13 days.

Monitoring

    A) Monitor vital signs and mental status.
    B) Monitor fluid and electrolyte status in patients with significant vomiting and/or diarrhea.
    C) Monitor CBC.
    D) Institute continuous cardiac monitoring and obtain serial ECGs to evaluate for evidence of QT prolongation.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital decontamination is not recommended because of the possibility of a dystonic reaction or CNS depression and subsequent aspiration.
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment is symptomatic and supportive.
    B) MONITORING OF PATIENT
    1) Monitor vital signs and mental status.
    2) Monitor fluid and electrolyte status in patients with significant vomiting and/or diarrhea.
    3) Institute continuous cardiac monitoring and obtain an ECGs to evaluate for evidence of QT prolongation.
    C) HYPOTENSIVE EPISODE
    1) Treat hypotension with intravenous fluids, add vasopressors if unresponsive to fluids. Norepinephrine is preferred, the manufacturer recommends avoidance of epinephrine and dopamine since beta stimulation may worsen hypotension in the setting of paliperidone-induced alpha blockade (Prod Info INVEGA(R) extended-release oral tablets, 2009).
    2) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    D) NEUROLEPTIC MALIGNANT SYNDROME
    1) May be successfully managed diphenhydramine, oral bromocriptine, benzodiazepines, or intravenous or oral dantrolene sodium in conjunction with cooling and other supportive care (May et al, 1983; Mueller et al, 1983; Leikin et al, 1987; Schneider, 1991; Barkin, 1992).
    a) BENZODIAZEPINES: In conjunction with cooling measures and supportive care, initial management of neuroleptic malignant syndrome should include administration of intravenous benzodiazepines for muscle relaxation (Goldfrank et al, 2002). Benzodiazepines may also be helpful in controlling agitation or reversal of catatonia (Caroff & Mann, 1993; Gratz et al, 1992).
    1) DIAZEPAM DOSE: 3 to 5 mg intravenous bolus to slow push initially, followed by 1 to 2.5 mg intravenously in 10 minutes.
    b) BROMOCRIPTINE DOSE: 5 mg three times a day orally (Mueller et al, 1983).
    c) DANTROLENE LOADING DOSE: 2.5 mg/kg, to a maximum of 10 mg/kg intravenously (Barkin, 1992).
    d) DANTROLENE MAINTENANCE DOSE: 2.5 mg/kg intravenously every 6 hours (Barkin, 1992); 1 mg/kg orally every 12 hours, up to 50 mg/dose has also been successful (May et al, 1983).
    1) EFFICACY: Variable; often ineffective as sole agent. Most efficacious in reducing rigidity and the fever that may be produced at a muscular level; will not always resolve mental status changes or psychotic symptoms that probably are more central in origin. Efficacy may be improved if given with a dopamine agonist (Granato et al, 1983; Blue et al, 1986; May et al, 1983).
    2) Some studies report NO beneficial effects and suggest that dantrolene might even worsen the course of neuroleptic malignant syndrome (Rosebush et al, 1991a; Rosebush & Stewart, 1989) .
    e) NON-PHARMACOLOGIC METHODS: Rapid cooling, hydration, and serial assessment of respiratory, cardiovascular, renal and neurologic function, and fluid status are used in conjunction with drug therapy and discontinuation of the antipsychotic agent (Knight & Roberts, 1986).
    2) In a review of 67 case reports of neuroleptic malignant syndrome, the onset of clinical response was shorter after treatment with DANTROLENE (mean 1.15 days) or BROMOCRIPTINE (1.03 days) than with supportive measures alone (6.8 days).
    a) The time to complete resolution was also shorter with these therapeutic interventions (Rosenberg & Green, 1989).
    3) RETROSPECTIVE STUDY: A study comparing 438 untreated patients with neuroleptic malignant syndrome and 196 treated cases found that administration of dantrolene, bromocriptine, or amantadine significantly reduced the death rate in these cases (Sakkas et al, 1991).
    a) Death rate of untreated cases was 21%; administration of dantrolene alone (no dosage reported) decreased death rate to 8.6% (n=58); with bromocriptine alone death rate was 7.8% (n=51); and with amantadine alone death rate was 5.9% (n=17).
    b) In combination with other drugs, each of these drugs significantly decreased the NMS-related death rate, although the decrease was slightly less than for single administrations.
    E) DRUG-INDUCED AKATHISIA
    1) MIRTAZAPINE: Mirtazapine is a potent antagonist of 5-HT2A/2C receptors and an antagonist of central alpha2 auto- and hetero-adrenergic receptors. Five patients with akathisia caused by risperidone and olanzapine were treated successfully with mirtazapine 15 mg/day. Although the mechanism of action of mirtazapine in treating akathisia is unknown, it may be due to its antagonist property of the H1 receptors and its dopaminergic activity in frontal cortex (Ranjan et al, 2006).

Enhanced Elimination

    A) LACK OF EFFECT
    1) Hemodialysis and hemoperfusion are UNLIKELY to be useful in a paliperidone overdose because of the high degree of protein binding and large volume of distribution.

Range Of Toxicity

Summary

    A) TOXICITY: Agitation, tachycardia, and hypertension were reported following an overdose ingestion of 81 mg over a three-day period. During clinical trials, the highest estimated ingested dose was 405 mg with extrapyramidal symptoms and gait unsteadiness reported. One study reported the following paliperidone doses and medical outcomes: In children younger than 6 years: no effects (median dose: 6 mg; range: 1.5 to 168 mg), minor effects (median dose: 12 mg; range: 3 to 90 mg), moderate effects (median dose: 12 mg; range, 3 to 63 mg). In children aged 6 to 12 years: no effects (median dose: 6 mg; range: 3 to 36 mg), minor effects (median dose: 6 mg; range: 6 to 180 mg), moderate effects (median dose: 6 mg; range: 1 to 108 mg). In patients 13 years and older: no effects (median dose: 36 mg; range: 1.5 to 300 mg), minor effects (median dose: 39 mg; range: 1.5 to 390 mg), moderate effects (median dose: 25.5 mg; range: 1.5 to 4600 mg).
    B) THERAPEUTIC DOSE: PALIPERIDONE: Extended release tablets: Initially 6 mg/day orally; may increase by 3 mg/day increments at intervals of more than 5 days, to a maximum of 12 mg/day. PALIPERIDONE PALMITATE: IM injection: INVEGA(R) SUSTENNA(R): Initiate with 234 mg IM on day 1 and 156 mg IM one week later; monthly maintenance dose for schizophrenia is 117 mg IM (range varies by indication, 39 to 234 mg). IM injection: INVEGA(R) TRINZA(TM): After 4 doses of monthly injections with Invega(R) Sustenna(R) (last 2 doses of same strength), the Invega Trinza(TM) dose equals 3.5 times the 1-month dose. PEDIATRIC: Extended release tablets: Safety and efficacy have not been established in children younger than 12 years of age. Age 12 to 17 years; weight 51 kg or greater: Initial 3 mg/day orally; may increase by 3 mg/day increments at intervals of more than 5 days, to a maximum of 12 mg/day. Age 12 to 17 years; weight less than 51 kg: Initial 3 mg/day orally; may increase by 3 mg/day increments at intervals of more than 5 days, to a maximum of 6 mg/day. IM injection: Safety and effectiveness not established in pediatric patients.

Therapeutic Dose

    7.2.1) ADULT
    A) PALIPERIDONE
    1) ORAL: EXTENDED RELEASE TABLETS: Initially 6 mg/day orally; may increase by 3 mg/day increments at intervals of more than 5 days, to a maximum of 12 mg/day (Prod Info INVEGA(R) oral extended release tablets, 2014).
    B) PALIPERIDONE PALMITATE
    1) INTRAMUSCULAR INJECTION: INVEGA(R) SUSTENNA(R): After establishing tolerability, initiate with 234 mg IM on day 1 and 156 mg IM one week later; monthly maintenance dose is 117 mg IM (range varies by indication, 39 mg to 234 mg) (Prod Info INVEGA(R) SUSTENNA(R) intramuscular extended-release injection suspension, 2014).
    2) INTRAMUSCULAR INJECTION: INVEGA(R) TRINZA(TM):
    a) Initial dose: After 4 doses of monthly injections with Invega(R) Sustenna(R) (last 2 doses of same strength), the Invega Trinza(TM) dose equals 3.5 times the 1-month dose. Give 273 mg IM if previous monthly dose was 78 mg IM; 410 mg IM if previous monthly dose was 117 mg IM; 546 mg IM if previous monthly dose was 156 mg IM; 819 mg IM if previous monthly dose was 234 mg IM. May give up to 7 days before or after the next scheduled 1-month dose (Prod Info INVEGA TRINZA(TM) intramuscular extended-release injection suspension, 2015).
    b) Maintenance dose: Give IM once every 3 months; may increase dose in 3-month increments within the range of 273 to 819 mg; several months may be needed for clinical response to be apparent (Prod Info INVEGA TRINZA(TM) intramuscular extended-release injection suspension, 2015)
    7.2.2) PEDIATRIC
    A) ORAL: EXTENDED RELEASE TABLETS: Safety and efficacy have not been established in children younger than 12 years of age (Prod Info INVEGA(R) oral extended release tablets, 2014).
    B) INTRAMUSCULAR INJECTION: Safety and effectiveness not established in pediatric patients (Prod Info INVEGA TRINZA(TM) intramuscular extended-release injection suspension, 2015; Prod Info INVEGA(R) SUSTENNA(R) intramuscular extended-release injection suspension, 2014)
    C) SCHIZOPHRENIA
    1) EXTENDED RELEASE TABLETS, (age 12 to 17 years; weight 51 kg or greater): Initial 3 mg/day orally; may increase by 3 mg/day increments at intervals of more than 5 days, to a maximum of 12 mg/day (Prod Info INVEGA(R) oral extended release tablets, 2014).
    2) EXTENDED RELEASE TABLETS, (age 12 to 17 years; weight less than 51 kg): Initial 3 mg/day orally; may increase by 3 mg/day increments at intervals of more than 5 days, to a maximum of 6 mg/day (Prod Info INVEGA(R) oral extended release tablets, 2014).

Maximum Tolerated Exposure

    A) CASE SERIES: In a retrospective, observational case series of 801 paliperidone overdoses (ages, 592 patients 13 years or older; 67 patients 6 to 12 years, 140 patients less than 6 years; 2 unknown ages), the following adverse effects were observed: drowsiness/lethargy (28.7%), tachycardia (23.3%), dystonia (14.2%), agitation/irritability (5.5%), tremor (4.5%), hypertension (3.6%), hypotension (3.5%), confusion (3.2%), dizziness/vertigo (2.5%), and muscle rigidity (2.2%). Dose information was available in 365 cases. Overall, major, moderate, and minor effects were observed in 0.5%, 33.7%, and 30.8% of patients, respectively. There were no effects in 35% of patients. In children younger than 6 years (n=91), 52 patients had no effects (median dose: 6 mg; range: 1.5 to 168 mg), 13 patients had minor effects (median dose: 12 mg; range: 3 to 90 mg), 26 patients had moderate effects (median dose: 12 mg; range, 3 to 63 mg). In children aged 6 to 12 years (n=28), 10 patients had no effects (median dose: 6 mg; range: 3 to 36 mg), 9 patients had minor effects (median dose: 6 mg; range: 6 to 180 mg), and 9 patients had moderate effects (median dose: 6 mg; range: 1 to 108 mg). In patients 13 years and older (n=246), 90 patients had no effects (median dose: 36 mg; range: 1.5 to 300 mg), 78 had minor effects (median dose: 39 mg; range: 1.5 to 390 mg), and 78 patients had moderate effects (median dose: 25.5 mg; range: 1.5 to 4600 mg) (Tsay et al, 2014).
    B) CASE REPORT: ADULT: A 28-year-old man with schizophrenia was prescribed paliperidone following a poor response with risperidone therapy. His initial paliperidone dose was 3 mg daily and titrated to 9 mg/day. On presentation to the emergency department, the patient was agitated, tachycardic (100 beats per minute), and hypertensive (150/98 mmHg) after tripling his prescribed paliperidone dose 3 days prior to presentation (total ingested dose was 81 mg). Neurologic examination was normal, with a full Glasgow Coma Scale score. An ECG indicated normal sinus rhythm with a normal QTc interval of 350 ms. With supportive care and a gradual tapering off of paliperidone, the patient recovered without sequelae (Chang et al, 2010).
    C) CASE REPORT: PEDIATRIC: A 2-year-old boy who was initially asymptomatic after being found with several 6 mg paliperidone extended-release tablets, presented 26 hours later with unusual behavior, disconjugate gaze, and nuchal rigidity. A pill count showed a missing paliperidone tablet. His vital signs included a pulse of 185 beats/min, a blood pressure of 108/68 mmHg, and a temperature of 37.2 degrees C. All laboratory results were normal. His dystonic reaction improved after receiving 15 mg of IV diphenhydramine. After he was transferred to a children's hospital, he received oral diphenhydramine (initially, 6.25 mg and then 5 mg every 6 hours) and an ECG revealed a heart rate of 114 beats/min and QTc interval of 443 msec. Although paliperidone was not detected in the urine screen using a gas chromatography-mass spectrometry, confirmatory tests on samples obtained 30 hours post-exposure revealed a paliperidone serum concentration of 120 ng/mL (normal 4.8 to 16.5 ng/mL) and a urine concentration of greater than 2000 ng/mL (no normal range). He was discharged 36 hours after presentation and continued to take diphenhydramine (5 mg every 6 hours) for 2 days (Thornton & Christian, 2015).
    D) CASE REPORT: PEDIATRIC: A 14-year-old girl presented to the emergency department (ED) with tachycardia 1 hour after an intentional ingestion of 180 mg of extended release paliperidone; however, she was awake and alert. Her symptoms resolved 5 hours after presentation and she was transferred to a psychiatric facility. Approximately 20 hours after ingestion, the patient developed tachycardia again, prompting a return to the ED. The patient developed a narrow complex tachycardia (190 beats/min) with orthostatic lightheadedness and mild hypotension (97/44 mm Hg) which did not resolve with adenosine. The patient was admitted to the hospital and treated with standard medical care, involving IV fluids; her tachycardia improved but did not did not resolve. A serum paliperidone concentration, obtained 40.5 hours after ingestion, was 170 ng/ml (therapeutic is 4.8 to 16.5 ng/ml). Her tachycardia persisted for 90 hours after ingestion and she was discharged to a psychiatric facility once she was medically cleared(Levine et al, 2011).
    E) During clinical trials, the highest estimated ingested dose was 405 mg with extrapyramidal symptoms and gait unsteadiness reported (Prod Info INVEGA(R) extended-release oral tablets, 2009).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) PEDIATRIC: A serum paliperidone concentration was 170 ng/ml (therapeutic is 4.8 to 16.5 ng/ml) at 40.5 hours after a 14-year-old girl intentionally ingested 180 mg of extended release paliperidone (Levine et al, 2011).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Paliperidone is the major active metabolite of risperidone. While the mechanism of action is unknown, its proposed therapeutic activity is antagonism of both the central dopamine Type 2 (D(2)) and serotonin Type 2 (5HT(2A)) receptors. It also has antagonistic effects on the alpha-1 adrenergic, alpha-2 adrenergic, and H1 histaminergic receptors; however, the degree of affinity is unclear. Paliperidone has no known affinity for cholinergic muscarinic or beta-1 and beta-2 adrenergic receptors (Prod Info INVEGA(R) oral extended release tablets, 2011).

Physicochemical

Molecular Weight

    A) PALIPERIDONE: 426.49 (Prod Info INVEGA(R) extended-release oral tablets, 2009)
    B) PALIPERIDONE PALMITATE: 664.89 (Prod Info INVEGA(R) SUSTENNA(TM) injectable extended-release suspension , 2009)

References

General Bibliography

    1) Barkin RM: Pediatric Emergency Medicine, Mosby YearBook, St Louis, MO, 1992, pp 500.
    2) Blue MG, Schneider SM, & Noro S: Successful treatment of neuroleptic malignant syndrome with sodium nitroprusside. Ann Intern Med 1986; 104:56-57.
    3) Caroff SN & Mann SC: Neuroleptic malignant syndrome. Med Clin North Am 1993; 77:185-203.
    4) Chang JP, Huang CC, & Su KP: Paliperidone overdose in a patient with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2010; 34(2):418-.
    5) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    6) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    7) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    8) Goldfrank L, Flomenbaum N, Lewin N, et al (Eds): Goldfrank's Toxicologic Emergencies, 7th ed. McGraw-Hill, New York, NY, 2002.
    9) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    10) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    11) Granato JE, Stern BJ, & Ringel A: Neuroleptic malignant syndrome: successful treatment with dantrolene and bromocriptine. Ann Neurol 1983; 14:89-90.
    12) Gratz SS, Levinson DF, & Simpson GM: The treatment and management of neuroleptic malignant syndrome. Prog Neuro-Psychopharmacol Biol Psychiat 1992; 16:425-443.
    13) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    14) Kim JN, Lee BC, Choi IG, et al: Paliperidone-induced leukopenia and neutropenia: a case report. Prog Neuropsychopharmacol Biol Psychiatry 2011; 35(1):284-285.
    15) Kleinman ME, Chameides L, Schexnayder SM, et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Part 14: pediatric advanced life support. Circulation 2010; 122(18 Suppl.3):S876-S908.
    16) Knight ME & Roberts RJ: Phenothiazine and butyrophenone intoxication in children. Pediatr Clin North Am 1986; 33:299-309.
    17) Lapid MI, Cunningham JL, Hugo Z, et al: Acute dystonia associated with paliperidone overdose. Psychosomatics 2011; 52(3):291-294.
    18) Leikin JB, Baron S, & Engle J: Treatment of neuroleptic malignant syndrome with diphenhydramine (abstract). Vet Hum Toxicol 1987; 29:480.
    19) Levine M, Lovecchio F, Tafoya P, et al: Paliperidone Overdose With Delayed Onset of Toxicity. Ann Emerg Med 2011; Epub:Epub.
    20) May DC, Morris SW, & Stewart RW: Neuroleptic malignant syndrome: response to dantrolene sodium. Ann Intern Med 1983; 98:183-184.
    21) Mueller PS, Vester JW, & Fermaglich J: Neuroleptic malignant syndrome: successful treatment with bromocriptine. JAMA 1983; 249:386-388.
    22) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    23) Peberdy MA , Callaway CW , Neumar RW , et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care science. Part 9: post–cardiac arrest care. Circulation 2010; 122(18 Suppl 3):S768-S786.
    24) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    25) Product Information: INVEGA TRINZA(TM) intramuscular extended-release injection suspension, paliperidone palmitate intramuscular extended-release injection suspension. Janssen Pharmaceuticals, Inc. (per manufacturer), Titusville, NJ, 2015.
    26) Product Information: INVEGA(R) SUSTENNA(R) extended-release solution for intramuscular injection, paliperidone palmitate extended-release solution for intramuscular injection. Ortho-McNeil-Janssen Pharmaceuticals, Inc., Titusville, NJ, 2010.
    27) Product Information: INVEGA(R) SUSTENNA(R) intramuscular extended-release injection suspension, paliperidone palmitate intramuscular extended-release injection suspension. Janssen Pharmaceuticals (per manufacturer), Titusville, NJ, 2014.
    28) Product Information: INVEGA(R) SUSTENNA(R) intramuscular extended-release injection suspension, paliperidone palmitate intramuscular extended-release injection suspension. Janssen Pharmaceuticals, Inc. (per FDA), Titusville, NJ, 2012.
    29) Product Information: INVEGA(R) SUSTENNA(TM) injectable extended-release suspension , paliperidone palmitate injectable extended-release suspension . Janssen, Titusville, NJ, 2009.
    30) Product Information: INVEGA(R) extended-release oral tablets, paliperidone extended-release oral tablets. ALZA Corportation, Vacaville, CA, 2010.
    31) Product Information: INVEGA(R) extended-release oral tablets, paliperidone extended-release oral tablets. Janssen, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc., Titusville, NJ, 2009.
    32) Product Information: INVEGA(R) oral extended release tablets, paliperidone oral extended release tablets. Janssen Pharmaceuticals, Inc. (per FDA), Titusville, NJ, 2014.
    33) Product Information: INVEGA(R) oral extended release tablets, paliperidone oral extended release tablets. Janssen Pharmaceuticals, Inc. (per manufacturer), Titusville, NJ, 2011.
    34) Product Information: INVEGA(R) oral extended-release tablets, paliperidone oral extended-release tablets. Ortho-McNeil-Janssen Pharmaceuticals, Titusville, NJ, 2011.
    35) Product Information: norepinephrine bitartrate injection, norepinephrine bitartrate injection. Sicor Pharmaceuticals,Inc, Irvine, CA, 2005.
    36) Ranjan S, Chandra PS, Chaturvedi SK, et al: Atypical antipsychotic-induced akathisia with depression: therapeutic role of mirtazapine. Ann Pharmacother 2006; 40(4):771-774.
    37) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    38) Rosebush P & Stewart T: A prospective analysis of 24 episodes of neuroleptic malignant syndrome. Am J Psychiatry 1989; 146:717-725.
    39) Rosebush PI, Stewart T, & Mazurek MF: The treatment of neuroleptic malignant syndrome: are dantrolene and bromocriptine useful adjuncts to supportive care?. Br J Psychiatry 1991a; 159:709-712.
    40) Rosenberg MR & Green M: Neuroleptic malignant syndrome: Review of response to therapy. Arch Intern Med 1989; 149:1927-1931.
    41) Sakkas P, Davis JM, & Janicak PG: Drug treatment of the neuroleptic malignant syndrome. Psychopharmacol Bull 1991; 27:381-384.
    42) Schneider SM: Neuroleptic malignant syndrome: controversies in treatment. Am J Emerg Med 1991; 9:360-362.
    43) Sengul MC, Kaya K, Yilmaz A, et al: Pulmonary thromboembolism due to paliperidone: report of 2 cases. Am J Emerg Med 2014; 32(7):814-2.
    44) Thornton SL & Christian MR: Delayed Toxicity from Unintentional Pediatric Paliperidone Ingestion with Analytical Confirmation (abstracts). Clin Toxicol (Phila) 2015; 53(7):767-768.
    45) Tsay ME, Klein-Schwartz W, & Anderson B: Toxicity and clinical outcomes of paliperidone exposures reported to U.S. Poison Centers. Clin Toxicol (Phila) 2014; 52(3):207-213.
    46) Tzimos A, Samokhvalov V, Kramer M, et al: Safety and tolerability of oral paliperidone extended-release tablets in elderly patients with schizophrenia: a double-blind, placebo-controlled study with six-month open-label extension. Am J Geriatr Psychiatry 2008; 16(1):31-43.
    47) Vermeir M, Naessens I, Remmerie B, et al: Absorption, metabolism, and excretion of paliperidone, a new monoaminergic antagonist, in humans. Drug Metab Dispos 2008; 36(4):769-779.