Clinical Toxicology (2014), 52, 207–213 Copyright © 2014 Informa Healthcare USA, Inc. ISSN: 1556-3650 print / 1556-9519 online DOI: 10.3109/15563650.2014.882000
POISON CENTRE
Toxicity and clinical outcomes of paliperidone exposures reported to U.S. Poison Centers M. E. TSAY, W. KLEIN-SCHWARTZ, and B. ANDERSON
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Department of Pharmacy Practice and Science, Maryland Poison Center, University of Maryland School of Pharmacy, Baltimore, MD, USA
Context. Paliperidone is an atypical antipsychotic that was approved in the U.S. in 2006, and is also available in Canada, Australia, New Zealand, Europe, and Asia. Information regarding paliperidone overdoses is limited to case reports. Serious toxicity has yet to be reported. Objective. To evaluate the toxicity of paliperidone exposures using a national poison center database. Methods. A retrospective, observational case series of single-substance paliperidone cases reported to the National Poison Data System from 2007 to 2012 was conducted. Cases were evaluated for demographics, reason for exposure, clinical effects, treatments, disposition, and coded medical outcomes. For cases with major effects the text fields in poison center charts were evaluated to verify accuracy of coded outcome. The relationship between dose and severity of medical outcome was analyzed for acute exposure cases. Results. There were 801 paliperidone cases that met inclusion criteria that included 592 persons of 13 years or greater, 67 children of 6–12 years, 140 children of less than 6 years, and 2 unknown ages. Most common reasons for exposure included: suicide attempt (39.6%), unintentional general (21.1%), therapeutic error (15.7%), and adverse drug reaction (11.9%). The most commonly observed clinical effects were drowsiness/lethargy (28.7%), tachycardia (23.3%), and dystonia (14.2%). Most patients were managed in the emergency department (40.3%) or were admitted to a health care facility (HCF) (42.7%). In 564 cases treated in a HCF, treatments included activated charcoal (25.7%), antihistamines (21.1%), and benzodiazepines (9.4%). Medical outcomes were no effect (35.0%), minor (30.8%), moderate (33.7%), and major effect (0.5%). There were no deaths. Of 491 acute exposures, dose was coded for 74.3% of exposures. There was a significant difference in the reported median dose between those with no effect (6 mg) and either minor effect (12 mg; p ⫽ 0.047) or moderate effect cases (12 mg; p ⫽ 0.020) in 91 children less than 6 years. Conclusions. The majority of patients experienced no or minor toxicity and were not admitted for medical care. Although a higher dose was associated with a more serious outcome in children less than 6 years, the data do not provide clear-cut triage guidelines. Keywords
Atypical; Antipsychotic; Toxicity; overdose
Introduction
started at 6 mg/day (3 mg/day for adolescents) and may be titrated up to a maximum daily dose of 12 mg (6 mg for adolescents). Dosing should be adjusted for elderly patients and those with renal impairment. Paliperidone ER tablets are formulated in 1.5, 3, 6, and 9 mg tablets and utilize the Osmotic-controlled Release Oral delivery System technology allowing for once-a-day dosing.2 Like other atypical antipsychotics, paliperidone ER carries a warning label for the potential to cause neuroleptic malignant syndrome, QT prolongation, tardive dyskinesia, metabolic changes, and cerebrovascular adverse reactions in elderly patients with dementia-related psychosis. Clinical trials of paliperidone ER reported more than 5% incidence (versus placebo) of extrapyramidal symptoms, tachycardia, and akathisia.2 While there are published data on adverse effects from therapeutic doses, there are only limited data on toxicities associated with supratherapeutic (higher than therapeutic) doses or overdoses. Published case reports of paliperidone overdoses display a wide dosage range of 42 –756 mg.3–7 Based on reports of
Invega®,
Paliperidone ER (extended release), is an atypical antipsychotic approved by the Food and Drug Administration (FDA) in the United States on December 20, 2006 for the treatment of schizophrenia and schizoaffective disorder. It is also available for use in Canada, Australia, New Zealand, Europe, and Asia. As an active metabolite of risperidone, paliperidone (9-hydroxyrisperidone) exhibits antagonistic properties at the D2 and 5-HT2A receptors. In addition, paliperidone has some antagonistic effects at α1-adrenoceptors as well as low binding affinities to both α2-adrenoceptors and H1 receptors.1 Indications for the treatment include acute and maintenance therapy of schizophrenia and schizoaffective disorder, or as an adjunct to mood stabilizers and/or antidepressants. Paliperidone is Received 11 September 2013; accepted 5 January 2014. Address correspondence to Mingzohn Ellen Tsay, Department of Pharmacy Practice and Science, Maryland Poison Center, University of Maryland School of Pharmacy, 220 Arch Street, Office level 1, Baltimore, MD 21201, USA. Tel: ⫹(410)-563-5589. E-mail: [email protected]
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both single- and multi-drug ingestions, overdosed patients have been observed to experience tachycardia and altered mental status.3–7 In one case involving a multi-drug ingestion, the patient experienced a dystonic reaction,6 and in another, the patient experienced acute kidney injury that eventually resolved.7 While serious toxicity or deaths have yet to be reported, data from case reports are insufficient to generalize the potential for serious toxicity. Therefore, a systematic review of poison center data was undertaken. The primary objective of this study is to evaluate the toxicity of paliperidone exposures. The secondary objective of this study is to evaluate the relationship between medical outcomes and the dose ingested.
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Methods A retrospective, observational case series of single-substance paliperidone exposures reported to the National Poison Data System (NPDS) between January 2007 and June 2012 was conducted. Human exposure cases that were followed to a known medical outcome were included. Information calls, confirmed non-exposures, cases with co-ingestants, and cases without a known medical outcome were excluded. Coded data entered by poison specialists are uploaded to the NPDS. Coded data include age, gender, reason, product, dose, dose certainty (i.e., exact, estimate, or maximum possible), clinical effects, treatments, disposition (i.e., treatment site including non-health care facility (HCF), emergency department, critical care unit, non-critical care unit, psychiatric admission, and other) and medical outcomes. The reasons (i.e., intent) for exposure include unintentional general (unintended exposures, also known as accidental), therapeutic error, adverse drug reaction, misuse, abuse, suicidal, withdrawal, and unknown. Poison center coding of known medical outcomes include no effect, minor, moderate, major, and death. Patients with minor outcomes exhibited clinical effects as a result of the exposure, but they were minimally bothersome and resolved quickly with no residual disability. Patients with moderate outcomes exhibited clinical effects as a result of the exposure that were more pronounced, more prolonged, or more systemic than minor symptoms, usually some form of treatment was indicated; not life-threatening with no residual clinical effects or disability. Patients with major outcomes exhibited clinical effects as a result of the exposure that were life-threatening or resulted in significant residual disability or disfigurement. Cases that fit the inclusion criteria were evaluated for demographics (age and gender) and reason for exposure. Primary outcome Severity of exposure was analyzed by evaluation of clinical effects, treatments, patient disposition, and medical outcomes. For cases that were coded with a major medical outcome, the original poison center was contacted for a redacted (i.e., with patient identifiers removed) poison center record to review and confirm the coded clinical effects.
The investigators independently reviewed the major effect cases to determine whether the case met the definition for major; for those cases in which investigators disagreed, the case was discussed by investigators and categorized once all unanimously came to an agreement. Secondary outcome Acute exposures with both dose and age were further analyzed for a relationship between dose ingested and medical outcome in children less than 6 years, children between 6 and 12 years, and individuals age 13 or greater. Doses were either entered manually or were calculated based on the milligram strength associated with the product ID code and number of tablets ingested. Cases were excluded if there was an unknown age, no dose information, unknown or nonquantifiable amount ingested (ex, “taste, drop, or lick”), or coded as dose formulations that do not exist commercially (liquid preparations). Quantitative data were summarized by medians and ranges and categorical data by frequencies and percentages. Median doses were compared using Kruskal–Wallis (KW) test and post-hoc Mann–Whitney test with Holm’s correction. Categorical data were analyzed using Chi-square. Analyses were performed with RStudio (Integrated development environment for R, Version 0.96.122, Boston, MA) and all reported p-values were two-sided. Statistical significance was defined as p ⬍ 0.05. The study was granted exempt status by the University Institutional Review Board.
Results There were a total of 1,252 single-substance paliperidone cases identified during the study period, with 801 (64.0%) cases that met inclusion criteria. Excluded cases included 433 cases not followed to a known medical outcome for the following reasons: 280 cases were coded as nontoxic or minimal clinical effects possible, 110 cases were lost to follow-up, and 43 cases with clinical effects judged to be unrelated. In addition, 13 were confirmed as non-exposure cases and 5 were duplicate cases. Of the cases that met inclusion criteria, 364 (45.4%) were female, 435 (54.3%) were male, and 2 (0.2%) were unknown genders. There were 592 (73.9%) persons of 13 years or greater, 67 (8.4%) children of 6–12 years, 140 (17.5%) children of less than 6 years, and 2 (0.2%) of unknown ages. The most frequently reported reason for exposure was suspected suicidal (317, 39.6%), followed by unintentional general (169, 21.1%), therapeutic error (126, 15.7%), adverse drug reaction (95, 11.9%), intentional misuse (46, 5.7%), intentional abuse (19, 2.4%), unknown intent (28, 3.5%), and withdrawal (1, 0.1%). The most frequent reason for exposure by age group was unintentional general (131, 93.6%) in children under 6 years of age, therapeutic error or adverse reaction (46, 68.7%) in 6–12 year olds and suicide attempts (315, 53.2%) in patients 13 years of age or greater. Clinical Toxicology vol. 52 no. 3 2014
Paliperidone toxicity 209 Table 1. Clinical effects following paliperidone exposures by patient age. Clinical effect Drowsiness/lethargy Tachycardia Dystonia Agitated/irritable Tremor Hypertension Hypotension Confusion Dizziness/vertigo Muscle rigidity
⬍ 6 years n ⫽ 140 (%)
6–12 years n ⫽ 67 (%)
ⱖ 13 years n ⫽ 592 (%)
Total (%) n ⫽ 801*
48 (34.3) 23 (16.4) 14 (10.0) 8 (5.7) 9 (6.4) 1 (0.7) 3 (2.1) 3 (2.1) 0 0
23 (34.3) 13 (19.4) 18 (26.9) 1 (1.5) 2 (3) 1 (1.5) 1 (1.5) 3 (4.5) 2 (3) 6 (9)
159 (26.9) 151 (25.5) 81 (13.7) 35 (5.9) 25 (4.2) 27 (4.6) 24 (4.1) 20 (3.4) 18 (3.0) 12 (2.0)
230 (28.7) 187 (23.3) 114 (14.2) 44 (5.5) 36 (4.5) 29 (3.6) 28 (3.5) 26 (3.2) 20 (2.5) 18 (2.2)
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*In two cases, ages were unknown; one experienced no clinical effects; the other experienced a dystonic reaction.
Table 1 displays the top 10 observed clinical effects. In the 521 patients who experienced clinical effects, the most commonly observed effects were drowsiness/lethargy, tachycardia, and dystonias. More serious clinical effects such as hypotension (28, 3.5%), conduction disturbances (16, 2.0%), ECG changes (6, 0.8%), seizures (5, 0.6%), respiratory depression (4, 0.5%), and coma (4, 0.5%) were infrequently reported among all patients exposed to paliperidone. The frequency of the three most commonly reported clinical effects varied by intent. Drowsy/lethargy was most often reported in abuse cases (42.1%), least often reported in those with adverse drug reaction (13.7%), and occurred in approximately 25–30% of those with all other intents. Tachycardia was more frequent in those with intentional intent (31.2%) compared to those with other reasons (16.3%). Dystonias occurred most often in patients with adverse reaction, misuse, abuse, and unknown reason (34.7%, 41.3%, 36.8%, and 25.0%, respectively), and less often for other intents (unintentional general, 10.1%; therapeutic error, 8.7%; and suicide, 6.3%). Of note, the 6–12 year olds age group experienced the highest frequency of dystonias (26.9%) due to adverse reactions (n ⫽ 8), therapeutic errors (n ⫽ 6), unintentional general (n ⫽ 2), or misuse/abuse (n ⫽ 2) which mostly occurred in the context of either acute-on-chronic (n ⫽ 8) or chronic (n ⫽ 4) therapy. Tremor occurred in 14.7% of all adverse drug reaction cases but under 5% for all other intents.
The remaining clinical effects noted in Table 1 occurred in less than 5% of cases for all intents. Of 564 patients treated at a HCF, 145 received charcoal (25.7%). Excluding those with adverse drug reaction treated in a HCF, 145 of 498 (29.1%) were treated with activated charcoal. Other treatments administered to HCF-managed patients included intravenous (IV) fluids (183, 32.4%), antihistamines (119, 21.1%), and/or benzodiazepines (53, 9.4%). Of the 113 dystonic patients, 83 received antihistamines and 15 received benzodiazepines. A total of 11 of 18 patients who had muscle rigidity also received antihistamines. In three cases, patients were intubated and ventilated. Tables 2 and 3 display the disposition and coded medical outcomes, stratified by intent. The majority of cases were treated at a HCF, either in the ED, non-critical care, or critical care unit (564, 70.4%). Patients with therapeutic errors were most often managed outside a HCF or discharged from the ED without an admission, while suicidal patients were most likely to be admitted. The majority of adverse reaction cases as well as misuse and abuse cases were managed in the ED. Overall, 65.8% of all patients were asymptomatic or experienced minor effects. Patients with unintentional exposures (unintentional general and therapeutic errors) were usually asymptomatic or experienced minor effects. When intent was adverse reactions, misuse or abuse patients were most likely to develop toxicity, with a relatively high frequency of
Table 2. Patient disposition by intent.
Intent
Non-Health Care Facility
Unintentional (%) n ⫽ 169 Therapeutic error (%) n ⫽ 126 Adverse drug reaction (%) n ⫽ 95 Misuse (%) n ⫽ 46 Abuse (%) n ⫽ 19 Suicide (%) n ⫽ 317 Unknown (%) n ⫽ 28 Total (%) n ⫽ 801
30 (17.8) 55 (43.7) 20 (21.1) 4 (8.7) 3 (15.8) 2 (0.6) 1 (3.6) 116* (14.5)
*One case was due to withdrawal. ED, emergency department; AMA, against medical advice. Copyright © Informa Healthcare USA, Inc. 2014
ED/Discharged
Admitted to non-critical care unit
Admitted to critical care unit
Admitted to psychiatric care facility
Left AMA or refused referral
76 (45) 52 (41.3) 49 (51.6) 23 (50) 10 (52.6) 93 (29.3) 20 (71.4) 323 (40.3)
32 (18.9) 11 (8.7) 10 (10.5) 6 (13) 2 (10.5) 56 (17.7) 2 (7.1) 119 (14.9)
25 (14.8) 4 (3.2) 7 (7.4) 4 (8.7) 2 (10.5) 78 (24.6) 2 (7.1) 122 (15.2)
4 (2.4) 1 (0.8) 1 (1) 9 (19.6) 0 84 (26.5) 2 (7.1) 101 (12.6)
2 (1.2) 3 (2.4) 8 (8.4) 0 2 (10.5) 4 (1.3) 1 (3.6) 20 (2.5)
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M. E. Tsay et al. Table 3. Adjusted medical outcome by intent.* Intent
No effect
Minor effect
Unintentional general (%) n ⫽ 169 Therapeutic error (%) n ⫽ 126 Adverse drug reaction (%) n ⫽ 95 Misuse (%) n ⫽ 46 Abuse (%) n ⫽ 19 Suicide (%) n ⫽ 317 Unknown (%) n ⫽ 28 Total (%) n ⫽ 801
88 (52) 59 (46.8) 3 (3.2) 10 (21.8) 3 (15.8) 108 (34) 9 (32.1) 280 (35.0)
33 (19.5) 43 (34.1) 28 (29.5) 15 (32.6) 6 (31.6) 115 (36.3) 6 (21.4) 247** (30.8)
Moderate effect 47 (27.8) 24 (19.0) 63 (66.3) 21 (45.7) 9 (47.4) 93 (29.3) 13 (46.4) 270 (33.7)
Major effect 1 (0.6) 0 1 (1.1) 0 1 (5.3) 1 (0.3) 0 4 (0.5)
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*# of major effect cases adjusted by review of charts. **One case was due to withdrawal.
moderate toxicity. Outcomes in suicidal patients were fairly evenly distributed between no effects, minor, and moderate effects. There were no fatalities, and only four cases met the definition of major medical outcome after adjustment through the manual review of cases coded as major effect. Redacted cases were obtained for 9 of 10 major effect cases, and both coded and free-text were reviewed by the investigators. In 6 of the 9 cases, the coded clinical effects and free-text portion of the case met the definition of minor or moderate effect rather than major effect. All patients with the exception of one (due to a late presentation) experienced tachycardia and lethargy, but half of the patients (6) experienced dystonic reactions. For the case for which the poison center chart was unavailable, the coded clinical effects and treatments supported the major effect outcome. Amongst the cases recoded from major effect to a less severe outcome were four patients with dystonias (three of which received and responded to diphenhydramine) and two patients with neurologic and/or cardiovascular clinical effects, persisting for 3 days in one case, which, while significant, were judged as not life threatening. Based on this investigation of the more serious cases, only 4 of the 801 cases experienced toxicity that met the standardized definition of major effect. A brief description of the four major cases follows: Case 1 A developmentally delayed 12-year-old male ingested 180 mg of paliperidone (acute-on-chronic) at an unknown time. He was admitted to the ICU with lethargy, tachycardia (140 beats/min) that worsened with position changes, and hypokalemia (3.0 mEq/L). Although the patient’s heart rate returned to normal one day post-presentation, he remained lethargic, developed dyskinesia with tongue movements that impaired his ability to swallow, and dystonic reactions that would last up to 25 min. He became tachycardic during dystonic reactions. The dystonia and dyskinesia persisted through his hospital stay of 3 days and was treated with antihistamines. Case 2 A 38-year-old male with a history of schizophrenia, mental retardation, and diabetes was transferred from a psychiatric facility to a hospital due to an adverse drug reaction. He
presented with dyskinesia, dystonia, tremors (which resolved with 25–50 mg of diphenhydramine), and diaphoresis. The patient takes 9 mg of paliperidone daily. He was admitted to a neurology service and symptoms improved with benzodiazepines and antihistamines. However, he developed rhabdomyolysis with a CPK of 4,719 IU/L and received IV fluids. He continued to experience episodes of tachycardia and was diaphoretic and tremulousness until days 3 and 5 of his hospital stay. He was treated with IV fluids, diphenhydramine, and bromocriptine. By days 5 the patient was discharged. Case 3 A 42-year-old female ingested an unknown amount of 9-mg paliperidone capsules in a suicide attempt, and was found unresponsive, and was intubated and placed on a ventilator. Four hours later she was able to breathe on her own but was tachycardic with a heart rate in the 120s beats/min and hypokalemic (3.4 mEq/L). The patient had a traumatic intubation, was put on antibiotics, and kept in the ICU for a total of 3 days. By the last day she was no longer lethargic and heart rate was normalized. Case 4 A 2-year-old ingested an unknown amount of paliperidone that was kept in the caretaker’s purse. He was admitted to a critical care unit and experienced ataxia, lethargy, ECG changes (other), hypotension, multiple discrete seizures, tachycardia, and tremors, and was managed with benzodiazepines, IV fluids, and supplemental oxygen. Of 491 acute exposure cases, 365 (74.3%) included dose information. In these 365 cases, 108 (29.6%) were coded “exact” dose, 209 (57.3%) were “estimated”, and 48 (13.2%) were “maximum dose possible”. Table 4 provides dose versus outcome by age group. There was a significant difference in outcome by reported mg dose in children less than 6 years (KW χ2(2) ⫽ 10.48, p ⫽ 0.0067). The median doses for minor effect (12 mg, range: 3–90) and moderate effect cases (12 mg; range, 3–63) were significantly higher than median dose for those children with no effect (6 mg; range 1.5–168) (p ⫽ 0.047 and 0.020, respectively). Given the wide range of weights Clinical Toxicology vol. 52 no. 3 2014
Paliperidone toxicity 211 Table 4. Acute ingestion dose versus medical outcomes for all reasons stratified by patient age. Median dose (range) (n ⫽ 365) ⬍ 6 years n ⫽ 91
Medical outcome* No effect Minor effect Moderate effect
6–12 years n ⫽ 28
ⱖ 13 years n ⫽ 246
6 mg (1.5—168 mg) n ⫽ 52 6 mg (3—36 mg) n ⫽ 10 36 mg (1.5—300 mg) n ⫽ 90 12 mg (3—90 mg) n ⫽ 13 6 mg (6—180 mg) n ⫽ 9 39 mg (1.5—390 mg) n ⫽ 78 12 mg (3—63 mg) n ⫽ 26 6 mg (1—108 mg) n ⫽ 9 25.5 mg† (1.5—4600 mg) n ⫽ 78
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Note: Within each age category, doses were compared between all medical outcome categories. *Four major effect cases not on table [unknown dose (2 cases); not acute ingestion (2 cases)] ¶Significant difference: p ⫽ 0.047 when compared with minor effect; p ⫽ 0.020 when compared with moderate effect. †Significant difference: p ⫽ 0.037 when compared with no effect; p ⫽ 0.037 when compared with minor effect.
in this age group, weight adjusted doses were also analyzed; the median mg/kg doses of 0.38 in no effect (n ⫽ 35; range, 0.10–14.21), 0.52 in minor effect (n ⫽ 8; range, 0.15– 6.60), and 0.85 in moderate effect (n ⫽ 19; range, 0.18–3.00) were significantly different (KW χ2(2) ⫽ 8.13, p ⫽ 0.017), with the median dose per kilogram significantly higher for children with moderate effects compared to those of no effects (p ⫽ 0.020). While median mg dose was significantly different for minor effect and no effect, this difference was not evident for median mg/kg dose. In children aged 6–12 years (KW χ2(2) ⫽ 0.36, p ⫽ 0.837), there was no significant difference in outcome by dose. In patients 13 years and older there was a significant difference in outcome by dose (KW χ2(2) ⫽ 6.8, p ⫽ 0.033). The median doses for no effect (N ⫽ 90; 36 mg; range, 1.5–300, p ⫽ 0.037) and for minor effect (N ⫽ 78; 39 mg, range, 1.5–390, p ⫽ 0.037) were significantly higher than median dose for moderate effect (N ⫽ 78; 25.5 mg; range, 1.5–4600).There was one suicide attempt in a 12-year-old who ingested 180 mg and experienced minor effects. In patients 13 years and older, median dose of 12 mg (1.5–180 mg) was lower for the 109 nonsuicidal patients than median dose of 60 mg (3–4600 mg) in the 137 suicidal patients (KW χ2(2) ⫽ 1570.5, p ⬍ 0.001). For both suicide attempts and other reasons there was no difference in dose by outcome (KW χ2(2) ⫽ 0.6, p ⫽ 0.741 and (KW χ2(2) ⫽ 1.72, p ⫽ 0.423, respectively).
Discussion From the limited published information in case reports of paliperidone overdoses, commonly observed clinical effects include tachycardia, altered mental status, and dystonic reactions. This investigation supports these findings. In all children under 13 years of age, drowsiness/lethargy and tachycardia were reported in 34% and 17%, respectively. These clinical effects were reported in approximately 26% of adolescents and adults. Dystonias occurred in 14% of patients overall, both in overdoses (e.g., suicide attempts) and with therapeutic doses, suggesting the presence of a lower dose threshold for the occurrence of dystonia. Paliperidone is not indicated for use in children less than 12 years, yet of the 67 cases in children 6–12 years of age, poison center staff coded the reason as therapeutic error or adverse reaction in 46 (69%) and the acuity as chronic or acute-on-chronic in 33 (49%) cases. Dystonias were more Copyright © Informa Healthcare USA, Inc. 2014
frequently reported in children of 6–12 years (27%) than those in younger children (10%) or in adolescents and adults (14%) (KW χ2(2) ⫽ 11.85, p ⫽ 0.0027). In 18 children of 6–12 years with dystonias, the coded reason was a therapeutic error or adverse reaction in 14 (78%), and acuities of acute-on-chronic or chronic were coded in 12 (67%). It is conceivable that in some instances these children 6–12 years were receiving paliperidone off-label with resultant dystonias. Based on coded medical outcomes, most patients (65%) experienced no toxicity or minor effects. Ten cases had major effects as coded outcomes. However, upon further review, half of these cases experienced clinical effects consistent with minor to moderate outcomes. Paliperidone exposures were largely managed with symptomatic and supportive care including the use of antihistamines and benzodiazepines, presumably for the treatment of acute dystonia. A total of 86.7% of patients with dystonias received either an antihistamine or benzodiazepine. Intubation and ventilator support was rare. Most patients did not require hospital admission, with approximately 40% of exposures managed and discharged from the emergency department. Only 15% of patients were admitted to an intensive care unit. These findings suggest that serious toxicity is uncommon with paliperidone-only ingestion. In children less than 6 years a significant difference was observed between the median dose ingested for exposures that led to no effect (6 mg; range, 1.5–168) and those that led to minor (12 mg; range, 3–90) or moderate effects (12 mg; range, 3–63). However, clinical effects such as acute dystonic reactions and tremors occurred at a relatively low dose of 3 mg (3–54 mg and 3–36 mg, respectively) in children less than 6 years. Overlapping lower-end doses between asymptomatic and moderately symptomatic children made it impossible to devise triage guidelines. Suspected suicides, therapeutic errors, and adverse drug reactions were all prominent reasons for exposures, which explain the wide range in doses ingested. In patients aged 13 years or older, exposures due to therapeutic errors (median dose, 12 mg; range, 1.5–39 mg) or adverse drug reaction (median dose, 6 mg; range, 1.5–12 mg) involved doses that mirror therapeutic doses, while doses in suicide attempts (median dose, 60 mg; range, 3–4600 mg) greatly exceeded the recommended maximum daily dose. The unexpected finding that in patients 13 years or older
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the median dose for moderate effect (25.5 mg; range, 1.5–4600) was significantly lower than median doses for either no effect (36 mg; range, 1.5–300) or minor effect (39 mg, range, 1.5–390) may partially be explained by the fact that some clinical effects associated with therapeutic errors and adverse drug reactions are serious enough to warrant the coding of the outcome as moderate effect, despite relatively low doses. Other factors that may have influenced these dose–outcome findings include inaccurate patient report on dose (especially in suicidal patients), estimation of dose, and/or the omission of dose ingested in 23% of patients in this age group. Suspected suicides occurred primarily in the persons 13 years and older (315 exposures), and rarely in children aged 6–12 years (2 exposures, with doses available only in one case, both in patients 12 years of age). First generation antipsychotics have been associated with a higher risk of the development of both extrapyramidal symptoms as well as prolactinemia due to their slower disassociation rate from the dopamine D2 receptors. Second generation antipsychotics have a much faster dissociation rate from the D2 receptors when compared to dopamine and cause fewer extrapyramidal symptoms due to the concept that dopamine neurotransmission would be allowed with transient occupation of the D2 receptor. The times for 50% dissociation from D2 receptors are: 30 min for 1.5 nM chlorpromazine, 38 min for 2 nM haloperidol, 27 min for 2 nm risperidone, 17 min for 5 nM olanzapine, 60 s for 2 nM paliperidone, 52 s for 10 nM aripiprazole, and 16 s for 200 nM of quetiapine.8 Compared to some second generation antipsychotics, paliperidone has a longer dissociation rate which may explain the presence of dystonic reactions observed in this case series. Although olanzapine has a much higher dissociation time, its potent anticholinergic effects are comparable to 2.1 nM of benztropine which provides anti-extrapyramidal effects.8 Paliperidone is the active metabolite of risperidone through CYP2D6 hydroxylation, so similarities in toxicity may be expected. In a case series of both single-substance risperidone overdoses and overdoses with co-ingestants, investigators found that tachycardia and dystonic reactions were the most common features of toxicity in risperidone only overdoses.9 Extrapyramidal symptoms were observed with a frequency of 11% in risperidone overdose cases, and more than 5% from clinical trials.10 In this study, extrapyramidal symptoms (dystonic reactions) were similarly observed in 14.2% of cases. Dystonias occurred in 34.7% of patients with adverse reactions, 8.7% of therapeutic errors and 6.6% of suspected suicide attempts. This demonstrates that while dystonic reactions occur in both therapeutic and overdose situations, it most frequently presents as an adverse reaction with therapeutic use. There are some limitations in this study. This is a retrospective review of poison center data which relies on history provided by the patient and clinical reports provided by hospital staff. Consequently, coded data provided by poison centers may be incomplete; under-reporting of clinical effects and treatments has been previously
described.11 There is no laboratory confirmation but paliperidone blood concentrations are not generally available. Poison center charts were reviewed only for cases coded as major effect and medical outcome was re-coded when cases did not adhere strictly to the NPDS definition for major effect. Poison center charts were not available for other outcomes so that it is conceivable that some of the minor and moderate outcomes were misclassified. However, even if some of the 516 minor and moderate outcome cases were misclassified, the numbers are sufficient to support the conclusion that the majority of patients experienced no or minimal toxicity. Dose information was provided in three-quarters of the acute exposures, and therefore may not be generalized to all paliperidone exposures. In addition, the dose was considered exact in only 30% of cases, so that the dose response is based largely on estimated doses.
Conclusions In conclusion, in this retrospective observational case series of national poison center data, the majority of patients experienced minor toxicity and did not require medical admission. However, a third of patients developed moderate or major toxicity and were admitted for medical care. Although a higher reported dose was associated with serious toxicity in children less than 6 years, the data do not provide clearcut triage guidelines.
Disclaimer The American Association of Poison Control Centers (AAPCC; http://www.aapcc.org) maintains the national database of information logged by the country’s 57 Poison Centers (PCs). Case records in this database are from selfreported calls: they reflect only information provided when the public or healthcare professionals report an actual or potential exposure to a substance (e.g., an ingestion, inhalation, or topical exposure, etc.), or request information/ educational materials. Exposures do not necessarily represent a poisoning or overdose. The AAPCC is not able to completely verify the accuracy of every report made to member centers. Additional exposures may go unreported to PCs and data referenced from the AAPCC should not be construed to represent the complete incidence of national exposures to any substance(s).
Acknowledgments We thank Larry Gonzales, B.S., senior IT specialist and Yolande Tra, Ph.D., senior statistician at the Maryland Poison Center for their assistance with data analysis.
Declaration of interest The authors report no declarations of interest. The authors alone are responsible for the content and writing of the paper. Clinical Toxicology vol. 52 no. 3 2014
Paliperidone toxicity 213
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1. Chwieduk CM, Keating GM. Paliperidone extended release: a review of its use in the management of schizophrenia. Drugs 2010; 70: 1295–1317. 2. Invega® (paliperidone) Extended-Release Tablets [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc., June 2011. 3. Levine M, Lovecchio F, Tafoya P, Graham R. Paliperidone overdose with delayed onset of toxicity. Ann Emerg Med 2011; 58:80–82. 4. Chang JP, Huang CC, Su KP. Paliperidone overdose in a patient with schizophrenia. Prog Neuropyschopharmacol Biol Psychiatry 2010; 34:418. 5. Gill JS, Pillai SK, Koh OH, Jambunathan S. Non-fatal paliperidone overdose: a case report. Turkish J Psychiatry 2010; 21:331–334.
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6. Lapid MI, Cunningham JL, Hugo Z, Kung S. Acute dystonia associated with paliperidone overdose. Psychosomatics 2011; 52:291–294. 7. Liang CS, Bai YM, Liou YJ, Chou YH. Acute renal failure after paliperidone overdose: a case report. J Clin Psychopharmacology 2012; 32:128. 8. Seeman P. An update of fast-off dopamine D2 atypical antipsychotics. Am J Psychiatry 2005; 162:1984–1985. 9. Page CB, Calver LA, Isbister GK. Risperidone overdose causes extrapyramidal effects but not cardiac toxicity. J Clin Psychopharmacol 2010; 30:387–390. 10. Risperdal®, Risperdal® M-TAB® (risperidone) tablets, oral solution, and orally disintegrating tablets [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc., Nov 2013. 11. Jaramillo JE, Marchbanks B, Willis B, Forrester MB. Evaluation of completeness of selected poison control center data fields. J Med Syst 2010; 34:499–507.
POISON CENTRE
Toxicity and clinical outcomes of paliperidone exposures reported to U.S. Poison Centers M. E. TSAY, W. KLEIN-SCHWARTZ, and B. ANDERSON
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Department of Pharmacy Practice and Science, Maryland Poison Center, University of Maryland School of Pharmacy, Baltimore, MD, USA
Context. Paliperidone is an atypical antipsychotic that was approved in the U.S. in 2006, and is also available in Canada, Australia, New Zealand, Europe, and Asia. Information regarding paliperidone overdoses is limited to case reports. Serious toxicity has yet to be reported. Objective. To evaluate the toxicity of paliperidone exposures using a national poison center database. Methods. A retrospective, observational case series of single-substance paliperidone cases reported to the National Poison Data System from 2007 to 2012 was conducted. Cases were evaluated for demographics, reason for exposure, clinical effects, treatments, disposition, and coded medical outcomes. For cases with major effects the text fields in poison center charts were evaluated to verify accuracy of coded outcome. The relationship between dose and severity of medical outcome was analyzed for acute exposure cases. Results. There were 801 paliperidone cases that met inclusion criteria that included 592 persons of 13 years or greater, 67 children of 6–12 years, 140 children of less than 6 years, and 2 unknown ages. Most common reasons for exposure included: suicide attempt (39.6%), unintentional general (21.1%), therapeutic error (15.7%), and adverse drug reaction (11.9%). The most commonly observed clinical effects were drowsiness/lethargy (28.7%), tachycardia (23.3%), and dystonia (14.2%). Most patients were managed in the emergency department (40.3%) or were admitted to a health care facility (HCF) (42.7%). In 564 cases treated in a HCF, treatments included activated charcoal (25.7%), antihistamines (21.1%), and benzodiazepines (9.4%). Medical outcomes were no effect (35.0%), minor (30.8%), moderate (33.7%), and major effect (0.5%). There were no deaths. Of 491 acute exposures, dose was coded for 74.3% of exposures. There was a significant difference in the reported median dose between those with no effect (6 mg) and either minor effect (12 mg; p ⫽ 0.047) or moderate effect cases (12 mg; p ⫽ 0.020) in 91 children less than 6 years. Conclusions. The majority of patients experienced no or minor toxicity and were not admitted for medical care. Although a higher dose was associated with a more serious outcome in children less than 6 years, the data do not provide clear-cut triage guidelines. Keywords
Atypical; Antipsychotic; Toxicity; overdose
Introduction
started at 6 mg/day (3 mg/day for adolescents) and may be titrated up to a maximum daily dose of 12 mg (6 mg for adolescents). Dosing should be adjusted for elderly patients and those with renal impairment. Paliperidone ER tablets are formulated in 1.5, 3, 6, and 9 mg tablets and utilize the Osmotic-controlled Release Oral delivery System technology allowing for once-a-day dosing.2 Like other atypical antipsychotics, paliperidone ER carries a warning label for the potential to cause neuroleptic malignant syndrome, QT prolongation, tardive dyskinesia, metabolic changes, and cerebrovascular adverse reactions in elderly patients with dementia-related psychosis. Clinical trials of paliperidone ER reported more than 5% incidence (versus placebo) of extrapyramidal symptoms, tachycardia, and akathisia.2 While there are published data on adverse effects from therapeutic doses, there are only limited data on toxicities associated with supratherapeutic (higher than therapeutic) doses or overdoses. Published case reports of paliperidone overdoses display a wide dosage range of 42 –756 mg.3–7 Based on reports of
Invega®,
Paliperidone ER (extended release), is an atypical antipsychotic approved by the Food and Drug Administration (FDA) in the United States on December 20, 2006 for the treatment of schizophrenia and schizoaffective disorder. It is also available for use in Canada, Australia, New Zealand, Europe, and Asia. As an active metabolite of risperidone, paliperidone (9-hydroxyrisperidone) exhibits antagonistic properties at the D2 and 5-HT2A receptors. In addition, paliperidone has some antagonistic effects at α1-adrenoceptors as well as low binding affinities to both α2-adrenoceptors and H1 receptors.1 Indications for the treatment include acute and maintenance therapy of schizophrenia and schizoaffective disorder, or as an adjunct to mood stabilizers and/or antidepressants. Paliperidone is Received 11 September 2013; accepted 5 January 2014. Address correspondence to Mingzohn Ellen Tsay, Department of Pharmacy Practice and Science, Maryland Poison Center, University of Maryland School of Pharmacy, 220 Arch Street, Office level 1, Baltimore, MD 21201, USA. Tel: ⫹(410)-563-5589. E-mail: [email protected]
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both single- and multi-drug ingestions, overdosed patients have been observed to experience tachycardia and altered mental status.3–7 In one case involving a multi-drug ingestion, the patient experienced a dystonic reaction,6 and in another, the patient experienced acute kidney injury that eventually resolved.7 While serious toxicity or deaths have yet to be reported, data from case reports are insufficient to generalize the potential for serious toxicity. Therefore, a systematic review of poison center data was undertaken. The primary objective of this study is to evaluate the toxicity of paliperidone exposures. The secondary objective of this study is to evaluate the relationship between medical outcomes and the dose ingested.
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Methods A retrospective, observational case series of single-substance paliperidone exposures reported to the National Poison Data System (NPDS) between January 2007 and June 2012 was conducted. Human exposure cases that were followed to a known medical outcome were included. Information calls, confirmed non-exposures, cases with co-ingestants, and cases without a known medical outcome were excluded. Coded data entered by poison specialists are uploaded to the NPDS. Coded data include age, gender, reason, product, dose, dose certainty (i.e., exact, estimate, or maximum possible), clinical effects, treatments, disposition (i.e., treatment site including non-health care facility (HCF), emergency department, critical care unit, non-critical care unit, psychiatric admission, and other) and medical outcomes. The reasons (i.e., intent) for exposure include unintentional general (unintended exposures, also known as accidental), therapeutic error, adverse drug reaction, misuse, abuse, suicidal, withdrawal, and unknown. Poison center coding of known medical outcomes include no effect, minor, moderate, major, and death. Patients with minor outcomes exhibited clinical effects as a result of the exposure, but they were minimally bothersome and resolved quickly with no residual disability. Patients with moderate outcomes exhibited clinical effects as a result of the exposure that were more pronounced, more prolonged, or more systemic than minor symptoms, usually some form of treatment was indicated; not life-threatening with no residual clinical effects or disability. Patients with major outcomes exhibited clinical effects as a result of the exposure that were life-threatening or resulted in significant residual disability or disfigurement. Cases that fit the inclusion criteria were evaluated for demographics (age and gender) and reason for exposure. Primary outcome Severity of exposure was analyzed by evaluation of clinical effects, treatments, patient disposition, and medical outcomes. For cases that were coded with a major medical outcome, the original poison center was contacted for a redacted (i.e., with patient identifiers removed) poison center record to review and confirm the coded clinical effects.
The investigators independently reviewed the major effect cases to determine whether the case met the definition for major; for those cases in which investigators disagreed, the case was discussed by investigators and categorized once all unanimously came to an agreement. Secondary outcome Acute exposures with both dose and age were further analyzed for a relationship between dose ingested and medical outcome in children less than 6 years, children between 6 and 12 years, and individuals age 13 or greater. Doses were either entered manually or were calculated based on the milligram strength associated with the product ID code and number of tablets ingested. Cases were excluded if there was an unknown age, no dose information, unknown or nonquantifiable amount ingested (ex, “taste, drop, or lick”), or coded as dose formulations that do not exist commercially (liquid preparations). Quantitative data were summarized by medians and ranges and categorical data by frequencies and percentages. Median doses were compared using Kruskal–Wallis (KW) test and post-hoc Mann–Whitney test with Holm’s correction. Categorical data were analyzed using Chi-square. Analyses were performed with RStudio (Integrated development environment for R, Version 0.96.122, Boston, MA) and all reported p-values were two-sided. Statistical significance was defined as p ⬍ 0.05. The study was granted exempt status by the University Institutional Review Board.
Results There were a total of 1,252 single-substance paliperidone cases identified during the study period, with 801 (64.0%) cases that met inclusion criteria. Excluded cases included 433 cases not followed to a known medical outcome for the following reasons: 280 cases were coded as nontoxic or minimal clinical effects possible, 110 cases were lost to follow-up, and 43 cases with clinical effects judged to be unrelated. In addition, 13 were confirmed as non-exposure cases and 5 were duplicate cases. Of the cases that met inclusion criteria, 364 (45.4%) were female, 435 (54.3%) were male, and 2 (0.2%) were unknown genders. There were 592 (73.9%) persons of 13 years or greater, 67 (8.4%) children of 6–12 years, 140 (17.5%) children of less than 6 years, and 2 (0.2%) of unknown ages. The most frequently reported reason for exposure was suspected suicidal (317, 39.6%), followed by unintentional general (169, 21.1%), therapeutic error (126, 15.7%), adverse drug reaction (95, 11.9%), intentional misuse (46, 5.7%), intentional abuse (19, 2.4%), unknown intent (28, 3.5%), and withdrawal (1, 0.1%). The most frequent reason for exposure by age group was unintentional general (131, 93.6%) in children under 6 years of age, therapeutic error or adverse reaction (46, 68.7%) in 6–12 year olds and suicide attempts (315, 53.2%) in patients 13 years of age or greater. Clinical Toxicology vol. 52 no. 3 2014
Paliperidone toxicity 209 Table 1. Clinical effects following paliperidone exposures by patient age. Clinical effect Drowsiness/lethargy Tachycardia Dystonia Agitated/irritable Tremor Hypertension Hypotension Confusion Dizziness/vertigo Muscle rigidity
⬍ 6 years n ⫽ 140 (%)
6–12 years n ⫽ 67 (%)
ⱖ 13 years n ⫽ 592 (%)
Total (%) n ⫽ 801*
48 (34.3) 23 (16.4) 14 (10.0) 8 (5.7) 9 (6.4) 1 (0.7) 3 (2.1) 3 (2.1) 0 0
23 (34.3) 13 (19.4) 18 (26.9) 1 (1.5) 2 (3) 1 (1.5) 1 (1.5) 3 (4.5) 2 (3) 6 (9)
159 (26.9) 151 (25.5) 81 (13.7) 35 (5.9) 25 (4.2) 27 (4.6) 24 (4.1) 20 (3.4) 18 (3.0) 12 (2.0)
230 (28.7) 187 (23.3) 114 (14.2) 44 (5.5) 36 (4.5) 29 (3.6) 28 (3.5) 26 (3.2) 20 (2.5) 18 (2.2)
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*In two cases, ages were unknown; one experienced no clinical effects; the other experienced a dystonic reaction.
Table 1 displays the top 10 observed clinical effects. In the 521 patients who experienced clinical effects, the most commonly observed effects were drowsiness/lethargy, tachycardia, and dystonias. More serious clinical effects such as hypotension (28, 3.5%), conduction disturbances (16, 2.0%), ECG changes (6, 0.8%), seizures (5, 0.6%), respiratory depression (4, 0.5%), and coma (4, 0.5%) were infrequently reported among all patients exposed to paliperidone. The frequency of the three most commonly reported clinical effects varied by intent. Drowsy/lethargy was most often reported in abuse cases (42.1%), least often reported in those with adverse drug reaction (13.7%), and occurred in approximately 25–30% of those with all other intents. Tachycardia was more frequent in those with intentional intent (31.2%) compared to those with other reasons (16.3%). Dystonias occurred most often in patients with adverse reaction, misuse, abuse, and unknown reason (34.7%, 41.3%, 36.8%, and 25.0%, respectively), and less often for other intents (unintentional general, 10.1%; therapeutic error, 8.7%; and suicide, 6.3%). Of note, the 6–12 year olds age group experienced the highest frequency of dystonias (26.9%) due to adverse reactions (n ⫽ 8), therapeutic errors (n ⫽ 6), unintentional general (n ⫽ 2), or misuse/abuse (n ⫽ 2) which mostly occurred in the context of either acute-on-chronic (n ⫽ 8) or chronic (n ⫽ 4) therapy. Tremor occurred in 14.7% of all adverse drug reaction cases but under 5% for all other intents.
The remaining clinical effects noted in Table 1 occurred in less than 5% of cases for all intents. Of 564 patients treated at a HCF, 145 received charcoal (25.7%). Excluding those with adverse drug reaction treated in a HCF, 145 of 498 (29.1%) were treated with activated charcoal. Other treatments administered to HCF-managed patients included intravenous (IV) fluids (183, 32.4%), antihistamines (119, 21.1%), and/or benzodiazepines (53, 9.4%). Of the 113 dystonic patients, 83 received antihistamines and 15 received benzodiazepines. A total of 11 of 18 patients who had muscle rigidity also received antihistamines. In three cases, patients were intubated and ventilated. Tables 2 and 3 display the disposition and coded medical outcomes, stratified by intent. The majority of cases were treated at a HCF, either in the ED, non-critical care, or critical care unit (564, 70.4%). Patients with therapeutic errors were most often managed outside a HCF or discharged from the ED without an admission, while suicidal patients were most likely to be admitted. The majority of adverse reaction cases as well as misuse and abuse cases were managed in the ED. Overall, 65.8% of all patients were asymptomatic or experienced minor effects. Patients with unintentional exposures (unintentional general and therapeutic errors) were usually asymptomatic or experienced minor effects. When intent was adverse reactions, misuse or abuse patients were most likely to develop toxicity, with a relatively high frequency of
Table 2. Patient disposition by intent.
Intent
Non-Health Care Facility
Unintentional (%) n ⫽ 169 Therapeutic error (%) n ⫽ 126 Adverse drug reaction (%) n ⫽ 95 Misuse (%) n ⫽ 46 Abuse (%) n ⫽ 19 Suicide (%) n ⫽ 317 Unknown (%) n ⫽ 28 Total (%) n ⫽ 801
30 (17.8) 55 (43.7) 20 (21.1) 4 (8.7) 3 (15.8) 2 (0.6) 1 (3.6) 116* (14.5)
*One case was due to withdrawal. ED, emergency department; AMA, against medical advice. Copyright © Informa Healthcare USA, Inc. 2014
ED/Discharged
Admitted to non-critical care unit
Admitted to critical care unit
Admitted to psychiatric care facility
Left AMA or refused referral
76 (45) 52 (41.3) 49 (51.6) 23 (50) 10 (52.6) 93 (29.3) 20 (71.4) 323 (40.3)
32 (18.9) 11 (8.7) 10 (10.5) 6 (13) 2 (10.5) 56 (17.7) 2 (7.1) 119 (14.9)
25 (14.8) 4 (3.2) 7 (7.4) 4 (8.7) 2 (10.5) 78 (24.6) 2 (7.1) 122 (15.2)
4 (2.4) 1 (0.8) 1 (1) 9 (19.6) 0 84 (26.5) 2 (7.1) 101 (12.6)
2 (1.2) 3 (2.4) 8 (8.4) 0 2 (10.5) 4 (1.3) 1 (3.6) 20 (2.5)
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No effect
Minor effect
Unintentional general (%) n ⫽ 169 Therapeutic error (%) n ⫽ 126 Adverse drug reaction (%) n ⫽ 95 Misuse (%) n ⫽ 46 Abuse (%) n ⫽ 19 Suicide (%) n ⫽ 317 Unknown (%) n ⫽ 28 Total (%) n ⫽ 801
88 (52) 59 (46.8) 3 (3.2) 10 (21.8) 3 (15.8) 108 (34) 9 (32.1) 280 (35.0)
33 (19.5) 43 (34.1) 28 (29.5) 15 (32.6) 6 (31.6) 115 (36.3) 6 (21.4) 247** (30.8)
Moderate effect 47 (27.8) 24 (19.0) 63 (66.3) 21 (45.7) 9 (47.4) 93 (29.3) 13 (46.4) 270 (33.7)
Major effect 1 (0.6) 0 1 (1.1) 0 1 (5.3) 1 (0.3) 0 4 (0.5)
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*# of major effect cases adjusted by review of charts. **One case was due to withdrawal.
moderate toxicity. Outcomes in suicidal patients were fairly evenly distributed between no effects, minor, and moderate effects. There were no fatalities, and only four cases met the definition of major medical outcome after adjustment through the manual review of cases coded as major effect. Redacted cases were obtained for 9 of 10 major effect cases, and both coded and free-text were reviewed by the investigators. In 6 of the 9 cases, the coded clinical effects and free-text portion of the case met the definition of minor or moderate effect rather than major effect. All patients with the exception of one (due to a late presentation) experienced tachycardia and lethargy, but half of the patients (6) experienced dystonic reactions. For the case for which the poison center chart was unavailable, the coded clinical effects and treatments supported the major effect outcome. Amongst the cases recoded from major effect to a less severe outcome were four patients with dystonias (three of which received and responded to diphenhydramine) and two patients with neurologic and/or cardiovascular clinical effects, persisting for 3 days in one case, which, while significant, were judged as not life threatening. Based on this investigation of the more serious cases, only 4 of the 801 cases experienced toxicity that met the standardized definition of major effect. A brief description of the four major cases follows: Case 1 A developmentally delayed 12-year-old male ingested 180 mg of paliperidone (acute-on-chronic) at an unknown time. He was admitted to the ICU with lethargy, tachycardia (140 beats/min) that worsened with position changes, and hypokalemia (3.0 mEq/L). Although the patient’s heart rate returned to normal one day post-presentation, he remained lethargic, developed dyskinesia with tongue movements that impaired his ability to swallow, and dystonic reactions that would last up to 25 min. He became tachycardic during dystonic reactions. The dystonia and dyskinesia persisted through his hospital stay of 3 days and was treated with antihistamines. Case 2 A 38-year-old male with a history of schizophrenia, mental retardation, and diabetes was transferred from a psychiatric facility to a hospital due to an adverse drug reaction. He
presented with dyskinesia, dystonia, tremors (which resolved with 25–50 mg of diphenhydramine), and diaphoresis. The patient takes 9 mg of paliperidone daily. He was admitted to a neurology service and symptoms improved with benzodiazepines and antihistamines. However, he developed rhabdomyolysis with a CPK of 4,719 IU/L and received IV fluids. He continued to experience episodes of tachycardia and was diaphoretic and tremulousness until days 3 and 5 of his hospital stay. He was treated with IV fluids, diphenhydramine, and bromocriptine. By days 5 the patient was discharged. Case 3 A 42-year-old female ingested an unknown amount of 9-mg paliperidone capsules in a suicide attempt, and was found unresponsive, and was intubated and placed on a ventilator. Four hours later she was able to breathe on her own but was tachycardic with a heart rate in the 120s beats/min and hypokalemic (3.4 mEq/L). The patient had a traumatic intubation, was put on antibiotics, and kept in the ICU for a total of 3 days. By the last day she was no longer lethargic and heart rate was normalized. Case 4 A 2-year-old ingested an unknown amount of paliperidone that was kept in the caretaker’s purse. He was admitted to a critical care unit and experienced ataxia, lethargy, ECG changes (other), hypotension, multiple discrete seizures, tachycardia, and tremors, and was managed with benzodiazepines, IV fluids, and supplemental oxygen. Of 491 acute exposure cases, 365 (74.3%) included dose information. In these 365 cases, 108 (29.6%) were coded “exact” dose, 209 (57.3%) were “estimated”, and 48 (13.2%) were “maximum dose possible”. Table 4 provides dose versus outcome by age group. There was a significant difference in outcome by reported mg dose in children less than 6 years (KW χ2(2) ⫽ 10.48, p ⫽ 0.0067). The median doses for minor effect (12 mg, range: 3–90) and moderate effect cases (12 mg; range, 3–63) were significantly higher than median dose for those children with no effect (6 mg; range 1.5–168) (p ⫽ 0.047 and 0.020, respectively). Given the wide range of weights Clinical Toxicology vol. 52 no. 3 2014
Paliperidone toxicity 211 Table 4. Acute ingestion dose versus medical outcomes for all reasons stratified by patient age. Median dose (range) (n ⫽ 365) ⬍ 6 years n ⫽ 91
Medical outcome* No effect Minor effect Moderate effect
6–12 years n ⫽ 28
ⱖ 13 years n ⫽ 246
6 mg (1.5—168 mg) n ⫽ 52 6 mg (3—36 mg) n ⫽ 10 36 mg (1.5—300 mg) n ⫽ 90 12 mg (3—90 mg) n ⫽ 13 6 mg (6—180 mg) n ⫽ 9 39 mg (1.5—390 mg) n ⫽ 78 12 mg (3—63 mg) n ⫽ 26 6 mg (1—108 mg) n ⫽ 9 25.5 mg† (1.5—4600 mg) n ⫽ 78
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Note: Within each age category, doses were compared between all medical outcome categories. *Four major effect cases not on table [unknown dose (2 cases); not acute ingestion (2 cases)] ¶Significant difference: p ⫽ 0.047 when compared with minor effect; p ⫽ 0.020 when compared with moderate effect. †Significant difference: p ⫽ 0.037 when compared with no effect; p ⫽ 0.037 when compared with minor effect.
in this age group, weight adjusted doses were also analyzed; the median mg/kg doses of 0.38 in no effect (n ⫽ 35; range, 0.10–14.21), 0.52 in minor effect (n ⫽ 8; range, 0.15– 6.60), and 0.85 in moderate effect (n ⫽ 19; range, 0.18–3.00) were significantly different (KW χ2(2) ⫽ 8.13, p ⫽ 0.017), with the median dose per kilogram significantly higher for children with moderate effects compared to those of no effects (p ⫽ 0.020). While median mg dose was significantly different for minor effect and no effect, this difference was not evident for median mg/kg dose. In children aged 6–12 years (KW χ2(2) ⫽ 0.36, p ⫽ 0.837), there was no significant difference in outcome by dose. In patients 13 years and older there was a significant difference in outcome by dose (KW χ2(2) ⫽ 6.8, p ⫽ 0.033). The median doses for no effect (N ⫽ 90; 36 mg; range, 1.5–300, p ⫽ 0.037) and for minor effect (N ⫽ 78; 39 mg, range, 1.5–390, p ⫽ 0.037) were significantly higher than median dose for moderate effect (N ⫽ 78; 25.5 mg; range, 1.5–4600).There was one suicide attempt in a 12-year-old who ingested 180 mg and experienced minor effects. In patients 13 years and older, median dose of 12 mg (1.5–180 mg) was lower for the 109 nonsuicidal patients than median dose of 60 mg (3–4600 mg) in the 137 suicidal patients (KW χ2(2) ⫽ 1570.5, p ⬍ 0.001). For both suicide attempts and other reasons there was no difference in dose by outcome (KW χ2(2) ⫽ 0.6, p ⫽ 0.741 and (KW χ2(2) ⫽ 1.72, p ⫽ 0.423, respectively).
Discussion From the limited published information in case reports of paliperidone overdoses, commonly observed clinical effects include tachycardia, altered mental status, and dystonic reactions. This investigation supports these findings. In all children under 13 years of age, drowsiness/lethargy and tachycardia were reported in 34% and 17%, respectively. These clinical effects were reported in approximately 26% of adolescents and adults. Dystonias occurred in 14% of patients overall, both in overdoses (e.g., suicide attempts) and with therapeutic doses, suggesting the presence of a lower dose threshold for the occurrence of dystonia. Paliperidone is not indicated for use in children less than 12 years, yet of the 67 cases in children 6–12 years of age, poison center staff coded the reason as therapeutic error or adverse reaction in 46 (69%) and the acuity as chronic or acute-on-chronic in 33 (49%) cases. Dystonias were more Copyright © Informa Healthcare USA, Inc. 2014
frequently reported in children of 6–12 years (27%) than those in younger children (10%) or in adolescents and adults (14%) (KW χ2(2) ⫽ 11.85, p ⫽ 0.0027). In 18 children of 6–12 years with dystonias, the coded reason was a therapeutic error or adverse reaction in 14 (78%), and acuities of acute-on-chronic or chronic were coded in 12 (67%). It is conceivable that in some instances these children 6–12 years were receiving paliperidone off-label with resultant dystonias. Based on coded medical outcomes, most patients (65%) experienced no toxicity or minor effects. Ten cases had major effects as coded outcomes. However, upon further review, half of these cases experienced clinical effects consistent with minor to moderate outcomes. Paliperidone exposures were largely managed with symptomatic and supportive care including the use of antihistamines and benzodiazepines, presumably for the treatment of acute dystonia. A total of 86.7% of patients with dystonias received either an antihistamine or benzodiazepine. Intubation and ventilator support was rare. Most patients did not require hospital admission, with approximately 40% of exposures managed and discharged from the emergency department. Only 15% of patients were admitted to an intensive care unit. These findings suggest that serious toxicity is uncommon with paliperidone-only ingestion. In children less than 6 years a significant difference was observed between the median dose ingested for exposures that led to no effect (6 mg; range, 1.5–168) and those that led to minor (12 mg; range, 3–90) or moderate effects (12 mg; range, 3–63). However, clinical effects such as acute dystonic reactions and tremors occurred at a relatively low dose of 3 mg (3–54 mg and 3–36 mg, respectively) in children less than 6 years. Overlapping lower-end doses between asymptomatic and moderately symptomatic children made it impossible to devise triage guidelines. Suspected suicides, therapeutic errors, and adverse drug reactions were all prominent reasons for exposures, which explain the wide range in doses ingested. In patients aged 13 years or older, exposures due to therapeutic errors (median dose, 12 mg; range, 1.5–39 mg) or adverse drug reaction (median dose, 6 mg; range, 1.5–12 mg) involved doses that mirror therapeutic doses, while doses in suicide attempts (median dose, 60 mg; range, 3–4600 mg) greatly exceeded the recommended maximum daily dose. The unexpected finding that in patients 13 years or older
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the median dose for moderate effect (25.5 mg; range, 1.5–4600) was significantly lower than median doses for either no effect (36 mg; range, 1.5–300) or minor effect (39 mg, range, 1.5–390) may partially be explained by the fact that some clinical effects associated with therapeutic errors and adverse drug reactions are serious enough to warrant the coding of the outcome as moderate effect, despite relatively low doses. Other factors that may have influenced these dose–outcome findings include inaccurate patient report on dose (especially in suicidal patients), estimation of dose, and/or the omission of dose ingested in 23% of patients in this age group. Suspected suicides occurred primarily in the persons 13 years and older (315 exposures), and rarely in children aged 6–12 years (2 exposures, with doses available only in one case, both in patients 12 years of age). First generation antipsychotics have been associated with a higher risk of the development of both extrapyramidal symptoms as well as prolactinemia due to their slower disassociation rate from the dopamine D2 receptors. Second generation antipsychotics have a much faster dissociation rate from the D2 receptors when compared to dopamine and cause fewer extrapyramidal symptoms due to the concept that dopamine neurotransmission would be allowed with transient occupation of the D2 receptor. The times for 50% dissociation from D2 receptors are: 30 min for 1.5 nM chlorpromazine, 38 min for 2 nM haloperidol, 27 min for 2 nm risperidone, 17 min for 5 nM olanzapine, 60 s for 2 nM paliperidone, 52 s for 10 nM aripiprazole, and 16 s for 200 nM of quetiapine.8 Compared to some second generation antipsychotics, paliperidone has a longer dissociation rate which may explain the presence of dystonic reactions observed in this case series. Although olanzapine has a much higher dissociation time, its potent anticholinergic effects are comparable to 2.1 nM of benztropine which provides anti-extrapyramidal effects.8 Paliperidone is the active metabolite of risperidone through CYP2D6 hydroxylation, so similarities in toxicity may be expected. In a case series of both single-substance risperidone overdoses and overdoses with co-ingestants, investigators found that tachycardia and dystonic reactions were the most common features of toxicity in risperidone only overdoses.9 Extrapyramidal symptoms were observed with a frequency of 11% in risperidone overdose cases, and more than 5% from clinical trials.10 In this study, extrapyramidal symptoms (dystonic reactions) were similarly observed in 14.2% of cases. Dystonias occurred in 34.7% of patients with adverse reactions, 8.7% of therapeutic errors and 6.6% of suspected suicide attempts. This demonstrates that while dystonic reactions occur in both therapeutic and overdose situations, it most frequently presents as an adverse reaction with therapeutic use. There are some limitations in this study. This is a retrospective review of poison center data which relies on history provided by the patient and clinical reports provided by hospital staff. Consequently, coded data provided by poison centers may be incomplete; under-reporting of clinical effects and treatments has been previously
described.11 There is no laboratory confirmation but paliperidone blood concentrations are not generally available. Poison center charts were reviewed only for cases coded as major effect and medical outcome was re-coded when cases did not adhere strictly to the NPDS definition for major effect. Poison center charts were not available for other outcomes so that it is conceivable that some of the minor and moderate outcomes were misclassified. However, even if some of the 516 minor and moderate outcome cases were misclassified, the numbers are sufficient to support the conclusion that the majority of patients experienced no or minimal toxicity. Dose information was provided in three-quarters of the acute exposures, and therefore may not be generalized to all paliperidone exposures. In addition, the dose was considered exact in only 30% of cases, so that the dose response is based largely on estimated doses.
Conclusions In conclusion, in this retrospective observational case series of national poison center data, the majority of patients experienced minor toxicity and did not require medical admission. However, a third of patients developed moderate or major toxicity and were admitted for medical care. Although a higher reported dose was associated with serious toxicity in children less than 6 years, the data do not provide clearcut triage guidelines.
Disclaimer The American Association of Poison Control Centers (AAPCC; http://www.aapcc.org) maintains the national database of information logged by the country’s 57 Poison Centers (PCs). Case records in this database are from selfreported calls: they reflect only information provided when the public or healthcare professionals report an actual or potential exposure to a substance (e.g., an ingestion, inhalation, or topical exposure, etc.), or request information/ educational materials. Exposures do not necessarily represent a poisoning or overdose. The AAPCC is not able to completely verify the accuracy of every report made to member centers. Additional exposures may go unreported to PCs and data referenced from the AAPCC should not be construed to represent the complete incidence of national exposures to any substance(s).
Acknowledgments We thank Larry Gonzales, B.S., senior IT specialist and Yolande Tra, Ph.D., senior statistician at the Maryland Poison Center for their assistance with data analysis.
Declaration of interest The authors report no declarations of interest. The authors alone are responsible for the content and writing of the paper. Clinical Toxicology vol. 52 no. 3 2014
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