INTRODUCTION — A second-generation of antipsychotic medications, commonly referred to as "atypical antipsychotics," was introduced in 1998. The term "atypical" refers to an antipsychotic medication that produces minimal extrapyramidal side effects (EPS) at clinically effective antipsychotic doses, has a low propensity to cause tardive dyskinesia (TD) with long-term treatment, and treats both positive and negative signs and symptoms of schizophrenia . Atypical agents currently available include clozapine (Clozaril), risperidone (Risperdal), olanzapine (Zyprexa), quetiapine (Seroquel), ziprasidone (Geodon), aripiprazole (Abilify), and paliperidone (Invega), the active metabolite of risperidone. Some newer atypical antipsychotics include asenapine (Saphris), iloperidone (Fanapt) and lurasidone (Latuda).
Atypical antipsychotics have largely replaced traditional agents as first-line therapy in the treatment of schizophrenia. Toxicologic exposures and fatalities associated with atypical agents pose a persistent problem in the United States and elsewhere [2-4]. Consequently, it is important for the practicing clinician to be familiar with the pharmacology and toxicology of these medications.
This topic review will discuss the basic pharmacology, presentation, and management of acute intoxication with atypical antipsychotics. Discussions of the clinical use of these drugs, details concerning potential side effects, and general management of drug overdose are found elsewhere.
●(See "Neuroleptic malignant syndrome".)
PHARMACOLOGY AND CELLULAR TOXICOLOGY — The pharmacology of atypical antipsychotic agents is complex. As a general rule, all exhibit dopamine (D2) receptor blockade, similar to first-generation antipsychotics, but with a lower binding affinity . In addition to lower D2 receptor potency and occupancy at therapeutic doses, atypical agents selectively antagonize mesolimbic D2 receptors more so than those in the nigrostriatum and prefrontal cortex. As a result, side effects attributable to nigrostriatal D2 blockade (eg, extrapyramidal symptoms, such as acute dystonia, parkinsonism, akathisia, and tardive dyskinesia) occur less frequently, as do side effects attributable to mesocortical (ie, prefrontal) D2 blockade (eg, neurocognitive impairment and negative symptoms).
Atypical antipsychotics are also serotonin (5-HT) antagonists at the 5-HT2A receptor subtype. This pharmacologic effect mitigates the negative signs and symptoms of schizophrenia by disinhibiting the dopamine system in the nigrostriatum and prefrontal cortex .
Serotonin-dopamine antagonism is the reason why atypical antipsychotics may be given at smaller doses, producing fewer extrapyramidal side effects, while maintaining clinical efficacy .
In addition to the common mechanisms noted above, each atypical agent has a unique pharmacodynamic profile that can be used to predict adverse effects in both therapeutic use and overdose. Although each agent has different affinities for specific receptors, most drugs fall into one of two groups. The first group consists of clozapine, olanzapine, and quetiapine, all of which demonstrate multiple receptor antagonism (alpha-1, histamine-1, and muscarinic-1). The second group consists of risperidone, paliperidone, and ziprasidone, which demonstrate alpha-1 adrenergic and histamine-1 receptor antagonism [6,7].
The atypical antipsychotic aripiprazole possesses a unique receptor profile. Postsynaptic partial dopamine agonism blunts positive symptoms, while basal D2 receptor activation produces fewer movement disorders than nonspecific dopamine antagonists [8,9]. Aripiprazole also binds to presynaptic dopamine autoreceptors, reducing dopamine release and synthesis [8,9]. These pre- and postsynaptic actions result in a neurotransmitter-level stabilizing effect, blunting excess activity and augmenting deficient activity. Aripiprazole also has a low affinity for serotonin, alpha-1 adrenergic, and histamine-1 receptors. This novel receptor affinity pattern explains the efficacy and favorable side effect profile of this agent [8,9].
The newer antipsychotics also have some unique features :
●Iloperidone has low antimuscarinic receptor and antihistaminic receptor activity and should result in less tachycardia sedation and agitation.
●Asenapine is taken via the sublingual route. If swallowed, its bioavailability significantly decreases from 35 to 2 percent. It has high affinity and antagonism for serotonin, alpha adrenergic, dopamine and histamine receptors but not muscarinic receptors. Consequently, hypotension and sedation are more likely to occur without tachycardia or agitation.
●Lurasidone possesses potent alpha-2C adrenoreceptor antagonism and low alpha-1 adrenergic antagonism. This may result in less hypotension. The alpha-2C adrenoreceptor is located presynaptically and functions as an inhibitory autoreceptor similar to alpha-2A adrenoreceptors, preventing norepinephrine release.
PHARMACOKINETICS — Atypical antipsychotics are completely and rapidly absorbed after oral administration, but undergo significant first-pass hepatic metabolism (table 1). Time to peak plasma concentration ranges from 1 to 10 hours. Atypical antipsychotics have a large volume of distribution. They are highly lipophilic, highly protein-bound, and accumulate in the brain, lung, and other tissues. Plasma concentrations with therapeutic dosing are quite low (nanograms per milliliter). These agents enter breast milk and fetal circulation.
The liver metabolizes atypical antipsychotics predominantly via cytochrome P450 enzymes (isoenzymes 1A2, 2D6, and 3A4). Therefore, serum levels may be affected by other medications that stimulate or inhibit the cytochrome P450 system.
Some atypical agents have active metabolites. Long elimination half-lives and active metabolites allow for once or twice-daily therapeutic dosing. The correlation between doses, serum concentration, and clinical effects is quite variable. Fetuses, infants, and the elderly have less ability to metabolize these agents because of decreased cytochrome p450 activity, while children metabolize them more rapidly [11,12]. While risperidone is subject to drug interactions affecting the CYP2D6 enzyme, in vivo studies suggest this isozyme plays a limited role in the clearance of paliperidone, the major active metabolite of risperidone. This property of paliperidone makes dose adjustment unnecessary in patients with mild to moderate hepatic impairment.
CLINICAL FEATURES OF OVERDOSE
Overview — In acute overdose, atypical antipsychotics cause only mild to moderate toxicity in the majority of patients, and may produce no symptoms (table 2) [5,13]. Although the number of reported exposures has increased dramatically, mortality remains low [4,14]. Toxic effects that do occur following overdose are largely an extension of a drug's physiologic effects (table 3). (See 'Pharmacology and cellular toxicology' above and 'History and physical examination' below.)
The toxic and lethal doses of atypical antipsychotics are highly variable and depend largely on the specific drug, the presence of co-intoxicants, age, and whether the patient is taking the drug for the first time. Children and unhabituated adults are more sensitive to the toxic effects of these agents. (See 'Pediatric considerations' below.)
Toxicity from atypical antipsychotics usually begins within one to two hours and peaks by four to six hours following ingestion, and the effects are similar for both adults and children. Resolution of toxicity usually occurs by 12 to 48 hours following ingestion but has reportedly taken up to six days .
History and physical examination — The diagnosis of atypical antipsychotic overdose is primarily based upon a history of ingestion and clinical findings. Central nervous system (CNS) effects occur most frequently (table 3). Extrapyramidal side effects (EPS) and neuroleptic malignant syndrome (NMS) are infrequent, but are more common in children . (See "Neuroleptic malignant syndrome".)
The most common clinical presentation consists of:
●Lethargy and sedation (from histamine blockade)
●Miosis, tachycardia, and orthostatic hypotension (from alpha adrenergic blockade)
●Anticholinergic toxicity, including confusion (from muscarinic blockade) (see "Anticholinergic poisoning")
Certain effects may be more common with specific agents. A large retrospective case series found that quetiapine overdose appears more likely to cause respiratory depression, depressed mental status, and hypotension compared to other antipsychotics . Numerous case reports have described rapid fluctuations between sedation and agitation in olanzapine overdose, deemed "agitation despite sedation." The incidence of seizures is higher for clozapine (10 percent) than for most atypical agents (less than 1 percent) .
The pharmacology of atypical antipsychotics is complex, and presentations of patients who have overdosed on these drugs vary, especially if the patient has ingested a multiple receptor antagonist (eg, clozapine or olanzapine). The development of pharmacobezoars following overdose of extended release formulations of quetiapine has been reported . (See 'Pharmacology and cellular toxicology' above and "Gastric bezoars".)
Possible historical features
●CNS – Fatigue/lethargy/sedation/agitation, confusion, dizziness, slurred speech, seizure, delirium, coma
●Cardiopulmonary – Dyspnea, chest pain, palpitations
●Anticholinergic manifestations – Blurry vision, dry mouth, constipation, urinary retention
●Gastrointestinal (rare) – Nausea, vomiting, abdominal pain
Possible examination findings
●CNS – Miosis (sometimes mydriasis), ataxia, dysarthria, dystonia, hypotonia, extrapyramidal side effects (eg, acute dystonia, parkinsonism, akathisia, tardive dyskinesia), rapidly fluctuating mental status (depression and agitation), hypersalivation, myoclonus, seizures, coma
●Cardiopulmonary – Tachycardia, orthostatic hypotension/mild hypertension, respiratory depression
●Anticholinergic – Facial flushing, dry mucous membranes, decreased sweating, mild hyperthermia
●Gastrointestinal – Abdominal tenderness, usually localized to the right upper quadrant, decreased bowel sounds
LABORATORY EVALUATION — Routine laboratory evaluation of the poisoned patient includes the following:
●Fingerstick glucose, to rule out hypoglycemia as the cause of any alteration in mental status
●Acetaminophen and salicylate levels, to rule out these common coingestions
●Electrocardiogram (ECG), to rule out conduction system poisoning by drugs that affect the QRS or QTc intervals
●Pregnancy test in women of childbearing age
No specific clinically useful test for atypical antipsychotic intoxication exists. Of note, atypical antipsychotics, particularly quetiapine, may produce a false positive test for tricyclic antidepressants .
Sinus tachycardia is the most common abnormal ECG finding, but other aberrations can occur. These include dose-related repolarization abnormalities (QTc prolongation, ST depression, T wave flattening) and supraventricular/ventricular dysrhythmias . Such ECG findings are usually clinically insignificant, despite some cases of QTc prolongation.
Of the atypical antipsychotics that increase the QTc interval, ziprasidone, quetiapine, and risperidone are all associated with this ECG finding, but only quetiapine and risperidone are associated with an increased risk of developing Torsades de pointes . Aripiprazole did not cause QTc prolongation or cardiotoxicity in preclinical trials or in the few published case reports of drug toxicity (table 4) [15,19-33].
Although unrelated to overdose, certain atypical agents have been shown to increase serum prolactin levels (risperidone), cause hyperglycemia (clozapine and olanzapine), increase liver transaminases (clozapine, olanzapine, quetiapine, risperidone, and ziprasidone), and induce agranulocytosis or leukopenia/neutropenia (clozapine and olanzapine) [34-37]. Most of these effects are idiosyncratic.
Additional testing may be needed depending upon the clinical situation, such as creatine phosphokinase and urine myoglobin in a patient found down and at risk for rhabdomyolysis, cerebrospinal fluid analysis in a patient with altered mental status of unclear etiology, or liver transaminases in a patient with significant abdominal pain.
Qualitative screening by gas chromatography/mass spectrometry may be used to confirm the presence of atypical agents, but this is almost never clinically indicated. Quantitative drug concentrations are not generally used, since they are not readily available and do not predict toxicity or guide treatment .
DIAGNOSIS — The diagnosis of second-generation (atypical) antipsychotic poisoning is made clinically based upon a history of ingestion and suggestive clinical findings. A definitive diagnosis may be established using gas chromatography/mass spectrometry, but this is almost never clinically indicated and the results typically cannot be obtained in time to affect management. The most common clinical findings associated with atypical antipsychotic poisoning include lethargy and sedation; miosis, tachycardia, and orthostatic hypotension; and, anticholinergic toxicity. Effects can vary by agent. (See "Anticholinergic poisoning".)
DIFFERENTIAL DIAGNOSIS — Atypical antipsychotics interact with multiple receptors. Therefore, signs and symptoms of atypical antipsychotic overdose are similar to those seen with many other agents, which can make differentiation among potential poisons difficult. Below is a list of drugs commonly encountered in the overdose patient and the potential manifestations of acute intoxication they share with atypical antipsychotics:
●Traditional antipsychotics (table 2): extrapyramidal side effects (EPS), tardive dyskinesia (TD), neuroleptic malignant syndrome (NMS), anticholinergic, alpha adrenergic-blockade, prolonged QTc, CNS/respiratory depression (see "Neuroleptic malignant syndrome" and "Anticholinergic poisoning")
●Ethanol/toxic alcohols (ethylene glycol, methanol): CNS/respiratory depression (see "Methanol and ethylene glycol poisoning: Pharmacology, clinical manifestations, and diagnosis" and "Ethanol intoxication in adults")
General management — The treatment for atypical antipsychotic overdose is primarily supportive. The general approach to any poisoned patient begins with stabilization of the airway, breathing, and circulation. General discussions of the management of poisoning are found elsewhere. Detailed management of intoxication with second-generation antipsychotics is discussed immediately below. A summary table of signs and symptoms is provided (table 3). (See "General approach to drug poisoning in adults" and "Gastrointestinal decontamination of the poisoned patient" and "Initial management of the critically ill adult with an unknown overdose".)
Every patient requires continuous cardiac monitoring, intravenous (IV) access, an electrocardiogram (ECG), and continual reevaluation for mental status changes. Altered mental status can range from profound depression to signs of extrapyramidal side effects (EPS), tardive dyskinesia (TD), neuroleptic malignant syndrome (NMS), or seizures (table 4) [37,38]. (See "Neuroleptic malignant syndrome".)
Hypotension secondary to alpha adrenergic (alpha) blockade is treated initially with IV boluses of isotonic crystalloid. Refractory hypotension, due to peripheral alpha blockade by atypical antipsychotics, can usually be treated with vasoconstrictive alpha agonists such as norepinephrine or phenylephrine. Drugs with beta 2 agonist effects (eg, epinephrine) should be avoided as they can exacerbate the vasodilatory effects of alpha blockade .
Cardiac dysrhythmias (supraventricular and ventricular) are treated according to standard advanced cardiac/pediatric life support guidelines, with a few exceptions. Antidysrhythmics that prolong the QTc interval, such as type IA (quinidine, procainamide), IC (flecainide, propafenone), and III (amiodarone, sotalol, ibutilide) medications should be avoided, as they may exacerbate conduction abnormalities. A type IB antidysrhythmic agent (eg, lidocaine) may be used. QRS prolongation may be treated with IV sodium bicarbonate, as with cyclic antidepressants and other Na+ channel blocking agents . (See "Advanced cardiac life support (ACLS) in adults" and "Tricyclic antidepressant poisoning".)
Seizures secondary to atypical antipsychotic toxicity are usually isolated and self-limited, and treatment with anticonvulsant agents is rarely needed. If treatment is necessary, benzodiazepines (such as lorazepam) are first-line therapy .
Decontamination and enhanced elimination — Whenever feasible, we suggest a single dose of activated charcoal (AC) with or without a cathartic (eg, sorbitol) be given as soon as the patient with second-generation antipsychotic poisoning has been stabilized . Gastric lavage is not recommended because these agents are associated with low mortality in overdose. AC should be withheld in patients who are sedated and may not be able to protect their airway, unless tracheal intubation is performed first. However, tracheal intubation should not be performed solely for the purpose of giving AC. (See "Gastrointestinal decontamination of the poisoned patient".)
The high-protein binding, large volume of distribution, and low plasma levels of atypical antipsychotics make extracorporeal removal, by either hemodialysis or hemoperfusion, unlikely to be of benefit . We do not recommend its use.
Extrapyramidal and anticholinergic effects — Acute extrapyramidal side effects (eg, dystonia) due to second-generation antipsychotic poisoning may be treated with anticholinergic agents, such as diphenhydramine or benztropine. Patients with neuroleptic malignant syndrome require supportive treatment, which may include active cooling, benzodiazepines, bromocriptine, or neuromuscular blockade, depending upon the degree of symptoms. Treatment for tardive dyskinesia includes benzodiazepines and supportive care [41,42]. (See "Neuroleptic malignant syndrome" and "Tardive dyskinesia: Etiology, risk factors, clinical features, and diagnosis" and "Tardive dyskinesia: Prevention, treatment, and prognosis".)
Anticholinergic effects of atypical antipsychotics may contribute to the severe agitation and altered level of consciousness seen in acute overdose. Benzodiazepines are usually adequate to control these symptoms. Physostigmine, a short-acting acetylcholinesterase inhibitor, has been successfully used to reverse the anticholinergic syndrome seen with clozapine and olanzapine [43-45]. (See "Anticholinergic poisoning".)
Physostigmine has potential adverse effects (bradycardia, bronchospasm, bradypnea), and its use as an antidote for atypical antipsychotic overdose is not clearly defined. We recommend that physostigmine only be used in the treatment of atypical antipsychotic poisoning in consultation with a medical toxicologist or poison control center. Patients with cyclic antidepressant toxicity should not receive physostigmine [43,44,46]. Anticholinergic toxicity and physostigmine therapy are discussed in detail elsewhere. (See "Anticholinergic poisoning", section on 'Antidotal therapy with physostigmine for severe toxicity'.)
Refractory toxicity — In the rare case of severe poisoning from a second-generation antipsychotic that fails to improve with the standard treatments described above, lipid emulsion therapy may be useful. However, support for this intervention consists solely of case reports and we cannot recommend routine treatment with lipid emulsion [47,48].
Disposition — Second-generation antipsychotic agents are associated with a rapid onset of symptoms following overdose, so disposition is generally determined within six hours of ingestion. Patients who remain asymptomatic after a six-hour observation period require no further medical evaluation, assuming no cardiac conduction abnormalities develop during the observation period and no other significant clinical issues are present. Psychiatry consultation is needed for suicidal patients. Patients with moderate to severe toxicity (CNS/respiratory depression, hypotension, agitation/delirium, dysrhythmias) should be admitted to a monitored bed or intensive care unit, depending on symptom severity.
PEDIATRIC CONSIDERATIONS — Mental health clinicians are treating children and adolescents with atypical antipsychotics at increasing rates for a range of psychiatric illnesses, despite limited data on their efficacy in this age group . The diversity of indications has contributed to the increased use of these agents, and increased episodes of overdose. In the United States, approximately 6,000 annual exposures to atypical antipsychotic agents occur in children 19 years of age and younger; international data is limited. Significant adverse effects, including major outcomes and death, are uncommon in reported single exposures .
Among the newer antipsychotics, asenapine is indicated in children 10 years and older for bipolar I disorder. The other new agents, iloperidone and lurasidone, do not have this US Food and Drug Administration (FDA)-approved pediatric indication.
Most published reports of overdose do not contain data on long-term consequences and are unable to provide conclusions about the significance of blood levels, the differences in duration of symptoms by age or size, or the relationship between the severity of symptoms and the dose ingested. Assessment and management in children is similar to that of adults; history and clinical presentation remain paramount. The most frequent clinical presentation of overdose in children includes nausea and vomiting, lethargy, drowsiness, somnolence, tachycardia, and central nervous system (CNS) depression [8,13,38,50].
Children may be at increased risk of toxicity with atypical antipsychotics. Children metabolize these drugs more rapidly, and, because children generally have less adipose tissue and lower levels of protein-binding, consequently there may be increased drug bioavailability . Therefore, we suggest that children who have ingested atypical antipsychotic medications and are asymptomatic be observed for six hours. Clinicians should maintain a low threshold for admitting mildly symptomatic children.
Supportive treatment and close observation are the mainstays of management. Sorbitol should not be given to young children because of the risk of excessive fluid loss. As with adults, the majority of toxicity in children due to atypical antipsychotics results in good outcomes [13,50]. Nevertheless, a small number of case reports describe instances when endotracheal intubation and admission to an intensive care unit were necessary [51,52]. (See "Gastrointestinal decontamination of the poisoned patient".)
Regional poison control centers — Regional poison control centers in the United States are available at all times for consultation on patients with known or suspected poisoning, and who may be critically ill, require admission, or have clinical pictures that are unclear (1-800-222-1222). In addition, some hospitals have medical toxicologists available for bedside consultation. Whenever available, these are invaluable resources to help in the diagnosis and management of ingestions or overdoses. Contact information for poison centers around the world is provided separately. (See "Society guideline links: Regional poison control centers".)
Society guideline links — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: General measures for acute poisoning treatment" and "Society guideline links: Treatment of acute poisoning caused by specific agents other than drugs of abuse".)
SUMMARY AND RECOMMENDATIONS
●First- versus second-generation antipsychotics – Atypical (second-generation) antipsychotic medications have largely replaced conventional first-generation medications for the treatment of schizophrenia because of their effectiveness and safer therapeutic and overdose profile (table 2). (See 'Introduction' above.)
●Pharmacology – The pharmacology of atypical antipsychotic agents is complex, involving several types of receptors. They all exhibit dopamine (D2) receptor blockade, similar to first-generation antipsychotics, but with a lower binding affinity. They are also antagonists at serotonin (5-HT), alpha-1, histamine-1, and muscarinic-1 receptors, with each having a unique pharmacodynamic profile that can be used to predict adverse effects in both therapeutic use and overdose (table 4). (See 'Pharmacology and cellular toxicology' above.)
●Clinical features of overdose – In acute overdose, atypical antipsychotics cause only mild to moderate toxicity in the majority of patients and may produce no symptoms. The toxic and lethal doses of atypical antipsychotics are highly variable and depend largely on the specific drug, the presence of co-intoxicants, patient age, and whether the patient is taking the drug for the first time (table 3). Children and unhabituated adults are more sensitive to the toxic effects of these agents. Atypical antipsychotics can cause a range of signs and symptoms, most often involving the central nervous system. The most common clinical presentation consists of (see 'Clinical features of overdose' above):
•Lethargy and sedation (from histamine blockade)
•Miosis, tachycardia, and orthostatic hypotension (from alpha adrenergic blockade)
•Anticholinergic toxicity, including confusion (from muscarinic blockade)
●Effects from specific agents – Certain effects in acute overdose may be more common with specific agents (see 'History and physical examination' above):
•Olanzapine – Rapid fluctuations between sedation and agitation can occur
•Clozapine – More often associated with seizures, although they are still uncommon
•Ziprasidone – Greatest effect on the QTc interval
●Differential diagnosis – Signs and symptoms of atypical antipsychotic overdose are shared by many agents, which can make differentiation among potential poisons difficult. Drugs commonly encountered in the overdose patient that may share manifestations of acute intoxication with atypical antipsychotics include traditional antipsychotics, cyclic antidepressants, anticonvulsants, antihistamines, opioids, muscle relaxants, sedative/hypnotics, ethanol/toxic alcohols, and antidysrhythmics. (See 'Differential diagnosis' above.)
●Laboratory evaluation – Obtain an electrocardiogram (ECG), salicylate and acetaminophen concentrations, a fingerstick glucose, and a qualitative pregnancy test in females of childbearing age. Obtain liver transaminases and a complete blood count in patients with altered mental status, abdominal pain, or other concerning findings (eg, possible acetaminophen co-ingestion). (See 'Laboratory evaluation' above.)
●Diagnosis – The diagnosis of atypical antipsychotic poisoning is made clinically based upon a history of ingestion and suggestive clinical findings. No specific, clinically useful test to identify atypical antipsychotic intoxication exists. A definitive diagnosis may be established using gas chromatography/mass spectrometry, but this is almost never clinically indicated, and the results typically cannot be obtained in time to affect management. (See 'Diagnosis' above.)
●Management – The management of atypical antipsychotic overdose is primarily supportive. Care includes continuous cardiac monitoring, intravenous (IV) access, and continual reevaluation for mental status. Management of specific findings includes the following (see 'General management' above):
•Hypotension is treated initially with IV crystalloid. Refractory hypotension due to peripheral alpha-adrenergic blockade can usually be treated with vasoconstrictive alpha agonists such as norepinephrine or phenylephrine.
•Seizures are generally brief and self-limited but may be treated with benzodiazepines (eg, lorazepam) if necessary.
●Gastrointestinal decontamination – In a patient with an acute overdose of an atypical antipsychotic medication, we suggest giving a single dose of activated charcoal (AC) with or without a cathartic (eg, sorbitol) (Grade 2C). AC should be withheld in patients who are sedated and may not be able to protect their airway, unless tracheal intubation is performed first. Tracheal intubation should not be performed solely for the purpose of giving AC. (See 'Decontamination and enhanced elimination' above.)
●Pediatric considerations – Children may be at increased risk of toxicity following atypical antipsychotic ingestion. We suggest that children who have ingested atypical antipsychotic medications and are asymptomatic be observed for six hours. Clinicians should maintain a low threshold for admitting mildly symptomatic children. Management is otherwise similar to adults. (See 'Pediatric considerations' above.)
●Disposition – Patients who remain asymptomatic after a six-hour observation period require no further medical evaluation, assuming no cardiac conduction abnormalities develop during the observation period and no other significant clinical issues are present. Patients with moderate to severe toxicity should be admitted to a monitored bed or intensive care unit, depending on symptom severity. (See 'Disposition' above.)
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