RISPERIDONE

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) R-64766
2) Molecular Formula: C23-H27-FN4-O2
3) CAS 106266-06-2

1.2.1) MOLECULAR FORMULA
1) RISPERIDONE - C23H27FN4O2

Available Forms Sources

1) GENERIC: Oral solution: 1 mg/mL; oral tablet: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg; oral tablet, disintegrating: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg.
2) RISPERDAL CONSTA: Intramuscular powder for suspension, extended release: 12.5 mg, 25 mg, 37.5 mg, 50 mg (Prod Info RISPERDAL(R) CONSTA(R) intramuscular long-acting injection , 2012).
3) RISPERDAL M-TAB: Oral tablet, disintegrating: 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg (Prod Info RISPERDAL(R) M-TAB(R) oral disintegrating tablets, 2012).
4) RISPERDAL: Oral solution: 1 mg/mL; oral tablet: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg (Prod Info RISPERDAL(R) oral tablets, oral solution, orally-disintegrating tablets, 2006).

1) Schizophrenia: RisperiDONE is approved for the treatment of schizophrenia (Prod Info RISPERDAL(R) oral tablets, oral solution, orally-disintegrating tablets, 2006).
2) Bipolar mania (monotherapy or combination therapy): RisperiDONE alone or in combination with lithium or valproate is approved for the short-term treatment of acute manic or mixed episodes associated with Bipolar I Disorder (Prod Info RISPERDAL(R) oral tablets, oral solution, orally-disintegrating tablets, 2006).
3) Irritability associated with autistic disorder: RisperiDONE is approved for the treatment of irritability associated with autistic disorder in children and adolescents, including symptoms of aggression towards others, deliberate self-injuriousness, temper tantrums and quickly changing moods (Prod Info RISPERDAL(R) oral tablets, oral solution, orally-disintegrating tablets, 2006).

Overview

Life Support

Clinical Effects

0.2.1)

A) USES: An atypical antipsychotic used to treat schizophrenia.
B) PHARMACOLOGY: A benzisoxazole derivative with high antagonist affinity for dopamine (D2) and serotonin (5-HT2) receptors.
C) TOXICOLOGY: Dopamine receptor blockade results in extrapyramidal symptoms, and alpha1-adrenergic effects are responsible for orthostatic hypotension. Its affinity, albeit low affinity, for histamine receptors contributes to anticholinergic effects.
D) EPIDEMIOLOGY: Unintentional and deliberate poisonings of atypical antipsychotics are common and occasionally severe.
E) WITH THERAPEUTIC USE

1) COMMON: Nausea, diarrhea, constipation, dizziness, somnolence, tachycardia, orthostatic hypotension, and extrapyramidal disorder.

F) WITH POISONING/EXPOSURE

1) MILD TO MODERATE TOXICITY: Tachycardia and hypotension are common. Depressed mental status, somnolence and extrapyramidal symptoms are also fairly common. In most cases, symptoms manifest mainly as mild central nervous system effects and reversible cardiovascular and neuromuscular effects.
2) SEVERE TOXICITY: QTc prolongation, extrapyramidal symptoms likely. Respiratory depression, seizure, or coma could potentially occur, as well as neuroleptic malignant syndrome.

0.2.3)

A) WITH POISONING/EXPOSURE

1) Hypotension may occur following overdose, as well as therapeutic use.

0.2.5)

A) WITH POISONING/EXPOSURE

1) Tachycardia, orthostasis and hypotension may occur with overdose.

0.2.6)

A) WITH POISONING/EXPOSURE

1) Delayed respiratory depression has been reported in a poor metabolizer after risperiDONE overdose. Rhinitis has been reported in patients in clinical trials.

0.2.7)

A) WITH THERAPEUTIC USE

1) Extrapyramidal disorder, neuroleptic malignant syndrome, somnolence, akathisia and seizure have been reported with therapeutic doses.

B) WITH POISONING/EXPOSURE

1) Drowsiness and sedation may occur with overdose.

0.2.8)

A) WITH THERAPEUTIC USE

1) Constipation, diarrhea, nausea, and dyspepsia have been reported following therapeutic administration of risperiDONE.
2) Pancreatitis has been reported with risperiDONE therapy.

0.2.9)

A) WITH THERAPEUTIC USE

1) Hepatitis has been reported with therapeutic doses.

0.2.12)

A) WITH POISONING/EXPOSURE

1) Hyponatremia, hypokalemia and hypomagnesemia have been reported rarely after overdose.

0.2.13)

A) WITH THERAPEUTIC USE

1) Leukopenia and neutropenia have been reported rarely following therapeutic use.

0.2.20)

A) RisperiDONE is classified as FDA pregnancy category C. Human and animal studies indicate that risperiDONE is excreted in breast milk and may affect the nursing child. RisperiDONE impaired mating, but not fertility, in female rats. Sperm motility and concentration, and serum testosterone were decreased in male dogs and remained decreased after risperiDONE was discontinued.

Laboratory Monitoring

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Management will primarily be symptomatic and supportive. Treat seizures with benzodiazepines. Manage mild hypotension with IV fluids.

B) MANAGEMENT OF SEVERE TOXICITY

1) Treat seizures with benzodiazepines. Manage hypotension with IV fluids and pressors if needed (norepinephrine is preferred). Treat ventricular dysrhythmias with sodium bicarbonate; add lidocaine or amiodarone if unresponsive to serum alkalinization. Manage severe extrapyramidal symptoms with anticholinergics and/or benzodiazepines. Treat neuroleptic malignant syndrome with benzodiazepines, bromocriptine, consider dantrolene, as well as cooling and supportive measures.

C) DECONTAMINATION

1) PREHOSPITAL: Prehospital gastrointestinal decontamination is not recommended due to the potential for somnolence, seizures and dystonic reaction.
2) HOSPITAL: Consider activated charcoal in a patient with a recent, substantial overdose who is alert or in whom airway is protected.

D) AIRWAY MANAGEMENT

1) Insure adequate ventilation and perform endotracheal intubation early in patients with serious cardiac toxicity, coma or significant CNS depression.

E) ANTIDOTE

1) None

F) SEIZURES

1) Administer IV benzodiazepines; add propofol, or barbiturates if seizures recur or persist.

G) HYPOTENSIVE EPISODES

1) Treat hypotension with intravenous fluids, add vasopressors if unresponsive to fluids. Norepinephrine is preferred; the manufacturer recommends avoidance of epinephrine and dopamine since beta stimulation may worsen hypotension in the setting of risperiDONE-induced alpha blockade.

H) DYSRHYTHMIAS

1) Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders (particularly hypokalemia, hypocalcemia, and hypomagnesemia). Sodium bicarbonate is generally first line therapy for QRS widening and ventricular dysrhythmias. Administer 1 to 2 mEq/kg, goal is serum pH 7.45 to 7.55. In patients unresponsive to bicarbonate, consider lidocaine or amiodarone.

I) NEUROLEPTIC MALIGNANT SYNDROME

1) Oral bromocriptine, benzodiazepines or oral or IV dantrolene in conjunction with cooling and other supportive measures.

J) ENHANCED ELIMINATION

1) Hemodialysis and hemoperfusion are UNLIKELY to be of value because of the high degree of protein binding.

K) PATIENT DISPOSITION

1) HOME CRITERIA: Children less than 12 years of age who are naive to risperiDONE can be observed at home following an unintentional ingestion of 1 mg or less and are only experiencing mild sedation. All patients, 12 years of age or older, who are naive to risperiDONE, can be observed at home following an unintentional ingestion of 5 mg or less and are experiencing only mild sedation. All patients who are taking risperiDONE on a chronic basis can be observed at home if they have acutely ingested no more than 5 times their current single dose (not daily dose) of risperiDONE. Patients who have not developed signs or symptoms more than 6 hours after ingestion are unlikely to develop toxicity.
2) OBSERVATION CRITERIA: Any patient with a deliberate ingestion or more than minor symptoms should be referred to a healthcare facility. Children less than 12 years of age who are naive to risperiDONE should be referred to a healthcare facility following an unintentional ingestion of more than 1 mg. All patients, 12 years of age or older, who are naive to risperiDONE should be referred to a healthcare facility following an unintentional ingestion of more than 5 mg. All patients who are taking risperiDONE on a chronic basis should be referred to a healthcare facility following an acute ingestion of more than 5 times their current single dose (not daily dose) of risperiDONE.
3) ADMISSION CRITERIA: Patients with deliberate ingestions demonstrating cardiotoxicity, seizures, or other persistent neurotoxicity should be admitted.
4) CONSULT CRITERIA: Consult a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity (ie, dysrhythmias, seizures) or in whom the diagnosis is unclear.

L) PITFALLS

1) When managing a suspected risperiDONE overdose, the possibility of coingestion of other CNS depressant or cardiotoxic agents should be determined.

M) PHARMACOKINETICS

1) Peak plasma concentrations of risperiDONE occurs within 1 to 2 hours after oral exposure. It is has a protein binding of 90%, and a volume of distribution of 1 to 2 L/kg. The mean elimination half-life of risperiDONE is 2.8 and 16 hours in extensive metabolizers (EM) and poor metabolizers (PM), respectively; along it's major metabolite, 9-hydroxy-risperiDONE, having a mean elimination half-life of 20 to 22 hours in both EM and PM.

N) TOXICOKINETICS

1) Half life of risperiDONE and its active metabolite do not appear to be prolonged in overdose.

O) DIFFERENTIAL DIAGNOSIS

1) Includes overdose ingestions of other centrally acting agents (tricyclic antidepressants, skeletal muscle relaxants, etc).

Range Of Toxicity

Clinical Effects

Summary Of Exposure

1) COMMON: Nausea, diarrhea, constipation, dizziness, somnolence, tachycardia, orthostatic hypotension, and extrapyramidal disorder.

Vital Signs

3.3.1)

A) WITH POISONING/EXPOSURE

1) Hypotension may occur following overdose, as well as therapeutic use.

3.3.4)

A) WITH THERAPEUTIC USE

1) HYPOTENSION

a) ORTHOSTATIC HYPOTENSION has been reported in patients taking risperiDONE therapeutically (Mesotten et al, 1989; Claus et al, 1992; Gesell & Stephen, 1997).

B) WITH POISONING/EXPOSURE

1) HYPOTENSION

a) ORTHOSTATIC HYPOTENSION may occur with overdose (Kopala et al, 1998; Himstreet & Daya, 1998).
b) CASE REPORT: A 15-year-old girl developed hypotension and orthostasis following a suicidal ingestion of risperiDONE 40 mg. Blood pressure upon admission was 66/30 mm Hg; over the next 2 days the patient required several fluid boluses to maintain blood pressure (Himstreet & Daya, 1998).
c) Hypotension has been reported after risperiDONE overdose (Acri & Henretig, 1998).
d) CASE REPORT: A 15-year-old girl developed transient lethargy, hypotension (98/55 mm Hg), and tachycardia after ingesting 110 mg of risperiDONE in a suicide attempt. Effects resolved with supportive care. Fifteen hours post-ingestion, a risperiDONE level was 14 ng/mL (13 ng/mL 9-hydroxyrisperiDONE and less than 3 ng/mL of risperiDONE) (Catalano et al, 2001).

Heent

3.4.3)

A) WITH THERAPEUTIC USE

1) ACCOMMODATION DISTURBANCES

a) In clinical trials, accommodation disturbances were present in at least 5% of patients receiving risperiDONE (Prod Info Risperdal(R), risperidone, 1999).

B) WITH POISONING/EXPOSURE

1) A bilateral miosis of 2 mm developed in a 41-year-old man after voluntary ingestion of 90 3-mg tablets (270 mg) of risperiDONE (Duenas-Laita et al, 1999).
2) CASE SERIES: Fatigue, tachycardia (orthostatic in one patient), dry mucous membranes, and miosis (a bilateral miosis of 1-2 mm and briskly reactive) were reported in 2 adolescents, a 16-year-old girl and a 15-year-old girl, after ingesting 24 mg (0.41 mg/kg) and 21 mg (0.41 mg/kg) of risperiDONE, respectively (Hodge et al, 2001).
3) It has been suggested that miosis may be common in risperiDONE overdose, occurring in 7 of 34 (24%) overdoses of risperiDONE alone in one series (Isbister & Whyte, 2002).

Cardiovascular

3.5.1)

A) WITH POISONING/EXPOSURE

1) Tachycardia, orthostasis and hypotension may occur with overdose.

3.5.2)

A) TACHYARRHYTHMIA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 21-year-old woman developed supraventricular tachycardia, with a heart rate of 163 beats/min, after ingesting 50 2 mg risperiDONE tablets. After gastric decontamination and treatment with adenosine and verapamil, she continued to have sinus tachycardia (120 beats/min) that persisted until discharge 3 days after overdose (Lee et al, 1997).
b) CASE REPORT: A 15-year-old girl developed transient lethargy, hypotension (98/55 mm Hg), and tachycardia after ingesting 110 mg of risperidone in a suicide attempt. Effects resolved with supportive care. Fifteen hours postingestion, a risperiDONE level was 14 ng/mL (13 ng/mL 9-hydroxyrisperiDONE and less than 3 ng/mL of risperiDONE) (Catalano et al, 2001).

B) TACHYCARDIA

1) WITH THERAPEUTIC USE

a) A compensatory increase in heart rate (7 to 8 beats/minute) develops at therapeutic doses of risperiDONE (Keegan, 1994).

2) WITH POISONING/EXPOSURE

a) INCIDENCE: In a case series involving 45 risperiDONE only overdoses admitted to a regional toxicology service, 26 (58%) patients had tachycardia (greater than or equal to 100 beats/minute) during the admission; no other cardiovascular events developed. The median length of stay was 16 hours and no intervention was needed (Page et al, 2010). . In a prospective series of 15 patients with overdose of risperiDONE alone, 6 patients (40%) developed tachycardia (Acri & Henretig, 1998). One patient developed supraventricular tachycardia.
b) DOSE RESPONSE: In a series of 32 cases of deliberate risperiDONE ingestion (dose range from 5 to 24 mg), tachycardia was reported in 17 (53%) patients. Of those individuals with tachycardia, the median dose of 55 mg was significantly different from the median dose of 14 mg for those without tachycardia (p = 0.0022), which suggested a dose-related response (Isbister & Whyte, 2002).
c) Tachycardia has been reported with risperiDONE overdose (Prod Info RISPERDAL(R) oral tablets, oral solution, orally disintegrating tablets, 2008; Duenas-Laita et al, 1999; Heather & Vicas, 1994; Lee et al, 1997).
d) CASE REPORT: A 33-year-old woman with depression and schizo-affective personality disorder presented to the emergency department with symptoms of anticholinergic toxicity 5 hours after intentionally ingesting an estimated dose of greater than 60 mg of risperiDONE. At the time of presentation, her heart rate (HR) was 128 beats/min and ECG showed a prolonged QTc of 481 msec. Laboratory values were within normal ranges. She was admitted to a telemetry unit for monitoring and supportive therapy. Within 36 hours of ingestion, symptoms of anticholinergic toxicity had resolved, the QTc interval and HR (62 beats/min) were normal and she was discharged to a psychiatric unit without further sequelae (Pollak et al, 2011).
e) CASE REPORT: A 28-year-old man developed episodes of sinus tachycardia after ingestion of 24 mg risperiDONE in a suicide attempt. Previous medical history was significant for paroxysmal atrial tachycardia (Kopala et al, 1998).
f) CASE REPORT: Fatigue, tachycardia (orthostatic in one patient), dry mucous membranes, and miosis were reported in 2 adolescents, a 16-year-old girl and a 15-year-old girl, after ingesting 24 mg (0.41 mg/kg) and 21 mg (0.41 mg/kg) of risperiDONE, respectively (Hodge et al, 2001).

C) HYPOTENSIVE EPISODE

1) WITH THERAPEUTIC USE

a) ORTHOSTATIC HYPOTENSION has been reported in patients taking risperiDONE therapeutically (Prod Info RISPERDAL(R) oral tablets, oral solution, orally disintegrating tablets, 2008; Ravin & Levenson, 1997; Gesell & Stephen, 1997).
b) INCIDENCE: Syncope occurred in 0.2% (6/2607) of risperiDONE-treated patients in Phase 2 and 3 studies in adults with schizophrenia; symptoms can potentially be minimized by limiting the initial dose to 2 mg total in healthy adults and 0.5 mg twice daily in the elderly (Prod Info RISPERDAL(R) oral tablets, oral solution, orally disintegrating tablets, 2008).

2) WITH POISONING/EXPOSURE

a) ORTHOSTATIC HYPOTENSION may occur with overdose (Prod Info RISPERDAL(R) oral tablets, oral solution, orally disintegrating tablets, 2008; Kopala et al, 1998; Himstreet & Daya, 1998).
b) INCIDENCE: In a prospective series of 15 patients with overdose of risperiDONE alone, 2 patients (13%) developed hypotension (Acri & Henretig, 1998).
c) CASE REPORT: A 15-year-old girl developed hypotension and orthostasis following a suicidal ingestion of risperiDONE 40 mg. Blood pressure upon admission was 66/30 mm Hg; over the next 2 days the patient required several fluid boluses to maintain blood pressure (Himstreet & Daya, 1998).
d) CASE REPORT: A 15-year-old girl developed transient lethargy, hypotension (98/55 mm Hg), and tachycardia after ingesting 110 mg of risperiDONE in a suicide attempt. Effects resolved with supportive care. Fifteen hours postingestion, a risperiDONE level was 14 ng/mL (13 ng/mL 9-hydroxyrisperiDONE and less than 3 ng/mL of risperiDONE) (Catalano et al, 2001).
e) CASE REPORT: 72-year-old woman developed bradycardia, hypotension, coma, hypothermia, and respiratory failure after receiving 6 mg risperiDONE daily (therapeutic dose in the elderly is 2 mg/day) (Rassam & Srinivasa, 2002). She recovered with supportive care.

D) PROLONGED QT INTERVAL

1) WITH THERAPEUTIC USE

a) RISPERIDONE

1) QRS and QTc prolongation have been reported in patients taking risperiDONE therapeutically (Duenas-Laita et al, 1999; Ravin & Levenson, 1997; Gesell & Stephen, 1997; Lo Vecchio et al, 1996; Brown et al, 1993).
2) CASE REPORT: A 7-year-old boy developed sinus dysrhythmia and a QTc interval of 0.46 seconds after a single dose of risperiDONE 1 mg for attention deficit hyperactivity disorder (Gesell & Stephen, 1997).

2) WITH POISONING/EXPOSURE

a) QRS and QTc prolongation have been reported in overdose (Prod Info RISPERDAL(R) oral tablets, oral solution, orally disintegrating tablets, 2008; Duenas-Laita et al, 1999; Ravin & Levenson, 1997; Gesell & Stephen, 1997; Lo Vecchio et al, 1996; Brown et al, 1993).
b) CASE REPORT: A 33-year-old woman with depression and schizo-affective personality disorder presented to the emergency department with symptoms of anticholinergic toxicity 5 hours after intentionally ingesting an estimated dose of greater than 60 mg of risperiDONE. At the time of presentation, her heart rate (HR) was 128 beats/min and ECG showed a prolonged QTc of 481 msec. Laboratory values were within normal ranges. She was admitted to a telemetry unit for monitoring and supportive therapy. Within 36 hours of ingestion, symptoms of anticholinergic toxicity had resolved, the QTc interval and HR (62 beats/min) were normal and she was discharged to a psychiatric unit without further sequelae (Pollak et al, 2011).
c) CASE REPORT: QRS and QTc prolongation (0.112 and 0.565 seconds, respectively) developed in a 29-year-old man after ingesting 100 to 240 mg of risperiDONE (Brown et al, 1993).
d) CASE REPORT: A 22-year-old woman developed slight QT interval prolongation following ingestion of 120 mg risperiDONE (Lo Vecchio et al, 1996).
e) CASE REPORT: A 72-year-old woman developed first degree heart block (40 beats/min), prolonged QTc interval, hypotension, hypothermia, coma and respiratory failure after receiving risperiDONE 6 mg/day (therapeutic dose in the elderly is 2 mg/day) (Rassam & Srinivasa, 2002). She recovered with supportive care.

E) CONDUCTION DISORDER OF THE HEART

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Prolongation of the QT interval, supraventricular tachycardia, bradycardia, and atrial flutter developed in a 41-year-old man after voluntary ingestion of 90 3-mg tablets (270 mg) of risperiDONE (Duenas-Laita et al, 1999).

F) HEART BLOCK

1) WITH POISONING/EXPOSURE

a) CASE REPORT: First-degree heart block with left axis deviation and left anterior hemiventricular block was reported in a 28-year-old male after ingestion of 24 mg of risperiDONE in a suicide attempt. Concurrent use of fluvoxamine, a potential inhibitor of risperiDONE metabolism, may have played a role (Kopala et al, 1998).
b) CASE REPORT: A 72-year-old woman developed first degree heart block (40 beats/min), prolonged QTc interval, hypotension, hypothermia, coma and respiratory failure after receiving risperiDONE 6 mg/day (therapeutic dose in the elderly is 2 mg/day) (Rassam & Srinivasa, 2002). She recovered with supportive care.

G) EDEMA

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 35-year-old man experienced edema with a 15 pound weight gain after more than 2 weeks of risperiDONE therapy. Other medications included divalproex sodium and clorazepate. The authors note that although edema is associated with divalproex therapy, it did not occur until risperiDONE was added. They suggest that both of these medications when used together may be more likely to cause edema (Baldassano & Ghaemi, 1996).

Respiratory

3.6.1)

A) WITH POISONING/EXPOSURE

1) Delayed respiratory depression has been reported in a poor metabolizer after risperiDONE overdose. Rhinitis has been reported in patients in clinical trials.

3.6.2)

A) RHINITIS

1) WITH THERAPEUTIC USE

a) Rhinitis was reported in 5% or more of adult patients in clinical trials, and was even more common in pediatric patients receiving therapeutic doses (Prod Info RISPERDAL(R) oral tablets, oral solution, orally disintegrating tablets, 2008).

B) DECREASED RESPIRATORY FUNCTION

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 26-year-old woman was found unconscious after ingesting 30 mg risperiDONE. Three days later, she developed respiratory distress and was transferred to another institution. On arrival she was hypotensive (80/50 mmHg), bradycardic (50 beats/min), with a Glasgow Coma Score of 8 out of 15. Chest radiograph was normal. Two hour later she developed respiratory depression (respiratory rate 5 breaths/min; pH 7.39, PO2 51 mm Hg, PCO2 54 mmHg, and HCO3 24.3 mmol/L), followed 10 minutes later by respiratory arrest. She was intubated and required mechanical ventilation for 6 days. She was discharged from the ICU on day 8 (Akyol et al, 2005).
b) CASE REPORT: A 72-year-old woman living in a nursing center with a history of schizophrenia was found unconscious (Glasgow coma scale - 3/15) and hypotensive and was taking risperiDONE 6 mg/daily (the suggested dose in the elderly is 0.5 mg up to 2 mg/day). Upon hospital admission the patient experienced a respiratory arrest requiring intubation and ventilation. By day 4 the patient was beginning to neurologically improve and was making some respiratory effort and was successfully extubated on day 6 and discharged from the ICU on day 7 (Rassam & Srinivasa, 2002).

Neurologic

3.7.1)

A) WITH THERAPEUTIC USE

1) Extrapyramidal disorder, neuroleptic malignant syndrome, somnolence, akathisia and seizure have been reported with therapeutic doses.

B) WITH POISONING/EXPOSURE

1) Drowsiness and sedation may occur with overdose.

3.7.2)

A) CENTRAL NERVOUS SYSTEM DEFICIT

1) WITH THERAPEUTIC USE

a) Drowsiness or sedation are adverse effects of therapeutic risperiDONE doses (Kane, 1993).
b) INCIDENCE: Somnolence appears to be dose-related and was reported in up to 41% of patients receiving high-dose (16 mg/day) therapy as compared to 16% in the placebo group (Prod Info RISPERDAL(R) oral tablets, oral solution, orally disintegrating tablets, 2008).

2) WITH POISONING/EXPOSURE

a) Drowsiness, lethargy, and slurred speech have been reported with risperiDONE overdose (Akyol et al, 2005; Catalano et al, 2001) (Heather & Vias, 1994).
b) INCIDENCE: In a prospective series of 15 patients with risperiDONE only overdose, 7 (47%) developed lethargy (Acri & Henretig, 1998).
c) CASE SERIES: Fatigue, tachycardia (orthostatic in one patient), dry mucous membranes, and miosis were reported in 2 adolescents, a 16-year-old girl and a 15-year-old girl, after ingesting 24 mg (0.41 mg/kg) and 21 mg (0.41 mg/kg) of risperiDONE, respectively (Hodge et al, 2001).

B) EXTRAPYRAMIDAL SIGN

1) WITH THERAPEUTIC USE

a) Dyskinesia, parkinsonism, and extrapyramidal effects are less frequent with risperiDONE therapy than with haloperidol (Borison et al, 1992; Chouinard et al, 1993; Claus et al, 1992; Lindenmayer JP, 1993).
b) CASE REPORT: Fifteen days after initiation of risperiDONE 2 mg per day, a 55-year-old man with neurofibromatosis developed rigidity, cogwheel movement, slowness, anorexia, abulia, inability to walk, and decreased blinking. Symptoms abated over the next 10 days after risperiDONE discontinuation (De Leon et al, 1997).
c) CASE REPORT: A 43-year-old man treated with risperiDONE 6 mg/day presented with episodic blepharospasm (Meige's disease) that occurred spontaneously or brought on by stress (Ananth et al, 2000).

2) WITH POISONING/EXPOSURE

a) INCIDENCE: In a case series involving 45 risperiDONE only overdoses admitted to a regional toxicology service, 5 (11%) dystonic reactions occurred within 2 (n=4) or 10 hours (n=1) of ingesting 8 to 248 mg of risperiDONE (median dose: 33 mg; IQR: 15 to 75 mg); no other CNS events were observed. The median length of stay was 16 hours. One patient was admitted for 36 hours with recurrent episodes (Page et al, 2010).
b) Extrapyramidal effects and atypical motor behavior have been reported with risperiDONE overdose (Heather & Vicas, 1994).
c) CASE REPORT: Transient extrapyramidal symptoms with spasms and cervico-facial dystonia developed in a 41-year-old man after voluntary ingestion of 90 3-mg tablets (270 mg) of risperiDONE. In addition, prolongation of the QT interval, supraventricular tachycardia, bradycardia, and atrial flutter were noted (Duenas-Laita et al, 1999).

C) CHOREA

1) WITH THERAPEUTIC USE

a) CASE REPORT: Chorea and tardive dyskinesia were reported in a 13-year-old girl receiving risperiDONE. Nine months after the initiation and dose decrease, chorea-like movements were still evident. RisperiDONE was discontinued and at month 16, the movement disorder was resolved (Carroll et al, 1999).

D) CATATONIC REACTION

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 61-year-old schizophrenic woman developed catatonia after beginning risperiDONE 2 mg daily (Bahro et al, 1999). Catatonic symptoms worsened when the risperiDONE dose was increased to 5 mg daily. Upon discontinuation of risperiDONE, symptoms resolved within 5 days.

E) MANIC BEHAVIOR

1) WITH THERAPEUTIC USE

a) CASE SERIES: Four cases of mania developing after starting risperiDONE therapy have been reported. Sexual disinhibition was one of the most predominant symptoms (Zolezzi & Badr, 1999).

F) NEUROLEPTIC MALIGNANT SYNDROME

1) WITH THERAPEUTIC USE

a) Potentially fatal symptoms associated with Neuroleptic Malignant Syndrome (NMS) have bee associated with the therapeutic use of antipsychotic agents (Prod Info RISPERDAL(R) oral tablets, oral solution, orally disintegrating tablets, 2008).
b) CASE REPORT: A 73-year-old woman developed neuroleptic malignant syndrome after taking risperiDONE 0.5 mg BID for multiinfarct dementia. NMS resolved over 2 days after discontinuation of risperiDONE, fluid replacement, and treatment with dantrolene and bromocriptine (Gleason & Conigliaro, 1997).
c) CASE REPORT: A 47-year-old man developed neuroleptic malignant syndrome after the administration of risperiDONE during a benzodiazepine (diazepam) withdrawal period. Symptoms abated over the next 9 days after discontinuation of risperiDONE and treatment with dantrolene, bromocriptine, and diazepam (Bobolakis, 2000).

G) DYSTONIA

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 7-year-old boy developed hypertonicity of the extremities, confusion, lethargy, and limited tongue movement after a single dose of risperiDONE 1 mg for attention deficit hyperactivity disorder. Two doses of diphenhydramine did not improve the dystonia; the child recovered the following day (Gesell & Stephen, 1997).

2) WITH POISONING/EXPOSURE

a) In a series of 15 patients with risperiDONE only overdose, 3 patients (20%) developed dystonia or spasms (Acri & Henretig, 1998).

H) ELECTROENCEPHALOGRAM ABNORMAL

1) WITH THERAPEUTIC USE

a) Fifteen days after initiation of risperiDONE 2 mg per day, a 55-year-old man developed extrapyramidal symptoms, with EEG revealing bifrontal slow-wave abnormalities (De Leon et al, 1997).

I) SEIZURE

1) WITH THERAPEUTIC USE

a) Seizures have been reported during therapeutic use with an incidence of 0.3% (9/2607) in premarketing trials in adult patients (Prod Info RISPERDAL(R) oral tablets, oral solution, orally disintegrating tablets, 2008).
b) CASE REPORT: A 64-year-old woman experienced a seizure 2 days after beginning risperiDONE therapy (Lane & Chang, 1998). She received two 1 mg doses and two 2 mg doses before having generalized tonic-clonic seizure. At the time of beginning risperiDONE therapy, she also received trimethoprim-sulfamethoxazole for urinary tract infection and astemizole for scalp itch. When risperiDONE therapy was restarted, no further seizures were noted.

2) WITH POISONING/EXPOSURE

a) A seizure was reported following a risperiDONE overdose of approximately 36 mg (Prod Info RISPERDAL(R) oral tablets, oral solution, orally disintegrating tablets, 2008).

J) DELIRIUM

1) WITH THERAPEUTIC USE

a) CASE REPORT: An 85-year-old woman with schizophreniform disorder was treated with risperiDONE 1 mg daily and then increased to 1 mg twice daily after 4 days with resultant delirium. The woman was restless, disoriented, and hallucinating. RisperiDONE was discontinued and she recovered after 18 hours (Tavcar & Dernovsek, 1998).
b) Three cases of possible risperiDONE-induced delirium were reported in patients aged 71-, 83-, and 83-years-old (Ravona-Springer et al, 1998). All were hospitalized patients being treated for major depression with psychotic features. In each case the mania abated after risperiDONE was discontinued. The authors acknowledge that the delirium may have been multifactorial in etiology, however, risperiDONE use appeared to be a risk factor.

K) DISTURBANCE IN SPEECH

1) WITH THERAPEUTIC USE

a) A 32-year-old Korean patient with a prior history of stuttering, demonstrated a recurrence of stuttering with risperiDONE 1 mg on day 5 of hospitalization. The dosage was increased to 8 mg daily on day 25 and the stuttering was more pronounced. Due to his auditory hallucinations and idea of reference, the dosage was maintained. On day 48 the stuttering was lessened (Lee et al, 2001).

L) COMA

1) WITH POISONING/EXPOSURE

a) Two patients became comatose and subsequently required mechanical ventilation following risperiDONE overdose ingestions of 14 mg and 90 mg, respectively. One patient received gastric lavage and forced diuresis and the other patient received gastric lavage and activated charcoal. Mechanical ventilation was discontinued 3 days postingestion, and both patients recovered without sequelae within 10 days postingestion (Nishikage et al, 2002).

M) AKATHISIA

1) WITH THERAPEUTIC USE

a) CASE REPORT: A patient with a diagnosis of paranoid schizophrenia and severe depression was treated with risperiDONE at a dose which was increased to 4 mg/day over a week. On day 8 of treatment he was diagnosed with akathisia. Mirtazapine 15 mg/day was added to his treatment, and after 5 weeks of the combined treatment, he showed improvement in his psychosis and depressive symptoms. On follow-up at approximately 2 months, he was doing well on risperiDONE 4 mg/day and mirtazapine 15 mg/day with no relapse of akathisia (Ranjan et al, 2006).
b) CASE REPORT: A patient with a diagnosis of paranoid schizophrenia was treated with risperiDONE at a dose which was increased to 4 mg/day over a week. The dose was increased to 6 mg/day over the next 2 weeks due to a lack of effect at 4 mg/day. At that dose, he was diagnosed with risperiDONE-induced parkinsonism and akathisia. The addition of trihexyphenidyl 4 mg/day relieved the parkinsonism symptoms but not the akathisia. Mirtazapine 15 mg/day was added to his treatment regimen and improvement in his symptoms was observed by day 6 of treatment. Over the next 3 weeks, he showed improvement in his psychopathology and was discharged on risperiDONE 6 mg/day, trihexyphenidyl 4 mg/day and mirtazapine 15 mg/day (Ranjan et al, 2006).

Gastrointestinal

3.8.1)

A) WITH THERAPEUTIC USE

1) Constipation, diarrhea, nausea, and dyspepsia have been reported following therapeutic administration of risperiDONE.
2) Pancreatitis has been reported with risperiDONE therapy.

3.8.2)

A) DRUG-INDUCED GASTROINTESTINAL DISTURBANCE

1) WITH THERAPEUTIC USE

a) Diarrhea, nausea, and increased saliva were reported in at least 5% of adult patients receiving risperiDONE. Dysphagia is also possible with risperiDONE therapy (Prod Info RISPERDAL(R) oral tablets, oral solution, orally disintegrating tablets, 2008).
b) In pediatric patients abdominal pain, dyspepsia, nausea, occurred in at least 15% of patients, and vomiting and diarrhea occurred in at least 5% or more of patients receiving therapeutic doses (Prod Info RISPERDAL(R) oral tablets, oral solution, orally disintegrating tablets, 2008).

B) PANCREATITIS

1) WITH THERAPEUTIC USE

a) A 32-year-old man was diagnosed with pancreatitis (amylase 1087 International Units/L) 3 weeks after starting risperiDONE therapy. RisperiDONE was tapered off over 2 weeks and his amylase declined to 147 International Units/L (Berent et al, 1997).

Hepatic

3.9.1)

A) WITH THERAPEUTIC USE

1) Hepatitis has been reported with therapeutic doses.

3.9.2)

A) TOXIC HEPATITIS

1) WITH THERAPEUTIC USE

a) CASE REPORT: An 81-year-old man developed hepatitis after 2 doses of risperiDONE 0.5 mg. The patient had right upper quadrant pain and jaundice, with liver function tests revealing an AST of 434 Units/L, ALT 101 Units/L, alkaline phosphatase 244 Units/L, and total bilirubin of 3.6 mg/dL. Liver function tests taken upon admission 5 days earlier were within normal limits and returned to baseline 2 weeks after discontinuation of risperiDONE (Phillips et al, 1998).

Genitourinary

3.10.2)

A) PRIAPISM

1) WITH THERAPEUTIC USE

a) Priapism, although rare, has been reported in association with risperiDONE use (Prod Info RISPERDAL(R) oral tablets, oral solution, orally disintegrating tablets, 2008).

B) HEMORRHAGIC CYSTITIS

1) WITH THERAPEUTIC USE

a) CASE REPORT: An 11-year-old boy with significant behavioral problems developed hemorrhagic cystitis one week after beginning risperiDONE therapy. Other medications included fluoxetine, valproic acid, benztropine, haloperidol, clonidine, trazodone, and nasal desmopressin. Ultrasonography showed a thickened bladder wall and mild hydronephrosis. RisperiDONE was withdrawn and symptoms resolved within a week (Hudson & Cain, 1998). Since this patient was taking several medications concurrently with risperiDONE, it is difficult to attribute the hemorrhagic cystitis solely to risperiDONE.

C) DYSURIA

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 38-year-old man experienced dysuria and ejaculatory dysfunction one week after starting risperiDONE. On day 12 of treatment, risperiDONE was discontinued with symptoms resolving 2 days later. The patient underwent rechallenge with risperiDONE and symptoms recurred in 2 days (Madhusoodanan & Brenner, 1996).

Hematologic

3.13.1)

A) WITH THERAPEUTIC USE

1) Leukopenia and neutropenia have been reported rarely following therapeutic use.

3.13.2)

A) LEUKOPENIA

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 63-year-old man developed leukopenia and neutropenia one week after starting risperiDONE 2 mg twice daily for schizophrenia. The reaction was confirmed upon rechallenge. He had experienced a similar reaction with clozapine (Dernovsek & Tavcar, 1997).

B) NEUTROPENIA

1) WITH THERAPEUTIC USE

a) CASE REPORT: An elderly patient, with a history of large B-cell lymphoma and receiving palliative management, was admitted for corticosteroid therapy. During his hospitalization, he developed confusion, agitation and delirium and was started on olanzapine. Due to difficulty weaning the patient off olanzapine, the patient was changed to risperiDONE. About 2 weeks later the patient developed marked neutropenia (neutrophils (0.3 x 10(9)/L)). Following a hematology consult, the medication was discontinued. Ten days later, his neutrophil count (2.1 x 10 (9)/L) had normalized and remained within normal limits (Farrell & Eastman, 2013).

Dermatologic

3.14.2)

A) ERUPTION

1) WITH THERAPEUTIC USE

a) Rash was reported in 5% or more of patients in clinical trials (Prod Info RISPERDAL(R) oral tablets, oral solution, orally disintegrating tablets, 2008).

Musculoskeletal

3.15.2)

A) INCREASED CREATINE KINASE LEVEL

1) WITH THERAPEUTIC USE

a) CASE REPORT/PEDIATRIC: A 13-year-old boy with a history of motor and vocal tics (Tourette syndrome) and conduct disorder was started on risperiDONE up to 3 mg/day starting at the age of 12. It worked well to improve symptoms and was well tolerated. However, during a routine examination and laboratory study, his creatine kinase (CK) was 3300 Units/L with no clinical symptoms. RisperiDONE was discontinued with improvement in CK level. Since the patient had an absence of tics and he had good control of his behavior, therapy was not restarted (Masi et al, 2014).
b) CASE REPORT/PEDIATRIC: A 14-year-old boy with a history of conduct disorder, mood dysregulation and multiple anxiety disorders was started on quetiapine and then it was replaced with risperiDONE (1.25 mg/day). After 2 months of risperiDONE therapy, a routine creatine kinase was 7284 Units/L without any evidence of clinical symptoms. Two weeks later, his CK fell to below 500 Units/L. Based on close monitoring, the decision was made to continue therapy at the same dosage (Masi et al, 2014).

B) RHABDOMYOLYSIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 47-year-old woman, with a history of schizophrenia, intentionally ingested risperiDONE 96 mg (16 times her daily dose), clonazepam 32 mg, midazolam 120 mg, flurazepam 480 mg and trihexyphenidyl 32 mg and developed rhabdomyolysis. Tachycardia (137 beats/min) without QT prolongation and myoclonus were noted upon admission. Laboratory examination showed an elevated creatine kinase (CK) (29,212 Units/L) and myoglobin (317 Units/L). Following continuous fluid hydration with normal saline, the CK level normalized within a week. The patient was then transferred to inpatient psychiatric care and was restarted on risperiDONE 6 mg/day and venlafaxine 75 mg/day with gradual improvement in psychotic and depressive symptoms. A CK level obtained during outpatient follow-up was normal (Hsu & Yeh, 2014).

Endocrine

3.16.2)

A) HYPERGLYCEMIA

1) WITH THERAPEUTIC USE

a) Hyperglycemia has been reported in patients following treatment with risperiDONE, and may be associated, in some cases, with ketoacidosis or hyperosmolar coma and death. Patients with diabetes mellitus, or who have predisposing risk factors for the development of diabetes mellitus, may experience a worsening of glucose control during risperiDONE therapy (Prod Info RISPERDAL(R) oral tablets, oral solution, orally disintegrating tablets, 2008).

B) DIABETES MELLITUS

1) WITH THERAPEUTIC USE

a) Two retrospective cases were described in which patients developed diabetes while being treated with risperiDONE for schizophrenia (Wirshing et al, 2001).

C) GALACTORRHEA NOT ASSOCIATED WITH CHILDBIRTH

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 17-year-old adolescent developed galactorrhea and breast tenderness within weeks of treatment with risperiDONE (Gupta et al, 2001).

D) THELARCHE

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 8-year-old girl was taking risperiDONE for approximately a year and started to develop breast tissue; galactorrhea was absent. The medication was stopped and she was restarted on aripiprazole 1 mg daily with no adverse effects (White et al, 2014).

Reproductive

3.20.1)

3.20.2)

A) CONGENITAL MALFORMATIONS

1) A systematic review of the literature found no significant correlation between first-trimester exposure to risperiDONE and risk of congenital malformations. However, of 432 pregnancies with first-trimester exposure, 22 malformations were observed, resulting in a malformation rate of 5.1% (Ennis & Damkier, 2015).

B) LACK OF EFFECT

1) One case report described a 40-year-old woman who was treated with a varying dose of risperiDONE throughout pregnancy and postpartum. The mother received 1 mg/day of risperiDONE during the first 8 months of pregnancy and an increased dose of 2 mg/day for the last month of pregnancy due to psychological distress. Maternal use of risperiDONE during pregnancy did not result in physical or neurologic abnormalities, and the infant showed no signs or symptoms of withdrawal (Weggelaar et al, 2011).

C) ANIMAL STUDIES

1) RATS, RABBITS: No increase in teratogenicity was observed when rats and rabbits were administered oral risperiDONE at 0.4 to 6 times the maximum recommended human dose (MRHD) (Prod Info RISPERDAL(R) CONSTA(R) intramuscular long acting injection, 2014; Prod Info RISPERDAL(R) M-TAB(R) oral disintegrating tablets, 2014; Prod Info RISPERDAL(R) oral tablets, oral solution, 2014).

3.20.3)

A) FETAL/NEONATAL ADVERSE EFFECTS

1) Exposure to risperiDONE 6 mg/day during pregnancy resulted in a ventricular septal defect-type murmur in an exposed infant which resolved within 2 months (Gentile, 2014).

B) PREGNANCY CATEGORY

1) RisperiDONE is classified as FDA pregnancy category C (Prod Info RISPERDAL(R) CONSTA(R) intramuscular long acting injection, 2014; Prod Info RISPERDAL(R) M-TAB(R) oral disintegrating tablets, 2014; Prod Info RISPERDAL(R) oral tablets, oral solution, 2014).
2) There are no adequate and well-controlled studies of risperidone use during pregnancy. However, third trimester antipsychotic drug exposure, including risperidone, has been associated with extrapyramidal and/or withdrawal symptoms in neonates. Therefore, risperidone should be used during pregnancy only if the maternal benefit justifies the fetal risk. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during risperidone therapy and for at least 12 weeks after the last injection of intramuscular risperidone (Prod Info RISPERDAL(R) CONSTA(R) intramuscular long acting injection, 2014; Prod Info RISPERDAL(R) M-TAB(R) oral disintegrating tablets, 2014; Prod Info RISPERDAL(R) oral tablets, oral solution, 2014).

C) LACK OF EFFECT

1) POSTMARKETING EXPERIENCE: A review of pooled data from the Benefit Risk Management Worldwide Safety database found no increase in risk of spontaneous abortions, structural malformations, or fetal teratogenic risk from in utero exposure to risperiDONE. The voluntary reports (516 cases were prospective and 197 cases were retrospective) of drug exposure during pregnancy identified 713 cases of pregnant women with psychiatric illnesses who received risperiDONE. Of the 68 prospective pregnancies reported with known outcome, organ malformations (3.8%) and spontaneous abortions (16.9%) were documented (non-medically induced abortions excluded). These results are consistent with findings in the general population Third-trimester exposure to risperiDONE was associated with drug withdrawal, or possible withdrawal-emergent syndrome (WES) in 13 retrospectively reported cases. The study lacked information on long-term neurodevelopmental outcomes in the neonate and developing child. In addition, many of the reports were confounded by concomitant medications, several of which are known teratogens (Coppola et al, 2007).
2) A prospective, observational study of 54 women (mean age, 30.7 years) recruited from the Emory Women’s Mental Health program exposed to antipsychotic medication during pregnancy showed permeability of the placental barrier. Outcomes were determined by maternal and umbilical cord blood samples taken at delivery and through data collected from maternal reports and medical records. Placental passage showed a significant difference between antipsychotic medications, olanzapine 72.1% (95% confidence interval (CI), 46.8% to 97.5%) being the highest, followed by haloperidol 65.5% (95% CI, 40.3% to 90.7%), risperiDONE 49.2% (95% CI, 13.6% to 84.8%), and quetiapine 24.1% (95% CI, 18.7% to 29.5%), showing the lowest placental passage. In the risperiDONE group, there were no reports of preterm labor or infants requiring neonatal intensive care admission. Of the 6 infants with maternal risperiDONE exposure, 1 infant weighed less than 2500 g (Newport et al, 2007).
3) CASE REPORT: A case report described 2 successive, normal pregnancies in a 23-year-old woman receiving risperiDONE therapy. The woman had an unplanned yet uneventful pregnancy 6 months after starting risperiDONE 3 mg/day for treatment of schizophrenia. She had spontaneous labor at 39 weeks gestation and delivered a healthy baby girl weighing 3.2 kg. There were no postnatal complications. Subsequently, her risperiDONE dose was decreased to 2 mg/day due to mental stability. Nine months later, she became pregnant again and was maintained on the 2 mg/day dose of risperiDONE without prenatal complications. Following spontaneous labor at 39 weeks, she delivered a healthy baby boy weighing 3 kg. Both of the infants were breastfed for 6 months. The children did not show any signs of neurodevelopmental delays or behavioral problems at 36 and 18 months of age, respectively (Mendhekar & Lohia, 2008).
4) A case report described a normal pregnancy and healthy baby born to a middle-aged woman with schizophrenia who was treated with risperiDONE prior to and throughout her pregnancy. Successfully maintained for 7 years on risperiDONE, her dose was gradually decreased from 3 mg/day to 1 mg/day at 6 months' gestation, then to 0.5 mg/day a few days prior to delivery. The baby was delivered at term and remained healthy over the first 3 months of life (Rodriguez-Salgado, 2008).

D) ANIMAL STUDIES

1) RATS, RABBITS: An increase in pup death was observed during the first 4 days of lactation when risperiDONE doses of 0.16 to 5 mg/kg (0.1 to 3 times the oral MRHD) were administered to the female rats. An increase in stillbirths was found when pregnant rats were given risperiDONE 2.5 mg/kg (1.5 times the oral MRHD). A decrease in the number of live pups at birth, a decrease in birth weight, and increased neonatal deaths were seen in the offspring of rats treated with 5 mg/kg (3 times the oral MRHD) of risperiDONE during gestation. Placental transfer of risperiDONE has been reported in rat pups (Prod Info RISPERDAL(R) oral tablets, oral solution, 2014; Prod Info RISPERDAL(R) CONSTA(R) intramuscular long acting injection, 2014; Prod Info RISPERDAL(R) M-TAB(R) oral disintegrating tablets, 2014; Prod Info RISPERDAL(R) oral tablets, oral solution, 2012).

3.20.4)

A) BREAST MILK

1) As both risperiDONE and its active 9-hydroxy metabolite were shown to be excreted in human breast milk, women should be advised to not breastfeed during treatment with risperidone and for at least 12 weeks after the last injection (Prod Info RISPERDAL(R) CONSTA(R) intramuscular long acting injection, 2014; Prod Info RISPERDAL(R) M-TAB(R) oral disintegrating tablets, 2014; Prod Info RISPERDAL(R) oral tablets, oral solution, 2014). It is estimated that a nursing infant would receive 0.84% of the maternal dose as risperiDONE and an additional 3.46% from 9-hydroxyrisperiDONE (as risperiDONE equivalents). Although this amount is not likely to result in sedation or extrapyramidal side effects in a full-term or older infant, the possibility of more serious adverse effects, such as neuroleptic malignant syndrome, should be considered (Hill et al, 2000).
2) One case report described a 40-year-old woman who was treated with a varying dose of risperiDONE throughout pregnancy and postpartum. She was advised not to breastfeed her infant. At a maternal dose of 1 mg/day, the mother consented to provide 7 serial serum samples and 6 breast milk samples over a 24 hour period in addition to 1 infant serum sample 6 hours after dosing, so that risperiDONE and 9-hydroxyrisperiDONE levels could be measured. The milk to plasma ratio calculated from the AUC for 9-hydroxyrisperiDONE was 0.88. The milk to plasma ratio for risperiDONE could not be calculated because all milk levels were below the assay detection level (Weggelaar et al, 2011).
3) CASE REPORT: One case report described a 21-year-old woman who was treated postpartum with risperiDONE. She was advised against nursing her infant. After a gradual increase in maternal dose to 6 mg/day, she agreed to provide serial samples (over 24 hours) of plasma and breast milk so that risperiDONE and 9-hydroxyrisperiDONE could be measured. The milk to plasma ratios calculated from the AUCs were 0.42 and 0.24 for risperiDONE and its active metabolite, respectively (Hill et al, 2000).

3.20.5)

A) ANIMAL STUDIES

1) FEMALE RATS: In 3 reproductive studies, risperiDONE was shown to impair mating, but not fertility, in Wistar rats at doses of 0.1 to 3 times the maximum recommended human dose (MRHD) on a mg/m(2) basis; this effect occurred only in female rats (Prod Info RISPERDAL(R) oral tablets, oral solution, 2014; Prod Info RISPERDAL(R) CONSTA(R) intramuscular long acting injection, 2014; Prod Info RISPERDAL(R) M-TAB(R) oral disintegrating tablets, 2014).
2) MALE DOGS: In a study in beagle dogs, sperm motility and concentration were decreased at risperiDONE doses of 0.6 to 10 times the MRHD. Dose-related decreases in serum testosterone were also noted. Serum testosterone and sperm parameters partially recovered but remained decreased after discontinuation of risperiDONE (Prod Info RISPERDAL(R) CONSTA(R) intramuscular long acting injection, 2014; Prod Info RISPERDAL(R) M-TAB(R) oral disintegrating tablets, 2014; Prod Info RISPERDAL(R) oral tablets, oral solution, 2014).

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor vital signs and mental status.
B) Obtain an ECG and institute continuous cardiac monitoring.
C) Monitor serum electrolytes including sodium, potassium, and magnesium, as well as glucose, and obtain CBC.

4.1.2)

A) Monitor serum electrolytes including sodium, potassium and magnesium, as well as glucose.
B) Obtain complete blood count.

4.1.4)

A) OTHER

1) MONITORING

a) Institute continuous cardiac monitoring and obtain ECG.

Treatment

Life Support

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Patients with deliberate ingestions demonstrating cardiotoxicity, seizures, or other persistent neurotoxicity should be admitted.

6.3.1.2) HOME CRITERIA/ORAL

A) Children less than 12 years of age who are naive to risperiDONE can be observed at home following an unintentional ingestion of 1 mg or less and are only experiencing mild sedation. All patients, 12 years of age or older, who are naive to risperiDONE, can be observed at home following an unintentional ingestion of 5 mg or less and are experiencing only mild sedation. All patients who are taking risperiDONE on a chronic basis can be observed at home if they have acutely ingested no more than 5 times their current single dose (not daily dose) of risperiDONE. Patients who have not developed signs or symptoms more than 6 hours after ingestion are unlikely to develop toxicity (Cobaugh et al, 2007).

6.3.1.3) CONSULT CRITERIA/ORAL

A) Call a Poison Center for assistance in managing patients with severe toxicity (ie, dysrhythmias, seizures) or in whom the diagnosis is unclear.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Any patient with a deliberate ingestion or more than minor symptoms should be referred to a healthcare facility. Children less than 12 years of age who are naive to risperiDONE should be referred to a healthcare facility following an unintentional ingestion of more than 1 mg. All patients, 12 years of age or older, who are naive to risperiDONE should be referred to a healthcare facility following an unintentional ingestion of more than 5 mg. All patients who are taking risperiDONE on a chronic basis should be referred to a healthcare facility following an acute ingestion of more than 5 times their current single dose (not daily dose) of risperiDONE (Cobaugh et al, 2007).

Monitoring

Oral Exposure

6.5.1)

A) PREHOSPITAL: Prehospital gastrointestinal decontamination is not recommended due to the potential for somnolence, seizures and dystonic reaction.

6.5.2)

A) ACTIVATED CHARCOAL

1) CHARCOAL ADMINISTRATION

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

2) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

6.5.3)

A) SUPPORT

1) Treatment is symptomatic and supportive. Monitor fluid and electrolyte balance closely.

B) SEIZURE

1) SUMMARY

a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).

2) DIAZEPAM

a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .

3) NO INTRAVENOUS ACCESS

a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).

4) LORAZEPAM

a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).

5) PHENOBARBITAL

a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).

6) OTHER AGENTS

a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):

1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

C) HYPOTENSIVE EPISODE

1) Treat hypotension and circulatory collapse with appropriate measures such as intravenous fluids and/or sympathomimetic agents. The manufacturer recommends avoidance of epinephrine and dopamine since beta stimulation may worsen hypotension in the setting of risperiDONE-induced alpha blockade (Prod Info RISPERDAL(R) oral tablets, oral solution, orally-disintegrating tablets, 2006). If hypotension is unresponsive to IV fluids, agents with alpha adrenergic effects such as norepinephrine or phenylephrine may be preferred.
2) NOREPINEPHRINE

a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
b) DOSE

1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

3) Phenylephrine hydrochloride injection is indicated for the treatment of vascular failure in shock, shocklike states, and drug-induced hypotension or hypersensitivity (Prod Info phenylephrine hcl injection, 1%, 2005).

a) DOSE: initial, 100 to 180 mcg/min continuous IV infusion; once blood pressure is stabilized, decrease rate to 40 to 60 mcg/min to maintain blood pressure (Prod Info phenylephrine hcl injection, 1%, 2005)

D) CONDUCTION DISORDER OF THE HEART

1) Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders (particularly hypokalemia, hypocalcemia, and hypomagnesemia). Sodium bicarbonate is generally first line therapy for QRS widening and ventricular dysrhythmias. In patients unresponsive to bicarbonate, consider lidocaine or amiodarone.
2) SERUM ALKALINIZATION

a) Administer sodium bicarbonate. A reasonable starting dose is 1 to 2 mEq/kg by intravenous bolus, repeated as needed. Maintain arterial pH between 7.45 and 7.55. Monitor serial ECGs and arterial blood gases frequently.

3) LIDOCAINE

a) LIDOCAINE/INDICATIONS

1) Ventricular tachycardia or ventricular fibrillation (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010; Vanden Hoek et al, 2010).

b) LIDOCAINE/DOSE

1) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010). Only bolus therapy is recommended during cardiac arrest.

a) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010).

2) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).

c) LIDOCAINE/MAJOR ADVERSE REACTIONS

1) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010).

d) LIDOCAINE/MONITORING PARAMETERS

1) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).

4) AMIODARONE

a) AMIODARONE/INDICATIONS

1) Effective for the control of hemodynamically stable monomorphic ventricular tachycardia. Also recommended for pulseless ventricular tachycardia or ventricular fibrillation in cardiac arrest unresponsive to CPR, defibrillation and vasopressor therapy (Link et al, 2015; Neumar et al, 2010). It should be used with caution when the ingestion involves agents known to cause QTc prolongation, such as fluoroquinolones, macrolide antibiotics or azoles, and when ECG reveals QT prolongation suspected to be secondary to overdose (Prod Info Cordarone(R) oral tablets, 2015).

b) AMIODARONE/ADULT DOSE

1) For ventricular fibrillation or pulseless VT unresponsive to CPR, defibrillation, and a vasopressor therapy give an initial dose of 300 mg IV followed by 1 dose of 150 mg IV. For stable ventricular tachycardias: Infuse 150 milligrams over 10 minutes, and repeat if necessary. Follow by a 1 milligram/minute infusion for 6 hours, then a 0.5 milligram/minute. Maximum total dose over 24 hours is 2.2 grams (Neumar et al, 2010).

c) AMIODARONE/PEDIATRIC DOSE

1) Infuse 5 milligrams/kilogram as a bolus for pulseless ventricular tachycardia or ventricular fibrillation; may repeat twice up to 15 mg/kg. Infuse 5 milligrams/kilogram over 20 to 60 minutes for perfusing tachycardias. Maximum single dose is 300 mg. Routine use with other drugs that prolong the QT interval is NOT recommended (Kleinman et al, 2010).

d) ADVERSE EFFECTS

1) Hypotension and bradycardia are the most common adverse effects (Neumar et al, 2010).

E) NEUROLEPTIC MALIGNANT SYNDROME

1) May be successfully managed diphenhydramine, oral bromocriptine, benzodiazepines, or intravenous or oral dantrolene sodium in conjunction with cooling and other supportive care (May et al, 1983; Mueller et al, 1983; Leikin et al, 1987; Schneider, 1991; Barkin, 1992).

a) BENZODIAZEPINES: In conjunction with cooling measures and supportive care, initial management of NMS should include administration of intravenous benzodiazepines for muscle relaxation (Goldfrank et al, 2002) Benzodiazepines may also be helpful in controlling agitation or reversal of catatonia (Caroff & Mann, 1993; Gratz et al, 1992).

1) DIAZEPAM DOSE: 3 to 5 mg intravenous bolus to slow push initially, followed by 1 to 2.5 mg intravenously in 10 minutes.

b) BROMOCRIPTINE DOSE: 5 mg 3 times a day orally (Mueller et al, 1983).
c) DANTROLENE LOADING DOSE: 2.5 mg/kg, to a maximum of 10 mg/kg intravenously (Barkin, 1992).
d) DANTROLENE MAINTENANCE DOSE: 2.5 mg/kg intravenously every 6 hours (Barkin, 1992); 1 mg/kg orally every 12 hours, up to 50 mg/dose has also been successful (May et al, 1983).

1) EFFICACY: Variable; often ineffective as a sole agent. Most efficacious in reducing rigidity and the fever that may be produced at a muscular level; will not always resolve mental status changes or psychotic symptoms that probably are more central in origin. Efficacy may be improved if given with a dopamine agonist (Granato et al, 1983; Blue et al, 1986; May et al, 1983).
2) Some studies report NO beneficial effects and suggest that dantrolene might even worsen the course of NMS (Rosebush & Stewart, 1989) (Rosebush et al, 1991a).

e) NON-PHARMACOLOGIC METHODS: Rapid cooling, hydration, and serial assessment of respiratory, cardiovascular, renal and neurologic function, and fluid status are used in conjunction with drug therapy and discontinuation of the antipsychotic agent (Knight & Roberts, 1986).

2) In a review of 67 case reports of neuroleptic malignant syndrome, the onset of clinical response was shorter after treatment with DANTROLENE (mean 1.15 days) or BROMOCRIPTINE (1.03 days) than with supportive measures alone (6.8 days).

a) The time to complete resolution was also shorter with these therapeutic interventions (Rosenberg & Green, 1989).

3) The intravenous administration of dopamine has also been reported to be effective in two case reports (Ungvari, 1987; Ryken & Merrell, 1989).
4) RETROSPECTIVE STUDY: A study comparing 438 untreated patients with neuroleptic malignant syndrome and 196 treated cases found that administration of dantrolene, bromocriptine, or amantadine significantly reduced the death rate in these cases (Sakkas et al, 1991).

a) Death rate of untreated cases was 21%; administration of dantrolene alone (no dosage reported) decreased death rate to 8.6% (n=58); with bromocriptine alone death rate was 7.8% (n=51); and with amantadine alone death rate was 5.9% (n=17).
b) In combination with other drugs, each of these drugs significantly decreased the NMS-related death rate, although the decrease was slightly less than for single administrations.

F) DRUG-INDUCED AKATHISIA

1) MIRTAZAPINE: Mirtazapine is a potent antagonist of 5-HT2A/2C receptors and an antagonist of central alpha2 auto- and hetero-adrenergic receptors. Five patients with akathisia caused by risperiDONE and olanzapine were treated successfully with mirtazapine 15 mg/day. Although the mechanism of action of mirtazapine in treating akathisia is unknown, it may be due to its antagonist property of the H1 receptors and its dopaminergic activity in frontal cortex (Ranjan et al, 2006).

Enhanced Elimination

1) Hemodialysis and hemoperfusion are UNLIKELY to be useful in a risperiDONE overdose because of the high degree of protein binding.

Abstracts

Case Reports

1) A 29-year-old man developed QRS and QTc prolongation (0.112 and 0.565) one hour after ingesting between 100 and 240 mg of risperiDONE. Initial laboratory studies revealed a sodium of 125 mmol/L and potassium of 2.9 mmol/L. He was treated with gastric lavage, activated charcoal, intravenous normal saline and potassium chloride. Electrolyte and ECG abnormalities resolved within 24 hours (Brown et al, 1993).

Range Of Toxicity

Summary

Therapeutic Dose

7.2.1)

A) BIPOLAR DISORDER

1) IM

a) MAINTENANCE MONOTHERAPY OR ADJUNCTIVE THERAPY: INITIAL: 25 mg IM every 2 weeks; may increase dose to 37.5 or 50 mg; maximum dose 50 mg. DO NOT administer IV (Prod Info RISPERDAL(R) CONSTA(R) intramuscular long acting injection, 2014).

2) ORAL TABLETS, DISINTEGRATING TABLETS, AND SOLUTION

a) INITIAL: 2 to 3 mg orally daily; may increase dose at increments of 1 mg/day; effective dose range is 1 to 6 mg per day (Prod Info RISPERDAL(R) oral tablets, oral solution, 2014).
b) MAINTENANCE: No evidence to support use past 3 weeks (Prod Info RISPERDAL(R) oral tablets, oral solution, 2014).
c) ORAL DISINTEGRATING TABLET ADMINISTRATION: DO NOT split or chew the tablet (Prod Info RISPERDAL(R) M-TAB(R) oral disintegrating tablets, 2014).

B) SCHIZOPHRENIA

1) IM

a) 25 mg IM every 2 weeks; may increase to 37.5 or 50 mg; MAX: 50 mg every 2 weeks; DO NOT administer IV (Prod Info RISPERDAL(R) CONSTA(R) intramuscular long acting injection, 2014)

2) ORAL TABLETS, DISINTEGRATING TABLETS, AND SOLUTION

a) INITIAL: 2 mg orally daily; may increase dose at increments of 1 to 2 mg at intervals of 24 hours or greater to a target dose of 4 to 8 mg; effective dose range is 4 to 16 mg per day (Prod Info RISPERDAL(R) oral tablets, oral solution, 2014).
b) MAINTENANCE: 2 to 8 mg per day may be effective at delaying relapse (Prod Info RISPERDAL(R) oral tablets, oral solution, 2014).
c) ORAL DISINTEGRATING TABLET ADMINISTRATION: DO NOT split or chew the tablet (Prod Info RISPERDAL(R) M-TAB(R) oral disintegrating tablets, 2014).

7.2.2)

A) BIPOLAR DISORDER

1) IM

a) Safety and effectiveness in pediatric patients have not been established (Prod Info RISPERDAL(R) CONSTA(R) intramuscular long acting injection, 2014).

2) ORAL TABLETS, DISINTEGRATING TABLETS, AND SOLUTION

a) INITIAL: 0.5 mg orally once daily in the morning or evening; may increase dose at increments of 0.5 to 1 mg at intervals of 24 hours or greater to a target dose of 1 to 2.5 mg; effective dose range is 1 to 6 mg per day (Prod Info RISPERDAL(R) oral tablets, oral solution, 2014).
b) MAINTENANCE: No evidence to support use past 3 weeks (Prod Info RISPERDAL(R) oral tablets, oral solution, 2014).
c) ORAL SOLUTION ADMINISTRATION: May administer from calibrated pipette or mixed in with a beverage, such as water, coffee, orange juice, and low-fat milk; DO NOT mix with cola or tea (Prod Info RISPERDAL(R) oral tablets, oral solution, 2014).
d) ORAL DISINTEGRATING TABLET ADMINISTRATION: DO NOT split or chew the tablet (Prod Info RISPERDAL(R) M-TAB(R) oral disintegrating tablets, 2014).

B) IRRITABILITY IN AUTISTIC DISORDER

1) ORAL TABLETS AND SOLUTION

a) 15 TO 20 KG: INITIAL: 0.25 mg orally daily; may increase to 0.5 mg by Day 4; may increase dose at increments of 0.25 mg after Day 4 at intervals greater than 2 weeks to a target dose of 0.5 mg for a minimum of 2 weeks; effective dose range is 0.5 to 3 mg per day (Prod Info RISPERDAL(R) oral tablets, oral solution, 2014).
b) GREATER THAN OR EQUAL TO 20 KG: INITIAL: 0.5 mg orally daily; may increase to 1 mg by Day 4; may increase dose at increments of 0.5 mg to a target dose of 1 mg; effective dose range is 0.5 to 3 mg per day (Prod Info RISPERDAL(R) oral tablets, oral solution, 2014).
c) ORAL SOLUTION ADMINISTRATION: May administer from calibrated pipette or mixed in with a beverage, such as water, coffee, orange juice, and low-fat milk; DO NOT mix with cola or tea (Prod Info RISPERDAL(R) oral tablets, oral solution, 2014).
d) ORAL DISINTEGRATING TABLETS ADMINISTRATION: DO NOT split or chew the tablet (Prod Info RISPERDAL(R) M-TAB(R) oral disintegrating tablets, 2014).

2) SCHIZOPHRENIA

a) IM

1) Safety and effectiveness in pediatric patients have not been established (Prod Info RISPERDAL(R) CONSTA(R) intramuscular long acting injection, 2014).

b) ORAL TABLETS, DISINTEGRATING TABLETS, AND SOLUTION

1) ADOLESCENTS

a) INITIAL: 0.5 mg orally once daily in the morning or evening; may increase dose at increments of 0.5 to 1 mg at intervals of 24 hours or greater to target dose of 3 mg; effective dose range is 1 to 6 mg per day (Prod Info RISPERDAL(R) oral tablets, oral solution, 2014).
b) MAINTENANCE: 2 to 8 mg per day may be effective at delaying relapse (Prod Info RISPERDAL(R) oral tablets, oral solution, 2014).
c) ORAL SOLUTION ADMINISTRATION: May administer from calibrated pipette or mixed in with a beverage, such as water, coffee, orange juice, and low-fat milk; DO NOT mix with cola or tea (Prod Info RISPERDAL(R) oral tablets, oral solution, 2014).
d) ORAL DISINTEGRATING TABLETS ADMINISTRATION: DO NOT split or chew the tablet (Prod Info RISPERDAL(R) M-TAB(R) oral disintegrating tablets, 2014).

Minimum Lethal Exposure

1) CASE REPORT: A 52-year-old woman with a history of esophageal cancer and mental illness, was found dead with a bottle of risperiDONE found near her body with 82 one mg tablets missing. RisperiDONE was detected in the blood (447.4 ng/mL) and urine (74.6 ng/mL); no other drugs were detected. Ethanol was also detected in the blood (1.83 mg/mL) and urine (2.23 mg/mL) postmortem. Her diagnosis of sudden death was attributable to risperiDONE (Hitosugi et al, 2014).

Maximum Tolerated Exposure

1) CHILD: In drug naive children, an ingestion of 1 mg in a child less than 12 years of age should be considered potentially toxic, and an ingestion of more than 5 mg should be considered potentially toxic in a child 12 years or older. In children who are using risperiDONE on a regular basis, a dose of more than 5 times their current single dose (not daily dose) should be considered potentially toxic (Cobaugh et al, 2007).

1) CASE SERIES: In a case series involving 45 risperiDONE only overdoses of 8 to 248 mg (median dose: 33 mg; IQR: 15 to 75 mg), dystonia (n=5) and tachycardia (n=26) were the primary events observed. No other significant cardiovascular or neurologic events occurred. The median length of stay was 16 hours. Intensive therapy was not required (Page et al, 2010).
2) CASE REPORT: Prolongation of the QT interval, supraventricular tachycardia, bradycardia, and atrial flutter developed in a 41-year-old man after ingestion of 90 3-mg tablets (270 mg) of risperiDONE. In addition, a bilateral miosis of 2 mm, and transient extrapyramidal symptoms with spasms and cervico-facial dystonia were noted. The patient was discharged 72 hours after admittance (Duenas-Laita et al, 1999).
3) CASE REPORT: A 33-year-old woman presented to the emergency department with tachycardia (heart rate: 128 beats/min) and QTc prolongation (481 msec) 5 hours after intentionally ingesting an estimated dose of greater than 60 mg of risperiDONE. A toxicology screen was negative. Within 36 hours of ingestion, symptoms of toxicity had resolved with supportive care and she was discharged to a psychiatric unit without further sequelae (Pollak et al, 2011).
4) CASE REPORT: A 47-year-old woman, with a history of schizophrenia, intentionally ingested risperiDONE 96 mg (16 times her daily dose), clonazepam 32 mg, midazolam 120 mg, flurazepam 480 mg and trihexyphenidyl 32 mg and developed rhabdomyolysis. Tachycardia (137 beats/min) without QT prolongation and myoclonus were noted upon admission. Laboratory examination showed an elevated creatine kinase (CK) (29,212 Units/L) and myoglobin (317 Units/L). Following continuous fluid hydration with normal saline, the CK level normalized within a week. The patient was then transferred to inpatient psychiatric care and was restarted on risperiDONE 6 mg/day and venlafaxine 75 mg/day with gradual improvement in psychotic and depressive symptoms. A CK level obtained during outpatient follow-up was normal (Hsu & Yeh, 2014).

1) A 15-year-old girl developed transient lethargy, hypotension (98/55 mm Hg), and tachycardia after ingesting 110 mg of risperiDONE. Effects resolved with supportive care (Catalano et al, 2001).
2) Fatigue, tachycardia (orthostatic in one patient), dry mucous membranes, and miosis (a bilateral miosis of 1-2 mm and briskly reactive) were reported in 2 adolescents, a 16-year-old girl and a 15-year-old girl, after ingesting 24 mg (0.41 mg/kg) and 21 mg (0.41 mg/kg) of risperiDONE, respectively (Hodge et al, 2001).

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) ADULT

a) CASE REPORT: An adult presented to an emergency department with symptoms of toxicity after intentionally ingesting greater than 60 mg (estimated dose) of risperiDONE. In this institution, the target therapeutic range for combined risperiDONE and 9-OHR (its active metabolite) is 19 to 260 nmol/L. The patient had a combined peak total concentration of risperiDONE and 9-OHR of 4098 nmol/L (a 15-fold increase) approximately 5 hours after ingestion. The patient recovered with supportive care (Pollak et al, 2011).
b) CASE REPORT: Ingestion of 50 2-mg risperiDONE tablets resulted in supraventricular tachycardia (163 beats/min), drowsiness, and extrapyramidal symptoms; serum risperiDONE and 9-hydroxyrisperiDONE metabolite levels were 1070 ng/mL and 100 ng/mL, respectively, upon admission. Urine concentrations of these entities were 5.6 mcg/mL and 2.8 mcg/mL, respectively (Lee et al, 1997).

2) CHILDREN

a) A 15-year-old girl developed transient lethargy, hypotension (BP 98/55 mm Hg), and tachycardia after ingesting 110 mg of risperiDONE. Effects resolved with supportive care. Fifteen hours postingestion, a risperiDONE level was 14 ng/mL (13 ng/mL 9-hydroxyrisperiDONE and less than 3 ng/mL of risperiDONE) (Catalano et al, 2001).

Toxicity Information

7.7.1)

A) ANIMAL DATA

1) LD50- (ORAL)MOUSE:

a) 63100 mcg/kg (RTECS, 2000)

2) LD50- (ORAL)RAT:

a) 56600 mcg/kg (RTECS, 2000)

3) LD50- (SUBCUTANEOUS)RAT:

a) 98 mg/kg (RTECS, 2000)

Pharmacology Toxicology

Pharmacologic Mechanism

Toxicologic Mechanism

1) In this study, risperiDONE and its active metabolite 9-OHR followed predictive rates of elimination following overdose, similar to therapeutic use, of observed half-lives of 1.8 and 17 hours, respectively. QTc was also found to rapidly correct as concentrations of risperiDONE and its metabolite declined. As drug concentrations decline, ongoing cardiac monitoring is unlikely to be necessary beyond 36 to 48 hours (Pollak et al, 2011).

Physicochemical

Physical Characteristics

Molecular Weight

Animal Toxicology

References

General Bibliography

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RISPERIDONE

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

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Treatment Overview

Range Of Toxicity

Summary Of Exposure

Vital Signs

Heent

Cardiovascular

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Summary

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Serum Plasma Blood Concentrations

Toxicity Information

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Toxicologic Mechanism

Physical Characteristics

Molecular Weight

General Bibliography