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BUSPIRONE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) BusPIRone is a azaspirodecanedione derivative with anxiolytic activities in humans. It is chemically and pharmacologically unrelated to benzodiazepines, barbiturates or other sedative/anxiolytic drugs. The drug has a high affinity for serotonin (5-HT1a) receptors with no significant affinity for benzodiazepine receptors and does not affect gamma-aminobutyric acid (GABA) binding (Prod Info BuSpar(R), 1995; (USPDI, 1999).

Specific Substances

    1) BUSPIRONE HYDROCHLORIDE
    2) MJ-9022-1
    3) 8-(4-(4-Pyrimidin-2-ylpiperasin-1-yl)butyl)
    4) -8-asaspiro(4.5)decane-7, 9-dione hydrochloride
    5) CAS 33386-08-2

Available Forms Sources

    A) FORMS
    1) BusPIRone is available as 5 and 10 mg tablets, and a 15 mg multi-scored tablet which may be divided to provide doses of 5, 7.5, 10 or 15 milligrams (USPDI, 1999).
    2) IPSAPIRONE - A related compound, ipsapirone, is currently undergoing clinical trials in the United States. Exposures should be managed as would a busPIRone ingestion (Personal Communication, 1990).
    B) USES
    1) BusPIRone is used in the management of anxiety disorders, or the short-term relief of anxiety symptoms; it is NOT indicated for stress related to daily life issues (USPDI, 1999).
    2) At the time of this review the role of busPIRone is uncertain as an adjunct therapy in the treatment of mental depression. or its possible use for the treatment of aggressive behavior in patients with neurological disorders or injury (USPDI, 1999).
    3) There is some evidence for the use of busPIRone in post-traumatic stress disorder, ADHD, and aggressive behavior; controlled studies are needed (Apter & Allen, 1999).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: BusPIRone is used for anxiety disorders.
    B) PHARMACOLOGY: BusPIRone is mainly a partial agonist at the serotonin receptor 1A (5-HT1A) and has some antagonist effects on the D2 dopamine receptor.
    C) TOXICOLOGY: The toxic effects are an extension of the pharmacology. Serotoninergic effects may be observed when used in combination with other serotoninergic agents.
    D) EPIDEMIOLOGY: Poisoning with busPIRone is only rarely reported, probably because it is not widely used.
    E) WITH THERAPEUTIC USE
    1) Somnolence, dizziness, irritability, blurred vision, headache, nausea, vomiting.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE POISONING: Somnolence, dizziness, irritability, nausea. Worsening anxiety may be observed even with therapeutic doses.
    2) SEVERE POISONING: CNS depression, serotoninergic effects (ie, hyperreflexia, clonus, altered mental status, hemodynamic instability) may be observed in combination with other serotoninergic agents. Seizures and delirium have been reported. Akathisia, tremor, and rigidity may be observed with higher doses. Sustained bradycardia was reported after coingestion with fluvoxamine.
    0.2.5) CARDIOVASCULAR
    A) WITH POISONING/EXPOSURE
    1) Mild bradycardia and hypotension were reported in volunteers given 100 mg and has been reported in 1 case of mixed drug overdose.
    0.2.7) NEUROLOGIC
    A) WITH THERAPEUTIC USE
    1) Drowsiness, fatigue, dizziness, and weakness have been reported with 10 to 20 mg doses. Lightheadedness, headache and somnolence have been reported in children and adolescents at 5 to 30 milligrams twice daily.
    2) Dysphoria, motor impairment, and paresthesias have been reported with busPIRone use. Toxic psychosis has been reported rarely with therapy.
    B) WITH POISONING/EXPOSURE
    1) In overdoses of up to 300 mg, the most common effect was drowsiness (48%).
    2) Seizures have been reported in one adult following a busPIRone-only overdose; no permanent sequelae was reported.
    0.2.8) GASTROINTESTINAL
    A) WITH THERAPEUTIC USE
    1) Non-specific GI distress occurred during clinical trials including nausea, vomiting, and diarrhea.
    0.2.10) GENITOURINARY
    A) WITH THERAPEUTIC USE
    1) Dysuria, enuresis, nocturia and priapism have been associated with therapeutic use.
    0.2.18) PSYCHIATRIC
    A) WITH THERAPEUTIC USE
    1) Panic attacks, mania and psychosis have been reported with therapeutic use. Withdrawal is probably a rare occurrence.
    0.2.20) REPRODUCTIVE
    A) BusPIRone is classified as FDA pregnancy category B. In animal studies, busPIRone was excreted in the breast milk of lactating rats.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, the manufacturer does not report any carcinogenic potential.

Laboratory Monitoring

    A) Monitor vital signs and mental status.
    B) BusPIRone plasma levels are not clinically useful or readily available.
    C) No specific lab work is needed in most patients.
    D) Monitor creatinine phosphokinase and lactate levels in patients with prolonged agitation, seizures, or coma.
    E) Obtain an ECG and institute continuous cardiac monitoring in patients with moderate to severe toxicity (ie, agitation, seizures, coma, serotonin toxicity).

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Primarily supportive care; activated charcoal may be helpful in patients presenting shortly after ingestion. Give benzodiazepines titrated to effect for anxiety and seizures.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Consider activated charcoal if patients present early after ingestion and are alert or airway is protected. Give benzodiazepines for anxiety, agitation, delirium, and seizures. Treat serotonin toxicity with benzodiazepines, cyproheptadine.
    C) DECONTAMINATION
    1) PREHOSPITAL: Not recommended because of potential for somnolence and seizures.
    2) HOSPITAL: Activated charcoal if recent, substantial ingestion, and patient is able to protect airway. Gastric lavage is not generally indicated as life-threatening toxicity is very rare.
    D) AIRWAY MANAGEMENT
    1) Early orotracheal intubation in patients with signs of severe intoxication (ie, CNS depression, seizures, agitation).
    E) ANTIDOTE
    1) None
    F) SEIZURES
    1) IV benzodiazepines, barbiturates.
    G) SEROTONIN SYNDROME
    1) Benzodiazepines are the mainstay of therapy. Cyproheptadine, a 5-HT antagonist, is also commonly used. Severe cases have been managed with benzodiazepine sedation and neuromuscular paralysis with non-depolarizing agents.
    H) ENHANCED ELIMINATION
    1) There is no role for repeat-dose activated charcoal. Hemodialysis is not useful given the large volume of distribution and high protein binding.
    I) PATIENT DISPOSITION
    1) HOME CRITERIA: There are no data on pediatric ingestions that can be managed at home; however, given the low toxicity, asymptomatic children with inadvertent overdoses can probably be managed at home.
    2) ADMISSION CRITERIA: Admit patients with CNS depression, exacerbated anxiety, agitation, seizure, or suicidal behavior.
    3) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity (ie, CNS depression, seizures, agitation, serotonin toxicity), or in whom the diagnosis is not clear.
    J) PITFALLS
    1) When managing a suspected busPIRone overdose, the treating physician should be cognizant of the possibility of multi-drug involvement.
    K) PHARMACOKINETICS
    1) Maximal plasma levels are reached after 60 to 90 minutes. Protein binding is 95%. Volume of distribution is 5.3 L/kg. Elimination primarily occurs by hepatic metabolism (CYP3A4). Be aware of pharmacokinetic interactions with inducers or inhibitors of CYP3A4. There is an active metabolite. The elimination half-life 2 to 3 hours.
    L) DIFFERENTIAL DIAGNOSIS
    1) Differential diagnosis is wide given the unspecific symptoms and signs of busPIRone overdose. Consider poisoning with other CNS depressants, serotoninergic drugs, lithium, or drugs associated with seizures. Consider CNS infection, panic attack, worsening anxiety in a depressive patient.

Range Of Toxicity

    A) Expect mild toxicity in busPIRone naive patients even at therapeutic dosages. Adding busPIRone to an established therapy with serotoninergic agents may lead to serotonin toxicity.
    B) Humans have tolerated 375 milligrams/day for 30 days but developed nausea, vomiting, tingling sensations, drowsiness, insomnia, and blurred vision.
    C) An adult survived an ingestion of 420 milligrams without permanent sequelae.

Clinical Effects

Summary Of Exposure

    A) USES: BusPIRone is used for anxiety disorders.
    B) PHARMACOLOGY: BusPIRone is mainly a partial agonist at the serotonin receptor 1A (5-HT1A) and has some antagonist effects on the D2 dopamine receptor.
    C) TOXICOLOGY: The toxic effects are an extension of the pharmacology. Serotoninergic effects may be observed when used in combination with other serotoninergic agents.
    D) EPIDEMIOLOGY: Poisoning with busPIRone is only rarely reported, probably because it is not widely used.
    E) WITH THERAPEUTIC USE
    1) Somnolence, dizziness, irritability, blurred vision, headache, nausea, vomiting.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE POISONING: Somnolence, dizziness, irritability, nausea. Worsening anxiety may be observed even with therapeutic doses.
    2) SEVERE POISONING: CNS depression, serotoninergic effects (ie, hyperreflexia, clonus, altered mental status, hemodynamic instability) may be observed in combination with other serotoninergic agents. Seizures and delirium have been reported. Akathisia, tremor, and rigidity may be observed with higher doses. Sustained bradycardia was reported after coingestion with fluvoxamine.

Heent

    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) Small pupils may be observed following overdose (USPDI, 1999).

Cardiovascular

    3.5.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Mild bradycardia and hypotension were reported in volunteers given 100 mg and has been reported in 1 case of mixed drug overdose.
    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH POISONING EXPOSURE
    a) Volunteers given 100 mg in a single dose developed mild bradycardia and hypotension (Prod Info BuSpar(R), 1995).
    B) BRADYCARDIA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT - Sustained bradycardia developed after ingestion of 200 mg busPIRone, 2000 mg fluvoxamine and 300 mg flurazepam. This was almost continuously below 50 bpm and lasted 7 days after the overdose (Langlois & Paquette, 1994).
    b) Volunteers given 100 mg in a single dose developed mild bradycardia and hypotension (Prod Info BuSpar(R), 1995).

Neurologic

    3.7.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Drowsiness, fatigue, dizziness, and weakness have been reported with 10 to 20 mg doses. Lightheadedness, headache and somnolence have been reported in children and adolescents at 5 to 30 milligrams twice daily.
    2) Dysphoria, motor impairment, and paresthesias have been reported with busPIRone use. Toxic psychosis has been reported rarely with therapy.
    B) WITH POISONING/EXPOSURE
    1) In overdoses of up to 300 mg, the most common effect was drowsiness (48%).
    2) Seizures have been reported in one adult following a busPIRone-only overdose; no permanent sequelae was reported.
    3.7.2) CLINICAL EFFECTS
    A) SEIZURE
    1) WITH THERAPEUTIC USE
    a) In a study using busPIRone in the treatment of alcohol withdrawal syndrome, one patient with a history of alcohol-related seizures reported an unwitnessed seizure (Dougherty & Gates, 1990).
    2) WITH POISONING/EXPOSURE
    a) Seizures are a possibility following overdose (Prod Info BuSpar(R), 1995).
    b) CASE REPORT - A 23-year-old female ingested 420 mg of busPIRone (8.4 mg/kg) in an apparent suicide attempt, and developed generalized tonic-clonic seizures approximately 36 hours after ingestion (Catalano et al, 1998). The authors concluded that the seizure activity was probably related to busPIRone toxicity, and that the delay in onset of symptoms may have been due to the protective effect of lorazepam that was given during transport. The patient made a complete recovery with no further seizure activity reported at 3-month follow-up.
    B) CENTRAL NERVOUS SYSTEM DEFICIT
    1) WITH THERAPEUTIC USE
    a) BusPIRone causes less CNS depression than the benzodiazepines and has minimal interaction with other CNS depressants (Riblet et al, 1980; USPDI, 1999).
    b) Fatigue, drowsiness, lassitude, dizziness, and weakness have been reported with 10 to 20 mg single doses (Prod Info BuSpar(R), 1995; (WHO, 1988; USPDI, 1999).
    1) INCIDENCE - In a multicenter trial of over 6,000 patients the most common side effects included dizziness, sleeplessness, headache, uneasiness, and fatigue. All occurred with an incidence of less than 8% (Robinson et al, 1988). Observed motor skills are not affected by busPIRone.
    2) In one study, somnolence was the most common adverse effect and occurred in 21.4% of subjects (Salazar et al, 2001).
    c) Children and adolescents on 5 to 30 milligrams of busPIRone twice daily in a 21 day open label dose escalation study experienced lightheadedness (67%), and headache (50%) (Salazar et al, 2001).
    2) WITH POISONING/EXPOSURE
    a) Fatigue, drowsiness, lassitude, dizziness, and weakness may be expected in overdose (Prod Info BuSpar(R), 1995; (WHO, 1988) Goetz et al, 1999; (USPDI, 1999).
    b) In overdoses of up to 300 mg, the most common effect was drowsiness (48%) (Goetz et al, 1989).
    C) PARESTHESIA
    1) WITH THERAPEUTIC USE
    a) Tingling in the extremities is noted with high therapeutic doses (Prod Info BuSpar(R), 1995; (USPDI, 1999).
    2) WITH POISONING/EXPOSURE
    a) Tingling in the extremities should be expected in overdose (Prod Info BuSpar(R), 1995; (USPDI, 1999).
    D) EXTRAPYRAMIDAL DISEASE
    1) WITH THERAPEUTIC USE
    a) WHO (1988) reported a few cases of extrapyramidal symptoms associated with the therapeutic use of busPIRone.
    b) CASE REPORTS
    1) Akathisia, tremors and rigidity were described in one patient receiving up to 2.4 grams/day (Sathananthan et al, 1975).
    2) A single 5 mg dose in a 62-year-old female caused generalized myoclonus, dystonias, and akathisia within 12 hours. Diphenhydramine (25 mg IM) and benztropine (1 mg IM) had little effect on the myoclonus. The dystonias and myoclonic jerks resolved following administration of 1 mg of clonazepam (Ritchie et al, 1988).
    3) Authors reported two cases of therapeutic busPIRone induced movement disorders. These were characterized as cervical-cranial dystonia and tremors in one patient and exacerbation of a pre-existing spasmodic torticollis and tardive dyskinesia. Both patient's symptoms improved upon discontinuation of busPIRone and suppressive therapy, but were still present in one case 1 year later and in the other case 5 years later (LeWitt et al, 1993).
    4) A 54-year-old man developed akathisia after one month of busPIRone 15 milligrams/day Symptoms resolved upon discontinuation of the drug (Patterson, 1988).
    E) DEPRESSIVE DISORDER
    1) WITH THERAPEUTIC USE
    a) Dysphoria has been reported with 40 mg doses (Kastenhoz & Crismon, 1984).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HYPOKINESIA
    a) RATS - At doses of 2.5 mg/kg subcutaneously in rats, busPIRone caused hypoactivity (Riblet et al, 1982).

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Non-specific GI distress occurred during clinical trials including nausea, vomiting, and diarrhea.
    3.8.2) CLINICAL EFFECTS
    A) INDIGESTION
    1) WITH THERAPEUTIC USE
    a) Non-specific GI distress occurred during clinical trials (Robinson et al, 1988).
    b) Nausea, vomiting, and diarrhea were reported following therapeutic use (Prod Info BuSpar(R), 1995; (USPDI, 1999).
    2) WITH POISONING/EXPOSURE
    a) Nausea, vomiting, and diarrhea were reported in overdose (Prod Info BuSpar(R), 1995; (USPDI, 1999).
    b) Dyspepsia occurred in 20% of children and adolescents on 5 to 15 milligrams twice daily (Salazar et al, 2001).

Genitourinary

    3.10.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Dysuria, enuresis, nocturia and priapism have been associated with therapeutic use.
    3.10.2) CLINICAL EFFECTS
    A) INCREASED FREQUENCY OF URINATION
    1) WITH THERAPEUTIC USE
    a) Dysuria, enuresis, and nocturia have been associated with the therapeutic use of busPIRone (Coates, 1990).
    B) PRIAPISM
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - Priapism and acute urinary retention was reported in a mentally retarded man after receiving busPIRone 15 to 30 mg/day for 6 months (Coates, 1990).

Reproductive

    3.20.1) SUMMARY
    A) BusPIRone is classified as FDA pregnancy category B. In animal studies, busPIRone was excreted in the breast milk of lactating rats.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) RATS, RABBITS: There was no evidence of fetal harm when rats and rabbits were administered busPIRone at doses approximately 30 times the maximum recommended human dose (Prod Info buspirone HCl oral tablets, 2014).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer has classified busPIRone as FDA pregnancy category B (Prod Info buspirone HCl oral tablets, 2014).
    2) Adequate and well-controlled studies have not been performed during pregnancy. In animal studies, there was no evidence of fetal harm or impaired fertility with busPIRone exposure. BusPIRone should be used during pregnancy only if clearly needed (Prod Info buspirone HCl oral tablets, 2014).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) It is unknown whether BusPIRone or its metabolites are excreted in human milk. In rat studies, busPIRone and its metabolites were shown to be excreted in breast milk. Therefore, busPIRone should not be used by a nursing woman unless the drug is clinically necessary (Prod Info buspirone HCl oral tablets, 2014).
    B) ANIMAL STUDIES
    1) RATS: BusPIRone and its metabolites were shown to be excreted in the breast milk of rats (Prod Info buspirone HCl oral tablets, 2014).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) RATS, RABBITS: There was no evidence of impaired fertility when rats and rabbits were administered busPIRone at doses approximately 30 times the maximum recommended human dose (Prod Info buspirone HCl oral tablets, 2014).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, the manufacturer does not report any carcinogenic potential.
    3.21.4) ANIMAL STUDIES
    A) LACK OF EFFECT
    1) RATS: A 24-month study of rats that were given 133 times the maximum recommended human oral dose of busPIRone found no evidence of carcinogenic potential (Prod Info BUSPAR(R) oral tablets, 2007).
    2) MICE: An 18-month study of mice that were given 167 times the maximum recommended human oral dose of busPIRone found no evidence of carcinogenic potential (Prod Info BUSPAR(R) oral tablets, 2007).

Genotoxicity

    A) There was no evidence of genotoxicity or mutagenicity with the following tests: Ames (with or without metabolic activation in 5 strains of Salmonella typhimurium) or mouse lymphoma L5178YTK+ cell cultures. There were no chromosome aberrations or abnormalities in bone marrow cells of mice given 1 or 5 daily doses of busPIRone. DNA damage did not occur with busPIRone in Wi-38 human cells (Prod Info BUSPAR(R) oral tablets, 2007).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and mental status.
    B) BusPIRone plasma levels are not clinically useful or readily available.
    C) No specific lab work is needed in most patients.
    D) Monitor creatinine phosphokinase and lactate levels in patients with prolonged agitation, seizures, or coma.
    E) Obtain an ECG and institute continuous cardiac monitoring in patients with moderate to severe toxicity (ie, agitation, seizures, coma, serotonin toxicity).
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) BusPIRone plasma levels are not clinically useful or readily available.
    2) No specific lab work is needed in most patients.
    3) Monitor creatinine phosphokinase and lactate levels in patients with prolonged agitation, seizures, or coma.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Monitor vital signs and mental status.
    2) ECG
    a) Obtain an ECG and institute continuous cardiac monitoring in patients with moderate to severe toxicity (ie, agitation, seizures, coma, serotonin toxicity).

Methods

    A) CHROMATOGRAPHY
    1) Liquid chromatography or gas chromatography-mass spectrometry have been used to determine busPIRone in biological specimens (Baselt, 2000).
    B) RADIOIMMUNOASSAY
    1) A radioimmunoassay has been described as being adequately sensitive to analyze busPIRone plasma concentrations following a single therapeutic dose (Baselt, 2000).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Admit patients with CNS depression, exacerbated anxiety, agitation, seizure, or suicidal behavior.
    6.3.1.2) HOME CRITERIA/ORAL
    A) There are no data on pediatric ingestions that can be managed at home; however, given the low toxicity, asymptomatic children with inadvertent overdoses can probably be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity (ie, CNS depression, seizures, agitation, serotonin toxicity), or in whom the diagnosis is not clear.

Monitoring

    A) Monitor vital signs and mental status.
    B) BusPIRone plasma levels are not clinically useful or readily available.
    C) No specific lab work is needed in most patients.
    D) Monitor creatinine phosphokinase and lactate levels in patients with prolonged agitation, seizures, or coma.
    E) Obtain an ECG and institute continuous cardiac monitoring in patients with moderate to severe toxicity (ie, agitation, seizures, coma, serotonin toxicity).

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) EMESIS/NOT RECOMMENDED
    1) Not recommended because of potential for somnolence and seizures.
    B) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    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).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Monitor vital signs and mental status.
    2) BusPIRone plasma levels are not clinically useful or readily available.
    3) No specific lab work is needed in most patients.
    4) Monitor creatinine phosphokinase and lactate levels in patients with prolonged agitation, seizures, or coma.
    5) Obtain an ECG and institute continuous cardiac monitoring in patients with moderate to severe toxicity (ie, agitation, seizures, coma, serotonin toxicity).
    B) SEIZURE
    1) At the time of this review, seizures have been reported in one patient following a busPIRone overdose (Catalano et al, 1998). The seizures were a late finding, which occurred approximately 36 hours after exposure. The authors suggested that the delay in onset of symptoms may have been due to the protective effect of lorazepam (given during transport to the ED).
    2) 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).
    3) 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 .
    4) 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).
    5) 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, 2010; Chin et al, 2008).
    6) 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).
    7) 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) DRUG-INDUCED DYSTONIA
    1) In one acute case involving a 5 milligram dose, diphenhydramine (25 milligrams intramuscularly) and benztropine (1 milligram intramuscularly) had little effect on the myoclonus. The dystonias and myoclonic jerks resolved following administration of 1 milligram of clonazepam (Ritchie et al, 1988).
    D) SEROTONIN SYNDROME
    1) There have been rare reports of serotonin syndrome associated with the concomitant use of busPIRone and some antidepressant agents (i.e., fluoxetine, fluvoxamine, trazodone) (Goldberg & Huk, 1992; Baetz & Malcom, 1995; Manos, 2000)
    2) SUMMARY
    a) Benzodiazepines are the mainstay of therapy. Cyproheptadine, a 5-HT antagonist, is also commonly used. Severe cases have been managed with benzodiazepine sedation and neuromuscular paralysis with non-depolarizing agents(Claassen & Gelissen, 2005).
    3) HYPERTHERMIA
    a) Control agitation and muscle activity. Undress patient and enhance evaporative heat loss by keeping skin damp and using cooling fans.
    b) MUSCLE ACTIVITY: Benzodiazepines are the drug of choice to control agitation and muscle activity. DIAZEPAM: ADULT: 5 to 10 mg IV every 5 to 10 minutes as needed, monitor for respiratory depression and need for intubation. CHILD: 0.25 mg/kg IV every 5 to 10 minutes; monitor for respiratory depression and need for intubation.
    c) Non-depolarizing paralytics may be used in severe cases.
    4) CYPROHEPTADINE
    a) Cyproheptadine is a non-specific 5-HT antagonist that has been shown to block development of serotonin syndrome in animals (Sternbach, 1991). Cyproheptadine has been used in the treatment of serotonin syndrome (Mills, 1997; Goldberg & Huk, 1992a). There are no controlled human trials substantiating its efficacy.
    b) ADULT: 12 mg initially followed by 2 mg every 2 hours if symptoms persist, up to a maximum of 32 mg in 24 hours. Maintenance dose 8 mg orally repeated every 6 hours (Boyer & Shannon, 2005).
    c) CHILD: 0.25 mg/kg/day divided every 6 hours, maximum dose 12 mg/day (Mills, 1997).
    5) HYPERTENSION
    a) Monitor vital signs regularly. For mild/moderate asymptomatic hypertension, pharmacologic intervention is usually not necessary.
    6) HYPOTENSION
    a) Administer 10 to 20 mL/kg 0.9% saline bolus and place patient supine. Further fluid therapy should be guided by central venous pressure or right heart catheterization to avoid volume overload.
    b) Pressor agents with dopaminergic effects may theoretically worsen serotonin syndrome and should be used with caution. Direct acting agents (norepinephrine, epinephrine, phentolamine) are theoretically preferred.
    c) NOREPINEPHRINE
    1) PREPARATION: Add 4 mL of 0.1% solution to 1000 mL of dextrose 5% in water to produce 4 mcg/mL.
    2) INITIAL DOSE
    a) ADULT: 2 to 3 mL (8 to 12 mcg)/minute.
    b) ADULT or CHILD: 0.1 to 0.2 mcg/kg/min. Titrate to maintain adequate blood pressure.
    3) MAINTENANCE DOSE
    a) 0.5 to 1 mL (2 to 4 mcg)/minute.
    7) SEIZURES
    a) DIAZEPAM
    1) MAXIMUM RATE: Administer diazepam IV over 2 to 3 minutes (maximum rate: 5 mg/min).
    2) ADULT DIAZEPAM DOSE: 5 to 10 mg initially, repeat every 5 to 10 minutes as needed. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 30 milligrams.
    3) PEDIATRIC DIAZEPAM DOSE: 0.2 to 0.5 mg/kg, repeat every 5 minutes as needed. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 10 milligrams in children over 5 years or 5 milligrams in children under 5 years of age.
    4) RECTAL USE: If an intravenous line cannot be established, diazepam may be given per rectum (not FDA approved), or lorazepam may be given intramuscularly.
    b) LORAZEPAM
    1) MAXIMUM RATE: The rate of IV administration of lorazepam should not exceed 2 mg/min (Prod Info Ativan(R), 1991).
    2) ADULT LORAZEPAM DOSE: 2 to 4 mg IV. Initial doses may be repeated in 10 to 15 minutes, if seizures persist (Prod Info ATIVAN(R) injection, 2003).
    3) PEDIATRIC LORAZEPAM DOSE: 0.1 mg/kg IV push (range: 0.05 to 0.1 mg/kg; maximum dose 4 mg); may repeat dose in 5 to 10 minutes if seizures continue. It has also been given rectally at the same dose in children with no IV access (Sreenath et al, 2010; Chin et al, 2008; Wheless, 2004; Qureshi et al, 2002; De Negri & Baglietto, 2001; Mitchell, 1996; Appleton, 1995; Giang & McBride, 1988).
    c) RECURRING SEIZURES
    1) If seizures cannot be controlled with diazepam or recur, give phenobarbital or propofol.
    d) PHENOBARBITAL
    1) SERUM LEVEL MONITORING: Monitor serum levels over next 12 to 24 hours for maintenance of therapeutic levels (15 to 25 mcg/mL).
    2) ADULT PHENOBARBITAL LOADING DOSE: 600 to 1200 mg of phenobarbital IV initially (10 to 20 mg/kg) diluted in 60 mL of 0.9% saline given at 25 to 50 mg/minute.
    3) ADULT PHENOBARBITAL MAINTENANCE DOSE: Additional doses of 120 to 240 mg may be given every 20 minutes.
    4) MAXIMUM SAFE ADULT PHENOBARBITAL DOSE: No maximum safe dose has been established. Patients in status epilepticus have received as much as 100 mg/min until seizure control was achieved or a total dose of 10 mg/kg.
    5) PEDIATRIC PHENOBARBITAL LOADING DOSE: 15 to 20 mg/kg of phenobarbital intravenously at a rate of 25 to 50 mg/min.
    6) PEDIATRIC PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 5 to 10 mg/kg may be given every 20 minutes.
    7) MAXIMUM SAFE PEDIATRIC PHENOBARBITAL DOSE: No maximum safe dose has been established. Children in status epilepticus have received doses of 30 to 120 mg/kg within 24 hours. Vasopressors and mechanical ventilation were needed in some patients receiving these doses.
    8) NEONATAL PHENOBARBITAL LOADING DOSE: 20 to 30 mg/kg IV at a rate of no more than 1 mg/kg/min in patients with no preexisting phenobarbital serum levels.
    9) NEONATAL PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 2.5 mg/kg every 12 hours may be given; adjust dosage to maintain serum levels of 20 to 40 mcg/mL.
    10) MAXIMUM SAFE NEONATAL PHENOBARBITAL DOSE: Doses of up to 20 mg/kg/min up to a total of 30 mg/kg have been tolerated in neonates.
    11) CAUTION: Adequacy of ventilation must be continuously monitored in children and adults. Intubation may be necessary with increased doses.
    8) CHLORPROMAZINE
    a) Chlorpromazine is a 5-HT2 receptor antagonist that has been used to treat cases of serotonin syndrome (Graham, 1997; Gillman, 1996). Controlled human trial documenting its efficacy are lacking.
    b) ADULT: 25 to 100 mg intramuscularly repeated in 1 hour if necessary.
    c) CHILD: 0.5 to 1 mg/kg repeated as needed every 6 to 12 hours not to exceed 2 mg/kg/day.
    9) NOT RECOMMENDED
    a) BROMOCRIPTINE: It has been used in the treatment of neuroleptic malignant syndrome but is NOT RECOMMENDED in the treatment of serotonin syndrome as it has serotonergic effects (Gillman, 1997). In one case the use of bromocriptine was associated with a fatal outcome (Kline et al, 1989).

Enhanced Elimination

    A) HEMODIALYSIS
    1) There is no role for repeat-dose activated charcoal. Hemodialysis is not useful given the large volume of distribution and high protein binding.

Abstracts

Case Reports

    A) ADVERSE EFFECTS
    1) In one study busPIRone was administered to 118 patients for the treatment of alcohol withdrawal syndrome. Patients received 5 mg to greater than 110 mg daily of busPIRone. One patient with a history of alcohol-related seizures reported an unwitnessed seizure. None of the other patients experienced side effects attributed to busPIRone (Dougherty & Gates, 1990).
    2) A 25-year-old man ingested 250 mg of busPIRone along with at least 25 mg of diazepam. The patient was assessed shortly after the overdose and no adverse effects were noted (Tiller et al, 1989).
    3) A case of intentional ingestion of 200 mg busPIRone, 2000 mg fluvoxamine and 300 mg flurazepam is reported. The patient described intense dizziness, vomiting and diarrhea. Sinus bradycardia (50 bpm) was continuously sustained for 7 1/2 days but blood pressure was maintained at acceptable levels (Langlois & Paquette, 1994).
    4) A 23-year-old woman ingested 420 milligrams of busPIRone and was initially lethargic and occasionally combative. Mental status improved, but she developed generalized tonic clonic seizures 36 hours after ingestion (Catalano et al, 1998).

Range Of Toxicity

Summary

    A) Expect mild toxicity in busPIRone naive patients even at therapeutic dosages. Adding busPIRone to an established therapy with serotoninergic agents may lead to serotonin toxicity.
    B) Humans have tolerated 375 milligrams/day for 30 days but developed nausea, vomiting, tingling sensations, drowsiness, insomnia, and blurred vision.
    C) An adult survived an ingestion of 420 milligrams without permanent sequelae.

Therapeutic Dose

    7.2.1) ADULT
    A) GENERAL
    1) The recommended initial dose is 15 mg/day (7.5 mg twice daily). The dose may be increased as needed to a maximum dose of 60 mg/day (Prod Info BusPIRone oral tablets, 2013).
    7.2.2) PEDIATRIC
    A) GENERAL
    1) The safety and efficacy of busPIRone were evaluated in two 6-week placebo-controlled clinical trials with pediatric patients ages 6 to 17 years (n=559) at doses of 15 to 60 mg/day (7.5 mg to 30 mg twice daily) . Efficacy was not significantly different between busPIRone and placebo in terms of the symptoms of generalized anxiety disorder. There were also no unexpected safety issues associated with busPIRone therapy in pediatric patients involved in these clinical studies. No long-term safety and efficacy data is available (Prod Info BUSPAR(R) oral tablets, 2007).

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) Humans have tolerated 375 milligrams/day for 30 days, developing side effects of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress (Prod Info BUSPAR(R) oral tablets, 2007).
    B) CASE REPORTS
    1) A 23-year-old woman ingested 420 milligrams of busPIRone and was initially lethargic and occasionally combative. Mental status improved, but she developed generalized tonic clonic seizures 36 hours after ingestion (Catalano et al, 1998).
    2) A 25-year-old male ingested a dose of 250 milligrams of busPIRone combined with 25 milligrams of diazepam with no adverse effects occurring (Tiller et al, 1989).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) GENERAL
    a) A single 20 mg dose of busPIRone in 12 healthy subjects, resulted in an average maximum plasma concentration of 1.15 mcg/L (range, 0.49 to 3.07) at 0.5 to 1.0 hours with an additional second peak observed in 7 of the volunteers averaging 0.47 mcg/L (range, 0.21 to 1.03) between 2 and 4 hours after administration (Baselt, 2000).
    1) Plasma concentrations of a metabolite, 1-PP, was approximately twice that of busPIRone after a single oral dose.
    2) In a multi-dose study, 12 healthy subjects received 10 milligrams of busPIRone daily for 10 days resulting in a maximum plasma busPIRone concentration on day 10 of 1.08 mcg/L +/- 0.80 and a maximum plasma 1-PP concentration of 7.63 mcg/L +/- 3.16 (Mahmood & Sahajwalla, 1999).
    3) In 12 children and 12 adolescents the mean maximum plasma busPIRone concentration was 0.54 to 0.67 mcg/L on 7.5 milligrams twice daily, 1.44 to 1.96 mcg/L on 15 milligrams twice daily and 2.64 to 3.96 mcg/L on 30 milligrams twice daily (Salazar et al, 2001).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) References: Riblet et al, 1982 Prod Info, 1988)
    1) LD50- (ORAL)MOUSE:
    a) 621.5 mg/kg
    b) 655 mg/kg
    2) LD50- (ORAL)RAT:
    a) 265 mg/kg
    b) 196 mg/kg

Pharmacology Toxicology

Pharmacologic Mechanism

    A) BusPIRone is a psychotropic agent which has anxiolytic properties in humans and has blocked apomorphine-induced stereotype and emesis and disrupts conditioned avoidance behavior in animals. BusPIRone does not appear to have cataleptogenic or anticonvulsant activity (Wood et al, 1983). The mechanism of action remains unknown.
    B) BusPIRone does not directly affect benzodiazepine receptors, or GABA receptors. It does influence dopaminergic transmission (Caccia et al, 1983).
    C) BusPIRone suppresses serotonergic activity while enhancing dopaminergic and noradrenergic cell firing (Eison & Temple, 1986). BusPIRone also acts on the dopaminergic system in the CNS (Mahmood & Sahajwalla, 1999).

Physicochemical

Physical Characteristics

    A) The tablets have an unpleasant taste that may discourage children (Prod Info, 1985).

Molecular Weight

    A) 385.50

References

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