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PIMAVANSERIN

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Pimavanserin is an atypical antipsychotic, used to treat hallucinations and delusions associated with Parkinson disease psychosis.

Specific Substances

    1) ACP-103
    2) Pimavanserina
    3) CAS 706779-91-1 (Pimavanserin)
    4) CAS 706782-28-7 (Pimavanserin tartrate)
    1.2.1) MOLECULAR FORMULA
    1) C25H34FN3O2 (Prod Info NUPLAZID(TM) oral tablets, 2016)

Available Forms Sources

    A) FORMS
    1) Pimavanserin is available as immediate-release, film-coated tablets containing 20 mg of pimavanserin tartrate, which is equivalent to 17 mg of pimavanserin free base (Prod Info NUPLAZID(TM) oral tablets, 2016).
    B) USES
    1) Pimavanserin is indicated for the treatment of hallucinations and delusions associated with Parkinson disease psychosis (Prod Info NUPLAZID(TM) oral tablets, 2016).

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: Pimavanserin is indicated for the treatment of hallucinations and delusions associated with Parkinson disease psychosis.
    B) PHARMACOLOGY: Although the antipsychotic effect of pimavanserin is not fully understood, it may be mediated through inverse agonist and antagonist activity at serotonin 5-HT(2A) and serotonin 5-HT(2C) receptors.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) MOST COMMON (5% or greater and twice the rate of placebo): Peripheral edema and confusional state. OTHER EFFECTS: Nausea, gait disturbance, and hallucinations.
    E) WITH POISONING/EXPOSURE
    1) Overdose information are limited. Dose-limiting nausea and vomiting were reported in healthy subjects. Concentration-dependent QTc interval prolongation has also been reported with pimavanserin use. In studies, QTc interval prolongation (maximum mean change from baseline: 13.5 msec) occurred after pimavanserin dose of twice the therapeutic dose.
    0.2.20) REPRODUCTIVE
    A) There are no adequate or well-controlled studies on the effect of pimavanserin on the pregnant woman or the unborn fetus. Weigh the mother's clinical need with the potential risks to the fetus. There are no adequate or well-controlled studies on the effect of pimavanserin on breastfeeding mothers, breastfed infants, or breast milk production. Weigh the mother's clinical need, the benefits of breastfeeding, and the potential risks to the infant.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, human carcinogenicity studies with pimavanserin have not been conducted.

Laboratory Monitoring

    A) Monitor vital signs and mental status following significant overdose.
    B) Obtain an ECG, and institute continuous cardiac monitoring.
    C) Monitor serum electrolytes in patients with significant nausea and vomiting.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe nausea and vomiting. Therapeutic doses of pimavanserin may cause prolongation of the QT interval. Concomitant use of pimavanserin and other drugs that prolong the QT interval may increase the risk of torsades de pointes. Treat torsades de pointes with IV magnesium sulfate, and correct electrolyte abnormalities; overdrive pacing may be necessary.
    C) DECONTAMINATION
    1) PREHOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    2) HOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    D) AIRWAY MANAGEMENT
    1) Endotracheal intubation may be necessary if significant CNS depression develops.
    E) ANTIDOTE
    1) None.
    F) ENHANCED ELIMINATION
    1) Hemodialysis is unlikely to be of value because of the high degree of protein binding (about 95%) and large volume of distribution.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.
    3) ADMISSION CRITERIA: Patients with severe symptoms despite treatment should be admitted.
    4) CONSULT CRITERIA: Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    H) PITFALLS
    1) When managing a suspected overdose, the treating physician should be cognizant of the possibility of multi-drug involvement.
    I) PHARMACOKINETICS
    1) Tmax: 6 hours (range, 4 to 24 hours). Protein binding: Approximately 95%. Vd: Mean apparent Vd was 2173 +/- 307 L. Metabolism: Pimavanserin is predominantly metabolized by CYP3A4 and CYP3A5, with lesser contribution from CYP2J2, CYP2D6, and various other CYP and FMO enzymes. Excretion: Approximately 0.55% was eliminated as unchanged drug in urine, with less than 1% recovered as the major active metabolite. Feces: Approximately 1.53% was recovered in feces after 10 days. Elimination half-life: Parent: Mean 57 hours. Metabolite: Mean 200 hours.
    J) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause prolonged QT interval.

Range Of Toxicity

    A) TOXICITY: A specific minimum toxic dose has not been established for pimavanserin. Dose-limiting nausea and vomiting were reported in healthy subjects. Concentration-dependent QTc interval prolongation has also been reported with pimavanserin use. In studies, QTc interval prolongation (maximum mean change from baseline: 13.5 msec) occurred after pimavanserin dose of twice the therapeutic dose.
    B) THERAPEUTIC DOSE: ADULT: 34 mg (two 17 mg tablets) orally once daily. PEDIATRIC: The safety and effectiveness have not been established in pediatric patients.

Clinical Effects

Summary Of Exposure

    A) USES: Pimavanserin is indicated for the treatment of hallucinations and delusions associated with Parkinson disease psychosis.
    B) PHARMACOLOGY: Although the antipsychotic effect of pimavanserin is not fully understood, it may be mediated through inverse agonist and antagonist activity at serotonin 5-HT(2A) and serotonin 5-HT(2C) receptors.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) MOST COMMON (5% or greater and twice the rate of placebo): Peripheral edema and confusional state. OTHER EFFECTS: Nausea, gait disturbance, and hallucinations.
    E) WITH POISONING/EXPOSURE
    1) Overdose information are limited. Dose-limiting nausea and vomiting were reported in healthy subjects. Concentration-dependent QTc interval prolongation has also been reported with pimavanserin use. In studies, QTc interval prolongation (maximum mean change from baseline: 13.5 msec) occurred after pimavanserin dose of twice the therapeutic dose.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) PERIPHERAL EDEMA
    1) WITH THERAPEUTIC USE
    a) In placebo-controlled studies, peripheral edema developed in 7% of 202 patients with hallucinations and delusions associated with Parkinson disease psychosis after receiving pimavanserin 34 mg once daily for up to 6 weeks and 2% of 231 patients after receiving placebo (Prod Info NUPLAZID(TM) oral tablets, 2016).
    B) PROLONGED QT INTERVAL
    1) WITH POISONING/EXPOSURE
    a) Concentration-dependent QTc interval prolongation has been reported with pimavanserin use (Prod Info NUPLAZID(TM) oral tablets, 2016).
    b) In studies, QTc interval prolongation (maximum mean change from baseline: 13.5 msec) occurred after pimavanserin dose of twice the therapeutic dose (Prod Info NUPLAZID(TM) oral tablets, 2016).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CLOUDED CONSCIOUSNESS
    1) WITH THERAPEUTIC USE
    a) In placebo-controlled studies, confusional state developed in 6% of 202 patients with hallucinations and delusions associated with Parkinson disease psychosis after receiving pimavanserin 34 mg once daily for up to 6 weeks and 3% of 231 patients after receiving placebo (Prod Info NUPLAZID(TM) oral tablets, 2016).
    B) ABNORMAL GAIT
    1) WITH THERAPEUTIC USE
    a) In placebo-controlled studies, gait disturbance developed in 2% of 202 patients with hallucinations and delusions associated with Parkinson disease psychosis after receiving pimavanserin 34 mg once daily for up to 6 weeks and less than 1% of 231 patients after receiving placebo (Prod Info NUPLAZID(TM) oral tablets, 2016).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) In placebo-controlled studies, nausea developed in 7% of 202 patients with hallucinations and delusions associated with Parkinson disease psychosis after receiving pimavanserin 34 mg once daily for up to 6 weeks and 4% of 231 patients after receiving placebo (Prod Info NUPLAZID(TM) oral tablets, 2016).
    2) WITH POISONING/EXPOSURE
    a) Dose-limiting nausea and vomiting have been reported in healthy volunteers (Prod Info NUPLAZID(TM) oral tablets, 2016).
    B) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) In placebo-controlled studies, constipation developed in 4% of 202 patients with hallucinations and delusions associated with Parkinson disease psychosis after receiving pimavanserin 34 mg once daily for up to 6 weeks and 3% of 231 patients after receiving placebo (Prod Info NUPLAZID(TM) oral tablets, 2016).

Reproductive

    3.20.1) SUMMARY
    A) There are no adequate or well-controlled studies on the effect of pimavanserin on the pregnant woman or the unborn fetus. Weigh the mother's clinical need with the potential risks to the fetus. There are no adequate or well-controlled studies on the effect of pimavanserin on breastfeeding mothers, breastfed infants, or breast milk production. Weigh the mother's clinical need, the benefits of breastfeeding, and the potential risks to the infant.
    3.20.3) EFFECTS IN PREGNANCY
    A) RISK SUMMARY
    1) There are no adequate or well-controlled studies on the effect of pimavanserin on the pregnant woman or the unborn fetus (Prod Info NUPLAZID(TM) oral tablets, 2016). Weigh the mother's clinical need with the potential risks to the fetus.
    B) ANIMAL STUDIES
    1) In animal studies, pimavanserin doses 2 times the maximum recommended human dose (MRHD) resulted in maternal toxicity (eg, dehydration, hunched posture, and rales), a decrease in pup survival, reduced litter size, reduced pup weights, and reduced food consumption (Prod Info NUPLAZID(TM) oral tablets, 2016).
    2) In female animals, pimavanserin doses 22 times the maximum recommended human dose (MRHD) resulted in a decrease in the number of corpora lutea, number of implants, viable implants and an increase in preimplantation loss, early resorptions, and postimplantation loss. No effects on sexual maturation, neurobehavioral function, including learning and memory, or reproductive function in the first generation pups were observed when animals were administered pimavanserin doses up to 14-times the MHRD (Prod Info NUPLAZID(TM) oral tablets, 2016).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) There are no adequate or well-controlled studies on the effect of pimavanserin on breastfeeding mothers, breastfed infants, or breast milk production. Weigh the mother's clinical need, the benefits of breastfeeding, and the potential risks to the infant (Prod Info NUPLAZID(TM) oral tablets, 2016).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) In male animals, pimavanserin doses 15 times the MRHD resulted in changes in sperm (eg, decreased density, decreased motility) and vacuolation in the epididymis (Prod Info NUPLAZID(TM) oral tablets, 2016).
    2) In female animals, pimavanserin doses 22 times the maximum recommended human dose (MRHD) resulted in a decrease in the number of corpora lutea, number of implants, viable implants and an increase in preimplantation loss, early resorptions, and postimplantation loss (Prod Info NUPLAZID(TM) oral tablets, 2016).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, human carcinogenicity studies with pimavanserin have not been conducted.
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, human carcinogenicity studies with pimavanserin have not been conducted.
    3.21.4) ANIMAL STUDIES
    A) LACK OF EFFECT
    1) In animal studies, pimavanserin doses up to 16 times the maximum recommended human dose of 34 mg/day based on AUC for 2 years, did not produce an increase in the incidence of tumors (Prod Info NUPLAZID(TM) oral tablets, 2016).

Genotoxicity

    A) Genotoxicity tests in in vitro (Ames reverse mutation test, mouse lymphoma assay) and in vivo (mouse bone marrow micronucleus assay) tests were negative for pimavanserin (Prod Info NUPLAZID(TM) oral tablets, 2016).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and mental status following significant overdose.
    B) Obtain an ECG, and institute continuous cardiac monitoring.
    C) Monitor serum electrolytes in patients with significant nausea and vomiting.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with severe symptoms despite treatment should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.

Monitoring

    A) Monitor vital signs and mental status following significant overdose.
    B) Obtain an ECG, and institute continuous cardiac monitoring.
    C) Monitor serum electrolytes in patients with significant nausea and vomiting.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) 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) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe nausea and vomiting. Therapeutic doses of pimavanserin may cause prolongation of the QT interval. Concomitant use of pimavanserin and other drugs that prolong the QT interval may increase the risk of torsades de pointes. Treat torsades de pointes with IV magnesium sulfate, and correct electrolyte abnormalities; overdrive pacing may be necessary.
    B) MONITORING OF PATIENT
    1) Monitor vital signs and mental status following significant overdose.
    2) Obtain an ECG, and institute continuous cardiac monitoring.
    3) Monitor serum electrolytes in patients with significant nausea and vomiting.
    C) PROLONGED QT INTERVAL
    1) Prolongation of the QT interval has been reported with pimavanserin. Avoid the use of pimavanserin with other drugs known to prolong the QT interval, including Class 1A antiarrhythmics, Class 3 antiarrhythmics, certain antipsychotics (eg, ziprasidone, chlorpromazine), and certain antibiotics (eg, gatifloxacin, moxifloxacin) (Prod Info NUPLAZID(TM) oral tablets, 2016). Concurrent use may also increase the risk of torsades de pointes. In patients with QT prolongation, monitor serum electrolytes including potassium, calcium and magnesium in patients with significant overdose; correct any abnormalities.
    2) SUMMARY
    a) Withdraw the causative agent. Hemodynamically unstable patients with Torsades de pointes (TdP) require electrical cardioversion. Emergent treatment with magnesium (first-line agent) or atrial overdrive pacing is indicated. Detect and correct underlying electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia). Correct hypoxia, if present (Drew et al, 2010; Neumar et al, 2010; Keren et al, 1981; Smith & Gallagher, 1980).
    b) Polymorphic VT associated with acquired long QT syndrome may be treated with IV magnesium. Overdrive pacing or isoproterenol may be successful in terminating TdP, particularly when accompanied by bradycardia or if TdP appears to be precipitated by pauses in rhythm (Neumar et al, 2010). In patients with polymorphic VT with a normal QT interval, magnesium is unlikely to be effective (Link et al, 2015).
    3) MAGNESIUM SULFATE
    a) Magnesium is recommended (first-line agent) for the prevention and treatment of drug-induced torsades de pointes (TdP) even if the serum magnesium concentration is normal. QTc intervals greater than 500 milliseconds after a potential drug overdose may correlate with the development of TdP (Charlton et al, 2010; Drew et al, 2010). ADULT DOSE: No clearly established guidelines exist; an optimal dosing regimen has not been established. Administer 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes (Neumar et al, 2010). Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram (4 to 8 mEq) per hour in patients not responding to the initial bolus or with recurrence of dysrhythmias (American Heart Association, 2005; Perticone et al, 1997). Rate of infusion may be increased if dysrhythmias recur. For persistent refractory dysrhythmias, a continuous infusion of up to 3 to 10 milligrams/minute in adults may be given (Charlton et al, 2010).
    b) PEDIATRIC DOSE: 25 to 50 milligrams/kilogram diluted to 10 milligrams/milliliter for intravenous infusion over 5 to 15 minutes up to 2 g (Charlton et al, 2010).
    c) PRECAUTIONS: Use with caution in patients with renal insufficiency.
    d) MAJOR ADVERSE EFFECTS: High doses may cause hypotension, respiratory depression, and CNS toxicity (Neumar et al, 2010). Toxicity may be observed at magnesium levels of 3.5 to 4.0 mEq/L or greater (Charlton et al, 2010).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respiratory rate, motor strength, deep tendon reflexes, serum magnesium, phosphorus, and calcium concentrations (Prod Info magnesium sulfate heptahydrate IV, IM injection, solution, 2009).
    4) OVERDRIVE PACING
    a) Institute electrical overdrive pacing at a rate of 130 to 150 beats per minute, and decrease as tolerated. Rates of 100 to 120 beats per minute may terminate torsades (American Heart Association, 2005). Pacing can be used to suppress self-limited runs of TdP that may progress to unstable or refractory TdP, or for override refractory, persistent TdP before the potential development of ventricular fibrillation (Charlton et al, 2010). In a case series overdrive pacing was successful in terminating TdP associated with bradycardia and drug-induced QT prolongation (Neumar et al, 2010).
    5) POTASSIUM REPLETION
    a) Potassium supplementation, even if serum potassium is normal, has been recommended by many experts (Charlton et al, 2010; American Heart Association, 2005). Supplementation to supratherapeutic potassium concentrations of 4.5 to 5 mmol/L has been suggested, although there is little evidence to determine the optimal range in dysrhythmia (Drew et al, 2010; Charlton et al, 2010).
    6) ISOPROTERENOL
    a) Isoproterenol has been successful in aborting torsades de pointes that was resistant to magnesium therapy in a patient in whom transvenous overdrive pacing was not an option (Charlton et al, 2010) and has been successfully used to treat torsades de pointes associated with bradycardia and drug induced QT prolongation (Keren et al, 1981; Neumar et al, 2010). Isoproterenol may have a limited role in pharmacologic overdrive pacing in select patients with drug-induced torsades de pointes and acquired long QT syndrome (Charlton et al, 2010; Neumar et al, 2010). Isoproterenol should be avoided in patients with polymorphic VT associated with familial long QT syndrome (Neumar et al, 2010).
    b) DOSE: ADULT: 2 to 10 micrograms/minute via a continuous monitored intravenous infusion; titrate to heart rate and rhythm response (Neumar et al, 2010).
    c) PRECAUTIONS: Correct hypovolemia before using; contraindicated in patients with acute cardiac ischemia (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    1) Contraindicated in patients with preexisting dysrhythmias; tachycardia or heart block due to digitalis toxicity; ventricular dysrhythmias that require inotropic therapy; and angina. Use with caution in patients with coronary insufficiency (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    d) MAJOR ADVERSE EFFECTS: Tachycardia, cardiac dysrhythmias, palpitations, hypotension or hypertension, nervousness, headache, dizziness, and dyspnea (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respirations and central venous pressure to guide volume replacement (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    7) OTHER DRUGS
    a) Mexiletine, verapamil, propranolol, and labetalol have also been used to treat TdP, but results have been inconsistent (Khan & Gowda, 2004).
    8) AVOID
    a) Avoid class Ia antidysrhythmics (eg, quinidine, disopyramide, procainamide, aprindine), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol) since they may further prolong the QT interval and have been associated with TdP.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis is unlikely to be of value because of the high degree of protein binding (about 95%) and large volume of distribution.

Range Of Toxicity

Summary

    A) TOXICITY: A specific minimum toxic dose has not been established for pimavanserin. Dose-limiting nausea and vomiting were reported in healthy subjects. Concentration-dependent QTc interval prolongation has also been reported with pimavanserin use. In studies, QTc interval prolongation (maximum mean change from baseline: 13.5 msec) occurred after pimavanserin dose of twice the therapeutic dose.
    B) THERAPEUTIC DOSE: ADULT: 34 mg (two 17 mg tablets) orally once daily. PEDIATRIC: The safety and effectiveness have not been established in pediatric patients.

Therapeutic Dose

    7.2.1) ADULT
    A) 34 mg (two 17 mg tablets) orally once daily; dose titration not necessary (Prod Info NUPLAZID(TM) oral tablets, 2016)
    7.2.2) PEDIATRIC
    A) The safety and effectiveness have not been established in pediatric patients (Prod Info NUPLAZID(TM) oral tablets, 2016).

Maximum Tolerated Exposure

    A) Dose-limiting nausea and vomiting were reported in healthy subjects. Concentration-dependent QTc interval prolongation has also been reported with pimavanserin use. In studies, QTc interval prolongation (maximum mean change from baseline: 13.5 msec) occurred after pimavanserin dose of twice the therapeutic dose (Prod Info NUPLAZID(TM) oral tablets, 2016).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) The antipsychotic effect of pimavanserin may be mediated through inverse agonist and antagonist activity at serotonin 5-HT(2A) and serotonin 5-HT(2C) receptors (Prod Info NUPLAZID(TM) oral tablets, 2016).

Physicochemical

Physical Characteristics

    A) White to off-white round tablets, freely soluble in water (Prod Info NUPLAZID(TM) oral tablets, 2016).

Molecular Weight

    A) 427.55 (Prod Info NUPLAZID(TM) oral tablets, 2016)

References

General Bibliography

    1) Alaspaa AO, Kuisma MJ, Hoppu K, et al: Out-of-hospital administration of activated charcoal by emergency medical services. Ann Emerg Med 2005; 45:207-12.
    2) American Heart Association: 2005 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2005; 112(24 Suppl):IV 1-203. Available from URL: http://circ.ahajournals.org/content/vol112/24_suppl/. As accessed 12/14/2005.
    3) Charlton NP , Lawrence DT , Brady WJ , et al: Termination of drug-induced torsades de pointes with overdrive pacing. Am J Emerg Med 2010; 28(1):95-102.
    4) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    5) Dagnone D, Matsui D, & Rieder MJ: Assessment of the palatability of vehicles for activated charcoal in pediatric volunteers. Pediatr Emerg Care 2002; 18:19-21.
    6) Drew BJ, Ackerman MJ, Funk M, et al: Prevention of torsade de pointes in hospital settings: a scientific statement from the American Heart Association and the American College of Cardiology Foundation. J Am Coll Cardiol 2010; 55(9):934-947.
    7) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    8) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    9) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    10) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    11) Guenther Skokan E, Junkins EP, & Corneli HM: Taste test: children rate flavoring agents used with activated charcoal. Arch Pediatr Adolesc Med 2001; 155:683-686.
    12) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
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    20) Product Information: Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, isoproterenol HCl intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection. Hospira, Inc. (per FDA), Lake Forest, IL, 2013.
    21) Product Information: NUPLAZID(TM) oral tablets, pimavanserin oral tablets. ACADIA Pharmaceuticals (per manufacturer), San Diego, CA, 2016.
    22) Product Information: magnesium sulfate heptahydrate IV, IM injection, solution, magnesium sulfate heptahydrate IV, IM injection, solution. Hospira, Inc. (per DailyMed), Lake Forest, IL, 2009.
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