ANTIPSYCHOTICS









Aripiprazole | Abilify® | Abilify Discmelt® | Abilify Maintena™ | Aristada® | Abilify MyCite®

Dosage forms

Tablet (Abilify®)
  • 2 mg
  • 5 mg
  • 10 mg
  • 15 mg
  • 20 mg
  • 30 mg
Orally-disintegrating tablet (Abilify Discmelt®)
  • 10 mg
  • 15 mg
Tablet with IEM (Abilify MyCite®)
  • 2 mg
  • 5 mg
  • 10 mg
  • 15 mg
  • 20 mg
  • 30 mg
  • Comes in kit with 30 tablets and 7 patches
Solution (Abilify®)
  • 1 mg/ml
  • Comes in 150 ml bottle
Prefilled syringe and vial (Abilify Maintena™)
  • 300 mg
  • 400 mg
Prefilled syringe (Aristada®)
  • 441 mg
  • 662 mg
  • 882 mg
  • Aristada is aripiprazole lauroxil

Dosing - Abilify® (tablets / discmelt / solution)

Schizophrenia (adults)
  • Starting: 10 - 15 mg once daily
  • Maintenance: - 10 - 20 mg once daily
  • Max: 30 mg once daily
  • Increase dose at intervals of ≥ 2 weeks
  • Solution can be substituted for tablet on mg-to-mg basis up to 25 mg
Schizophrenia (13 - 17 years old)
  • Starting: 2 mg once daily for 2 days, then 5 mg once daily for 2 days, then 10 mg once daily
  • Maintenance: 10 mg once daily
  • Max: 30 mg once daily
  • After initial dosing, increase dose by increments of 5 mg/day
  • Doses > 10 mg/day have not been shown to be more efficacious
Bipolar I (adults)
  • Starting: 10 - 15 mg once daily
  • Maintenance: - 10 - 20 mg once daily
  • Max: 30 mg once daily
  • Increase dose at intervals of ≥ 2 weeks
  • Solution can be substituted for tablet on mg-to-mg basis up to 25 mg
Bipolar I (10 - 17 years old)
  • Starting: 2 mg once daily for 2 days, then 5 mg once daily for 2 days, then 10 mg once daily
  • Maintenance: 10 mg once daily
  • After initial dosing, increase dose in increments of 5 mg/day
Depression in adults (adjunctive with antidepressant)
  • Starting: 2 - 5 mg once daily
  • Maintenance: 2 - 15 mg once daily
  • Increase dose by up to 5 mg a day at intervals of ≥ 1 week
Irritability associated with autistic disorder (6 - 17 years)
  • Starting: 2 mg once daily
  • Maintenance: 5 - 15 mg once daily
  • Increase dose by up to 5 mg/day at intervals of ≥ 1 week
Tourette’s disorder (6 - 18 years)
  • Dosing (< 50 kg): 2 mg once daily for 2 days, then 5 mg once daily. May increase to 10 mg once daily if necessary.
  • Dosing (≥ 50 kg): 2 mg once daily for 2 days, then 5 mg once daily for 5 days, then 10 mg once daily
  • After initial dosing, increase dose at intervals of ≥ 1 week

Dosing - Abilify Maintena™

Schizophrenia/Bipolar I (adults)
  • Dosing: 400 mg IM once a month
  • Patients should demonstrate tolerability of oral Abilify® before using
  • After initial injection, continue oral aripiprazole for 14 days
  • See Abilify Maintena™ PI for guidelines on missed injections

Dosing - Aristada™

Schizophrenia (adults)
  • Dosing: 441 - 882 mg IM once monthly. 882 mg dose may also be given every 6 weeks.
  • Patients should demonstrate tolerability of oral Abilify® before using
  • After initial injection, continue oral aripiprazole for 21 days
  • Converting from oral:
    • 10 mg/day = 441 mg/month
    • 15 mg/day = 662 mg/month
    • ≥ 20 mg/day = 882 mg/month
  • See Aristada PI sec 2.2 for guidelines on missed injections

Efficacy


Generic / Price

  • Abilify tablet - YES/$
  • Abilify ODT - YES/$$$$
  • Abilify MyCite - NO/$$$$
  • Abilify solution - YES/$$$$
  • Abilify Maintena - NO/$$$$
  • Aristada - NO/$$$$

Other

Tablet and discmelt
  • May take without regard to food
  • Discmelt is placed on tongue where it dissolves
Abilify MyCite®
  • Abilify MyCite is a system composed of a tablet with an ingestible event marker (IEM) sensor, a wearable sensor patch, a smartphone app, and a web-based portal for healthcare providers. The IEM is a 1 mm sized sensor embedded in the Abilify Mycite tablet. Upon contact with gastric fluid, magnesium and cuprous chloride within the IEM react to activate and power the device. The IEM then communicates the ingestion to the MyCite Patch. Detected ingestions can be reviewed on the app and in the portal.
  • The IEM sensor detects most ingestions within 30 minutes, but may take up to 2 hours
  • The patch is applied every 7 days to the left side of the body just above the lower edge of the rib cage. The patch should be removed for MRIs.
  • Swallow tablets whole; do not divide, crush, or chew
Solution
  • Solution can be substituted for tablet on mg-to-mg basis up to 25 mg
  • Once bottle is opened, good for 6 months
  • Store at room temperature
Abilify Maintena
  • For intramuscular injection in the deltoid or gluteal muscle
  • Store at room temperature
Aristada
  • For intramuscular injection in the deltoid (441 mg dose only) or gluteal muscle (all doses)
  • Store at room temperature

Pharmacokinetics (tablet)

  • Half-life (aripiprazole): 75 hours
  • Half-life (active metabolite): 94 hours

Mechanism of action

  • Dopamine D2 receptor partial agonist
  • Serotonin 5-HT1A receptor partial agonist
  • Serotonin 5-HT2A receptor antagonist

FDA-approved indications

Abilify tablets/solution
  • Schizophrenia
  • Bipolar I - Acute treatment of manic and mixed episodes
  • Depression - adjunct with antidepressants
  • Tourette's disorder
  • Irritability associated with autistic disorder
Abilify MyCite
  • Schizophrenia
  • Bipolar I
  • Depression - adjunct with antidepressants
Abilify Maintena
  • Schizophrenia
  • Bipolar I - maintenance monotherapy
Aristada
  • Schizophrenia

Side effects



Side effect Aripiprazole Placebo
Headache 27% 23%
Agitation 19% 17%
Insomnia 18% 13%
Anxiety 17% 13%
Nausea 15% 11%
Skin irritation
(MyCite patch)
12.4% N/A
Somnolence 11% 6%
Constipation 11% 7%
Vomiting 11% 6%
Dizziness 10% 7%
Akathisia 10% 4%
Other
  • Extrapyramidal symptoms - 8 to 13% of patients in trials
  • Weight gain - up to 8% of patients
  • Orthostatic hypotension - 1% of patients
  • Difficulty swallowing - incidence not well-defined
  • Hyperprolactinemia - incidence not well-defined
  • Priapism (erection lasting longer than 4 hours) - rare


Drug interactions

  • CYP3A4 strong inhibitors - administer half of recommended dose
  • Known CYP2D6 Poor Metabolizers + CYP3A4 strong inhibitors - administer a quarter of recommended dose
  • CYP3A4 strong inducers - double recommended dose over 1 to 2 weeks
  • CYP2D6 strong inhibitors - administer half of recommended dose
  • CYP2D6 strong inhibitor + CYP3A4 inhibitor - administer a quarter of recommended dose
  • Carbamazepine - carbamazepine is a strong CYP3A4 inducer. Double aripiprazole dose when taken together.
  • Alpha blockers - aripiprazole can block alpha receptors. It may potentiate the effects of alpha blockers.
  • Dopamine agonists (Mirapex®, Sinemet®, etc.) - aripiprazole may block the activity of dopamine agonists used in Parkinson's, RLS, etc.

Lab interactions

  • Urine drug screen - there have case reports of false-positive amphetamines on urine drug screens in children exposed to aripiprazole. Subsequent confirmatory testing with gas chromatography-mass spectrometry was negative. [PMID 26527556]

Contraindications / Precautions

  • Poor CYP2D6 metabolizers - reduce dose by one-half and adjust as needed
  • Elderly with dementia-related psychosis - antipsychotics may increase the risk of death in elderly patients with dementia-related psychosis. In studies lasting 10-weeks, the incidence of death was 4.5% in antipsychotic-treated patients and 2.6% in placebo-treated patients.
  • Stroke and TIA in elderly patients with dementia-related psychosis - in placebo-controlled trials, elderly patients with dementia-related psychosis who were treated with risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and TIA
  • Suicide in depression - possible increase risk when starting therapy in patients ≤ 24 years old
  • Falls - antipsychotics may cause somnolence, postural hypotension, and motor and sensory instability which can lead to falls. Use caution in susceptible patients.
  • Neuroleptic malignant syndrome (NMS)
  • Tardive dyskinesia
  • Diabetes - atypical antipsychotics have been associated with weight gain and diabetes in some patients. In trials lasting up to 24 weeks, aripiprazole had no significant effect on blood sugars. Long-term effects are unknown. See diabetes below for ADA monitoring recommendations.
  • Cholesterol - atypical antipsychotics have been associated with increases in cholesterol in some patients. In trials lasting up to 24 weeks, aripiprazole had no significant effect on lipid parameters. Long-term effects are unknown. See cholesterol below for ADA monitoring recommendations.
  • Body temperature dysregulation - disruption in the body's ability to reduce core temperature has been reported with antipsychotics. Use caution in patients who may be at risk of core temperature elevations (e.g. strenuous exercise, extreme heat, taking anticholinergics, dehydration).
  • Leukopenia - antipsychotics have been associated with a decrease in white blood cells in some patients. Monitor CBC closely in susceptible patients.
  • Seizure - antipsychotics may increase seizure risk. Use caution in susceptible patients.
  • Orthostatic hypotension and syncope - atypical antipsychotics may cause orthostatic hypotension and syncope in some patients. Use caution in susceptible patients.
  • Cognitive and motor impairment - antipsychotics may cause sedation. Use caution before driving or performing tasks that require mental alertness.
  • Impulse-control problems - cases of uncontrollable urges to gamble, binge eat, shop, and have sex have been reported in patients taking aripiprazole
  • Liver disease - no dose adjustment necessary
  • Kidney disease - no dose adjustment necessary

Asenapine | Saphris® | Secuado®

Dosage forms

Sublingual tablet (Saphris®)
  • 5 mg
  • 10 mg
Patch (Secuado®)
  • 3.8 mg/24 hours
  • 5.7 mg/24 hours
  • 7.6 mg/24 hours
  • Comes in carton with 30 patches

Dosing - Tablet

Schizophrenia (adults)
  • Starting: 5 mg twice a day
  • Maintenance: 5 - 10 mg twice a day
  • Max: 10 mg twice a day
  • Increase dose at intervals of 1 week
Bipolar mania (adults)
  • Starting: 5 - 10 mg twice a day
  • Maintenance: 5 - 10 mg twice a day
  • Max: 10 mg twice a day
Bipolar mania (10 - 17 years old)
  • Starting: 2.5 mg twice a day
  • Maintenance: 2.5 - 10 mg twice a day
  • Max: 10 mg twice a day
Bipolar mania - adjunct to lithium or valproate (adults)
  • Starting: 5 mg twice a day
  • Maintenance: 5 - 10 mg twice a day
  • Max: 10 mg twice a day

Dosing - Patch

Schizophrenia (adults)
  • Starting: 3.8 mg/24 hours patch applied once daily
  • Maintenance: 3.8 mg - 7.6 mg/24 hours patch applied once daily
  • Max: 7.6 mg/24 hours patch applied once daily
  • Increase dose at intervals of 1 week
  • 3.8 mg/24 hours patch corresponds to 5 mg twice daily of sublingual asenapine and 7.6 mg/24 hours corresponds to 10 mg twice daily
  • Apply to the upper arm, upper back, abdomen, or hip
  • Showering is permitted, but use during swimming or taking a bath has not been evaluated
  • Do not apply heat to the patch because it will increase absorption

Generic / Price

  • Sublingual tablet - YES/$$$$
  • Patch - NO/$$$$

Other

Saphris
  • Saphris is a sublingual tablet that dissolves under the tongue
  • It should not be crushed, chewed, or swallowed
  • Patients should not eat or drink for 10 minutes after administration

Pharmacokinetics

Tablet
  • Tmax: 1 hour
  • Half-life: 24 hours
Patch
  • Tmax: 12 - 24 hour
  • Half-life: 30 hours

Mechanism of action

  • Dopamine D2 receptor antagonist
  • Serotonin (5-HT2A) receptor antagonist

FDA-approved indications

Tablet
  • Schizophrenia
  • Bipolar - acute mania
Patch
  • Schizophrenia

Side effects



Side effect Asenapine Placebo
Somnolence 24% 6%
Headache 12% 11%
Dizziness 11% 3%
Akathisia 4% 2%
Other
  • Weight gain (≥ 7% increase) - 15% after one-year of therapy
  • Extrapyramidal symptoms - up to 10% of patients in trials
  • Orthostatic hypotension - < 1% of patients
  • Difficulty swallowing - incidence not well-defined
  • Hyperprolactinemia (elevated prolactin level) - incidence not well-defined
  • Priapism (erection lasting longer than 4 hours) - rare
  • Local skin reactions (patch) - up to 15%


Drug interactions


Contraindications / Precautions

  • Prolonged QT syndrome - DO NOT USE. Asenapine may prolong the QT interval.
  • Elderly with dementia-related psychosis - antipsychotics may increase the risk of death in elderly patients with dementia-related psychosis. In studies lasting 10-weeks, the incidence of death was 4.5% in antipsychotic-treated patients and 2.6% in placebo-treated patients.
  • Stroke and TIA in elderly patients with dementia-related psychosis - in placebo-controlled trials, elderly patients with dementia-related psychosis who were treated with risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and TIA
  • Neuroleptic malignant syndrome (NMS)
  • Tardive dyskinesia
  • Diabetes - atypical antipsychotics have been associated with weight gain and diabetes in some patients. In trials lasting up to 6 weeks, asenapine caused a slight increase in blood sugars. Long-term effects are unknown. See diabetes below for ADA monitoring recommendations.
  • Cholesterol - atypical antipsychotics have been associated with increases in cholesterol in some patients. See cholesterol below for ADA monitoring recommendations.
  • Falls - antipsychotics may cause somnolence, postural hypotension, and motor and sensory instability which can lead to falls. Use caution in susceptible patients.
  • Leukopenia - antipsychotics have been associated with a decrease in white blood cells in some patients. Monitor CBC closely in susceptible patients.
  • Seizure - antipsychotics may increase seizure risk. Use caution in susceptible patients.
  • Orthostatic hypotension and syncope - atypical antipsychotics may cause orthostatic hypotension and syncope in some patients. Use caution in susceptible patients.
  • Cognitive and motor impairment - antipsychotics may cause sedation. Use caution before driving or performing tasks that require mental alertness.
  • Body temperature dysregulation - disruption in the body's ability to reduce core temperature has been reported with antipsychotics. Use caution in patients who may be at risk of core temperature elevations (e.g. strenuous exercise, extreme heat, taking anticholinergics, dehydration).
  • Liver disease
    • Mild to moderate (Child-Pugh A/B) - no dose adjustment necessary
    • Severe (Child-Pugh C) - DO NOT USE
  • Kidney disease - No dose adjustment necessary

Brexpiprazole (Rexulti®)

Dosage forms

Tablet
  • 0.25 mg
  • 0.5 mg
  • 1 mg
  • 2 mg
  • 3 mg
  • 4 mg

Dosing

Schizophrenia
  • Starting: 1 mg once daily on Days 1 to 4, increase dose to 2 mg once daily on Days 5 to 7, then to 4 mg on Day 8 if needed
  • Maintenance: 2 - 4 mg once daily
  • Max: 4 mg once daily
  • May take without regard to food
Depression (adjunctive with antidepressant)
  • Starting: 0.5 - 1 mg once daily
  • Maintenance: 2 mg once daily
  • Max: 3 mg once daily
  • Increase dose at weekly intervals
  • May take without regard to food
Dosing with CYP2D6 and CYP3A4 modulators

Concurrent medication Brexpiprazole dose
Strong CYP2D6 inhibitor Half usual dose
Strong CYP3A4 inhibitor Half usual dose
Strong/moderate CYP2D6 inhibitor + strong/moderate CYP3A4 inhibitor Quarter of usual dose
Strong CYP3A4 inducer Double usual dose over 1 - 2 weeks
Dosing for CYP2D6 poor metabolizers
  • CYP2D6 poor metabolizer - half the usual dose
  • CYP2D6 poor metabolizer + strong/moderate CYP3A4 inhibitor - quarter the usual dose

Generic / Price

- NO/$$$$

Pharmacokinetics

  • Time to max level: within 4 hours
  • Half-life: 91 hours

Mechanism of action

  • Dopamine D2 receptor partial agonist
  • Serotonin 5-HT1A receptor partial agonist
  • Serotonin 5-HT2A receptor antagonist

FDA-approved indications

  • Schizophrenia
  • Depression (adjunctive with antidepressant)

Side effects



Side effect Rexulti Placebo
Increase in triglycerides 10% 6%
Akathisia 7% 5%
Extrapyramidal symptoms (excluding akathisia) 5% 4%
Somnolence 5% 3%
Tremor 3% 1%
Sedation 3% 1%
Upset stomach 3% 2%
Diarrhea 3% 2%
Increase in CPK 2% 1%

Other

  • Weight gain - in 6 week trials, patients on brexpiprazole gained an average of 2.6 lbs (1.2 kg) while patients on placebo gained 0.4 lbs (0.2 kg)
  • Difficulty swallowing - incidence not well-defined


Drug interactions

  • CYP3A4 modulators - brexpiprazole is a CYP3A4 sensitive substrate. See Dosage for recommendations on concomitant dosing.
  • CYP2D6 modulators - brexpiprazole is a CYP2D6 sensitive substrate. See Dosage for recommendations on concomitant dosing.
  • Dopamine agonists (Mirapex®, Sinemet®, etc.) - brexpiprazole may block the activity of dopamine agonists used in Parkinson's, RLS, etc.

Contraindications / Precautions

  • Elderly with dementia-related psychosis - antipsychotics may increase the risk of death in elderly patients with dementia-related psychosis. In studies lasting 10-weeks, the incidence of death was 4.5% in antipsychotic-treated patients and 2.6% in placebo-treated patients.
  • Stroke and TIA in elderly patients with dementia-related psychosis - in placebo-controlled trials, elderly patients with dementia-related psychosis who were treated with risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and TIA
  • Neuroleptic malignant syndrome (NMS)
  • Tardive dyskinesia
  • Suicide in depression - possible increase risk when starting therapy in patients ≤ 24 years old
  • Falls - antipsychotics may cause somnolence, postural hypotension, and motor and sensory instability which can lead to falls. Use caution in susceptible patients.
  • Pathological gambling and other compulsive behaviors - cases of intense and uncontrollable urges, particularly for gambling, have been reported in patients taking brexpiprazole. Other types of reported urges include sexual, shopping, and eating or binge eating.
  • Diabetes - atypical antipsychotics have been associated with weight gain and diabetes in some patients. In trials lasting up to 6 weeks, brexpiprazole had no significant effect on blood sugars. Long-term effects are unknown. See diabetes below for ADA monitoring recommendations.
  • Cholesterol - atypical antipsychotics have been associated with increases in cholesterol in some patients. In trials lasting up to 6 weeks, brexpiprazole had no significant effect on lipid parameters. Long-term effects are unknown. See cholesterol below for ADA monitoring recommendations.
  • Leukopenia - antipsychotics have been associated with a decrease in white blood cells in some patients. Monitor CBC closely in susceptible patients.
  • Seizure - antipsychotics may increase seizure risk. Use caution in susceptible patients.
  • Orthostatic hypotension and syncope - atypical antipsychotics may cause orthostatic hypotension and syncope in some patients. Use caution in susceptible patients.
  • Cognitive and motor impairment - antipsychotics may cause sedation. Use caution before driving or performing tasks that require mental alertness.
  • Body temperature dysregulation - disruption in the body's ability to reduce core temperature has been reported with antipsychotics. Use caution in patients who may be at risk of core temperature elevations (e.g. strenuous exercise, extreme heat, taking anticholinergics, dehydration).
  • Liver disease
    • Moderate to severe (Child-Pugh B/C) - max of 2 mg/day in depression and 3 mg/day in schizophrenia
  • Kidney disease
    • CrCl < 60 ml/min - max of 2 mg/day in depression and 3 mg/day in schizophrenia

Cariprazine (Vraylar®)

Dosage forms

Capsule
  • 1.5 mg
  • 3 mg
  • 4.5 mg
  • 6 mg

Dosing

Schizophrenia
  • Starting: 1.5 mg once daily. May increase to 3 mg once daily on Day 2.
  • Maintenance: 1.5 - 6 mg once daily
  • Max: 6 mg once daily
  • May take without regard to food
  • Cariprazine has a long half-life and changes in dose will not be fully reflected in plasma for several weeks
Bipolar I - manic or mixed episode
  • Starting: 1.5 mg once daily. Increase to 3 mg once daily on Day 2.
  • Maintenance: 3 - 6 mg once daily
  • Max: 6 mg once daily
  • May take without regard to food
  • Cariprazine has a long half-life and changes in dose will not be fully reflected in plasma for several weeks
Dosing with CYP3A4 inducers and inhibitors
  • Initiating a strong CYP3A4 inhibitor while on stable cariprazine dose
    • Reduce cariprazine dose by half
    • For 1.5 mg dose, give every other day
  • Initiating cariprazine while taking a strong CYP3A4 inhibitor
    • Give cariprazine 1.5 mg on Day 1 and Day 3 with no dose on Day 2
    • From Day 4 onward, give 1.5 mg once daily
    • Maximum dose is 3 mg once daily
  • Cariprazine with a CYP3A4 inducer
    • Has not been studied
    • Not recommended

Generic / Price

- NO/$$$$

Pharmacokinetics

  • Cariprazine has 2 major active metabolites - DCAR, DDCAR
  • Half-lives:
    • Cariprazine: 2 - 4 days
    • DDCAR: 1 - 3 weeks
    • DCAR: ?

Mechanism of action

  • Cariprazine is a partial agonist at dopamine D2 and serotonin 5-HT1A receptors
  • Cariprazine is an antagonist at serotonin 5-HT2A receptors

FDA-approved indication

  • Treatment of schizophrenia
  • Acute treatment of manic or mixed episodes associated with bipolar I disorder

Side effects



Side effect Cariprazine Placebo
Extrapyramidal symptoms 32% 14%
Insomnia 13% 11%
Somnolence 8% 5%
Constipation 7% 5%
Nausea 7% 5%
Restlessness 6% 3%
Vomiting 5% 3%
Dizziness 5% 2%
Fatigue 3% 1%
Hypertension 3% 1%
Other
  • Weight gain - in a 6-week trial, patients taking 4.5 - 6 mg of cariprazine gained an average of 2.2 pounds while placebo-treated patients gained an average of 0.66 pounds
  • Difficulty swallowing - incidence not well-defined


Drug interactions


Contraindications / Precautions

  • Late-occurring adverse reactions - steady-state for cariprazine and its active metabolites may not be achieved for a number of weeks. Because of this, adverse effects may not appear until weeks after the drug is initiated.
  • Elderly with dementia-related psychosis - antipsychotics may increase the risk of death in elderly patients with dementia-related psychosis. In studies lasting 10-weeks, the incidence of death was 4.5% in antipsychotic-treated patients and 2.6% in placebo-treated patients.
  • Stroke and TIA in elderly patients with dementia-related psychosis - in placebo-controlled trials, elderly patients with dementia-related psychosis who were treated with risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and TIA
  • Neuroleptic malignant syndrome (NMS)
  • Tardive dyskinesia
  • Diabetes - atypical antipsychotics have been associated with weight gain and diabetes in some patients. In trials lasting up to 6 weeks, cariprazine had no significant effect on blood sugars. Long-term effects are unknown. See diabetes below for ADA monitoring recommendations.
  • Cholesterol - atypical antipsychotics have been associated with increases in cholesterol in some patients. In trials lasting up to 6 weeks, cariprazine had no significant effect on lipid parameters. Long-term effects are unknown. See cholesterol below for ADA monitoring recommendations.
  • Leukopenia - antipsychotics have been associated with a decrease in white blood cells in some patients. Monitor CBC closely in susceptible patients.
  • Seizure - antipsychotics may increase seizure risk. Use caution in susceptible patients.
  • Falls - antipsychotics may cause somnolence, postural hypotension, and motor and sensory instability which can lead to falls. Use caution in susceptible patients.
  • Orthostatic hypotension and syncope - atypical antipsychotics may cause orthostatic hypotension and syncope in some patients. Use caution in susceptible patients.
  • Cognitive and motor impairment - antipsychotics may cause sedation. Use caution before driving or performing tasks that require mental alertness.
  • Body temperature dysregulation - disruption in the body's ability to reduce core temperature has been reported with antipsychotics. Use caution in patients who may be at risk of core temperature elevations (e.g. strenuous exercise, extreme heat, taking anticholinergics, dehydration).
  • Liver disease
    • Mild to moderate (Child-Pugh A/B) - no dose adjustment necessary
    • Severe (Child-Pugh C) - DO NOT USE
  • Kidney disease
    • CrCl ≥ 30 ml/min - no dose adjustment necessary
    • CrCl < 30 ml/min - DO NOT USE

Clozapine | Clozaril® | Fazaclo ODT® | Versacloz®

Dosage forms

Tablet (Clozapine®)
  • 12.5 mg
  • 25 mg
  • 50 mg
  • 100 mg
  • 200 mg
Orally disintegrating tablet (Fazaclo ODT®)
  • 12.5 mg
  • 25 mg
  • 100 mg
  • 150 mg
  • 200 mg
Suspension (Versacloz®)
  • 50 mg/ml
  • Comes in 100 ml bottle

Dosing

Schizophrenia
  • Starting: 12.5 mg once or twice daily
  • Maintenance: 300 - 450 mg a day given in divided doses
  • Max: 900 mg a day
  • Increase in increments of 25 - 50 mg daily until target dose reached. Subsequently, the dose can be increased once or twice weekly in increments of up to 100 mg.
  • When stopping, reduce dose gradually over a period of 1-2 weeks to avoid cholinergic rebound
  • If ≥ 2 days elapse since last dose, reinitiate with 12.5-mg once daily or twice daily to prevent hypotension
  • See lab monitoring recommendations
  • Providers and pharmacies must be registered in the Clozapine REMS program in order to prescribe or dispense clozapine

Generic / Price

  • Tablet - YES/$$
  • Fazaclo ODT® - YES/$$$-$$$$
  • Versacloz® - NO/$$$$

Other

All
  • May take without regard to food
  • The Fazaclo ODT® is an orally disintegrating tablet. It may also be chewed or swallowed
Versacloz®
  • Store at room temperature
  • Shake well for 10 seconds before use
  • Bottle good for 100 days after opening

Pharmacokinetics

  • Half-life (single dose): 8 hours
  • Half-life (steady state): 12 hours

Mechanism of action

  • Dopamine-2 receptor antagonist
  • Serotonin 5-HT2A receptor antagonist

FDA-approved indications

  • Treatment-resistant schizophrenia
  • Reduction in risk of recurrent suicidal behavior in schizophrenia and schizoaffective disorder

Side effects


Side effect Clozapine Olanzapine
Salivary hypersecretion 48% 6%
Somnolence 46% 25%
Weight gain (≥ 7% increase) 35% 46%
Lightheaded 27% 12%
Constipation 25% 10%
Insomnia 20% 33%
Nausea 17% 10%
Vomiting 17% 9%
Upset stomach 14% 8%
  • Orthostatic hypotension - incidence not well-defined
  • Difficulty swallowing - incidence not well-defined
  • Priapism (erection lasting longer than 4 hours) - rare


Drug interactions

  • Drugs that prolong the QT interval - DO NOT COMBINE
  • Anticholinergic medications - clozapine has anticholinergic effects and it may potentiate the effects of other anticholinergic medications. Use caution when combining.
  • Clozapine is a CYP1A2, CYP3A4, and CYP2D6 substrate
  • CYP1A2 strong inhibitors - use one-third of clozapine dose
  • CYP1A2 moderate or weak inhibitors - monitor for adverse reactions; consider reducing clozapine dose if necessary
  • CYP2D6 inhibitors - monitor for adverse reactions; consider reducing clozapine dose if necessary
  • CYP3A4 inhibitors - monitor for adverse reactions; consider reducing clozapine dose if necessary
  • CYP3A4 inducers - may be necessary to increase clozapine dose; combining clozapine with strong CYP3A4 inducers is not recommended
  • CYP1A2 inducers - may be necessary to increase clozapine dose
  • Dopamine agonists (Mirapex®, Sinemet®, etc.) - clozapine may block the activity of dopamine agonists used in Parkinson's, RLS, etc.
  • Alpha blockers - clozapine can block alpha receptors. It may potentiate the effects of alpha blockers.

Contraindications / Precautions

  • Clozapine Agranulocytosis
  • Prolonged QT syndrome - DO NOT USE. Clozapine may prolong the QT interval.
  • Eosinophilia - in trials, 1% of patients treated with clozapine developed eosinophilia. DRESS syndrome has also occurred in some patients.
  • Poor CYP2D6 metabolizers - may need to reduce dose
  • Orthostatic hypotension, bradycardia, and syncope - clozapine has been associated with hypotension, bradycardia, and syncope in some patients. The risk is highest when starting therapy. Titrate dose slowly to avoid hypotension.
  • Anticholinergic effects - clozapine has potent anticholinergic activity. Use caution in patients with urinary retention, prostatic hypertrophy, constipation, and/or a history of paralytic ileus or related conditions. Cases of GI hypomobility resulting in intestinal obstruction, fecal impaction, megacolon and intestinal ischemia or infarction have occurred with clozapine. Monitor patients on clozapine for constipation and consider preventative laxative therapy when appropriate. Avoid use with other anticholinergic medications when possible.
  • Constipation - clozapine may worsen constipation and lead to severe complications. See Anticholinergic effects above.
  • Elderly with dementia-related psychosis - antipsychotics may increase the risk of death in elderly patients with dementia-related psychosis. In studies lasting 10-weeks, the incidence of death was 4.5% in antipsychotic-treated patients and 2.6% in placebo-treated patients.
  • Stroke and TIA in elderly patients with dementia-related psychosis - in placebo-controlled trials, elderly patients with dementia-related psychosis who were treated with risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and TIA
  • Myocarditis, cardiomyopathy, and mitral valve incompetence - myocarditis and cardiomyopathy have been reported in patients receiving clozapine. Myocarditis typically presents within the first 2 months of treatment, but may occur at any time. Nonspecific flu-like symptoms often precede overt heart failure. Clozapine-induced cardiomyopathy may lead to mitral valve incompetence.
  • Neuroleptic malignant syndrome (NMS)
  • Tardive dyskinesia
  • Diabetes - atypical antipsychotics have been associated with weight gain and diabetes in some patients. In trials, clozapine has been shown to raise blood sugars. See diabetes below for ADA monitoring recommendations.
  • Cholesterol - atypical antipsychotics have been associated with increases in cholesterol in some patients. In trials, clozapine had an adverse effect on lipid parameters. See cholesterol below for ADA monitoring recommendations.
  • Seizure - antipsychotics may increase seizure risk. Use caution in susceptible patients.
  • Falls - antipsychotics may cause somnolence, postural hypotension, and motor and sensory instability which can lead to falls. Use caution in susceptible patients.
  • Cognitive and motor impairment - antipsychotics may cause sedation. Use caution before driving or performing tasks that require mental alertness.
  • Glaucoma - may cause pupil dilation
  • Body temperature dysregulation - disruption in the body's ability to reduce core temperature has been reported with antipsychotics. Use caution in patients who may be at risk of core temperature elevations (e.g. strenuous exercise, extreme heat, taking anticholinergics, dehydration).
  • Hepatotoxicity - cases of hepatotoxicity and liver failure have been reported in patients taking clozapine. Monitor for signs of liver failure (e.g. fatigue, malaise, anorexia, nausea, jaundice) and check liver function tests periodically.
  • Liver disease - dose adjustment may be necessary. Manufacturer makes no specific recommendation.
  • Kidney disease -dose adjustment may be necessary. Manufacturer makes no specific recommendation.

Iloperidone (Fanapt®)

Dosage forms

Tablet
  • 1 mg
  • 2 mg
  • 4 mg
  • 6 mg
  • 8 mg
  • 10 mg
  • 12 mg
Titration pack
  • 2 X 1 mg
  • 2 X 2 mg
  • 2 X 4 mg
  • 2 X 6 mg

Dosing

Schizophrenia
  • Starting: 1 mg twice a day
  • Maintenance: 6 - 12 mg twice a day
  • Max: 12 mg twice a day
  • Increase dose daily as tolerated. Do not increase by more than 4 mg a day.
  • Orthostatic hypotension may occur if dose is increased too fast
  • See Drug Interactions for dosing with specific medications

Generic / Price

- NO/$$$$

Other

  • May take without regard to food
  • If ≥ 3 days elapse since last dose, reinitiate at 1 mg twice a day and titrate

Pharmacokinetics

  • Iloperidone has 2 active metabolites - P88 and P95
  • Half-lives for iloperidone, P88, and P95 in CYP2D6 extensive metabolizers are 18, 26, and 23 hours, respectively, and in poor metabolizers are 33, 37, and 31 hours, respectively

Mechanism of action

  • Dopamine D2 receptor antagonist
  • Serotonin type 2 (5-HT2) receptor antagonist

FDA-approved indications

- Schizophrenia

Side effects



Side effect Fanapt Placebo
Hyperprolactinemia (elevated prolactin level) 26% 12%
Dizziness 20% 7%
Weight gain 18% 4%
Somnolence 15% 5%
Extrapyramidal symptoms 15% 11%
Rapid heart rate 12% 1%
Nausea 10% 8%
Dry mouth 10% 1%
Other
  • Orthostatic hypotension - up to 5% of patients
  • Difficulty swallowing - incidence not well-defined
  • Priapism (erection lasting longer than 4 hours) - rare


Drug interactions

  • Iloperidone is a CYP2D6 and CYP3A4 sensitive substrate
  • Drugs that prolong the QT interval - DO NOT COMBINE
  • CYP2D6 strong inhibitors - reduce iloperidone dose by one-half
  • CYP3A4 strong inhibitors - reduce iloperidone dose by one-half
  • CYP3A4 substrates - in vitro studies have shown that iloperidone is a CYP3A4 inhibitor. Iloperidone may affect CYP3A4 substrates.
  • Alpha blockers - iloperidone can block alpha receptors. It may potentiate the effects of alpha blockers.
  • Dopamine agonists (Mirapex®, Sinemet®, etc.) - iloperidone may block the activity of dopamine agonists used in Parkinson's, RLS, etc.

Contraindications / Precautions

  • Prolonged QT syndrome - DO NOT USE. Iloperidone may prolong the QT interval.
  • Poor CYP2D6 metabolizers - reduce dose by one-half
  • Elderly with dementia-related psychosis - antipsychotics may increase the risk of death in elderly patients with dementia-related psychosis. In studies lasting 10-weeks, the incidence of death was 4.5% in antipsychotic-treated patients and 2.6% in placebo-treated patients.
  • Stroke and TIA in elderly patients with dementia-related psychosis - in placebo-controlled trials, elderly patients with dementia-related psychosis who were treated with risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and TIA
  • Neuroleptic malignant syndrome (NMS)
  • Tardive dyskinesia
  • Diabetes - atypical antipsychotics have been associated with weight gain and diabetes in some patients. In trials lasting 4 weeks, iloperidone was shown to raise blood sugars in some patients. Long-term effects are unknown. See diabetes below for ADA monitoring recommendations.
  • Cholesterol - atypical antipsychotics have been associated with increases in cholesterol in some patients. In trials lasting 4 weeks, iloperidone was shown to raise lipid parameters in some patients. Long-term effects are unknown. See cholesterol below for ADA monitoring recommendations.
  • Body temperature dysregulation - disruption in the body's ability to reduce core temperature has been reported with antipsychotics. Use caution in patients who may be at risk of core temperature elevations (e.g. strenuous exercise, extreme heat, taking anticholinergics, dehydration).
  • Falls - antipsychotics may cause somnolence, postural hypotension, and motor and sensory instability which can lead to falls. Use caution in susceptible patients.
  • Leukopenia - antipsychotics have been associated with a decrease in white blood cells in some patients. Monitor CBC closely in susceptible patients.
  • Seizure - antipsychotics may increase seizure risk. Use caution in susceptible patients.
  • Orthostatic hypotension and syncope - atypical antipsychotics may cause orthostatic hypotension and syncope in some patients. Use caution in susceptible patients.
  • Cognitive and motor impairment - antipsychotics may cause sedation. Use caution before driving or performing tasks that require mental alertness.
  • Liver disease - has not been studied. Not recommended.
  • Kidney disease - No dose adjustment necessary

Lumateperone (Caplyta®)

Dosage forms

Capsule
  • 42 mg

Dosing

Schizophrenia (adults)
  • Dosing: 42 mg once daily with food
  • Max: 42 mg once daily with food
  • Dose titration is not required

Generic / Price

- NO/$$$$

Pharmacokinetics

  • Half-life: 18 hours

Mechanism of action

  • The mechanism of action of lumateperone in the treatment of schizophrenia is unknown. However, the efficacy of lumateperone could be mediated through a combination of antagonist activity at central serotonin 5-HT2A receptors and postsynaptic antagonist activity at central dopamine D2 receptors.

FDA-approved indications

- Schizophrenia in adults

Side effects



Side effect Caplyta
(N=406)
Placebo
(N=412)
Somnolence / Sedation 24% 10%
Nausea 9% 5%
Extrapyramidal symptoms 6.7% 6.3%
Dry mouth 6% 2%
Dizziness 5% 3%
CK increase 4% 1%
Fatigue 3% 1%
Vomiting 3% 2%
Liver function abnormal 2% 1%
Decreased appetite 2% 1%


Drug interactions

  • CYP3A4 moderate or strong inhibitors - DO NOT COMBINE. Lumateperone is a sensitive CYP3A4 substrate and CYP3A4 inhibitors increase exposure.
  • CYP3A4 inducers - DO NOT COMBINE. Lumateperone is a sensitive CYP3A4 substrate and CYP3A4 inducers decrease exposure.
  • UGT inhibitors - DO NOT COMBINE. UGT inhibitors increase exposure to lumateperone. Examples of UGT inhibitors include valproic acid and probenecid.

Contraindications / Precautions

  • Elderly with dementia-related psychosis - antipsychotics may increase the risk of death in elderly patients with dementia-related psychosis. In studies lasting 10-weeks, the incidence of death was 4.5% in antipsychotic-treated patients and 2.6% in placebo-treated patients.
  • Stroke and TIA in elderly patients with dementia-related psychosis - in placebo-controlled trials, elderly patients with dementia-related psychosis who were treated with risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and TIA
  • Neuroleptic malignant syndrome (NMS)
  • Tardive dyskinesia
  • Diabetes - atypical antipsychotics have been associated with diabetes in some patients. In trials lasting 4 - 6 weeks, average change in fasting glucose was similar between lumateperone-treated patients and placebo-treated patients. See diabetes below for ADA monitoring recommendations.
  • Weight gain - atypical antipsychotics have been associated with weight gain in some patients. In trials, average change in weight was similar between lumateperone-treated patients and placebo-treated patients.
  • Cholesterol - atypical antipsychotics have been associated with increases in cholesterol in some patients. In trials lasting 4 - 6 weeks, average changes in cholesterol were similar between lumateperone-treated patients and placebo-treated patients. See cholesterol below for ADA monitoring recommendations.
  • Leukopenia - antipsychotics have been associated with a decrease in white blood cells in some patients. Monitor white blood counts closely in susceptible patients.
  • Orthostatic hypotension and syncope - atypical antipsychotics can cause orthostatic hypotension and syncope in some patients. In trials, orthostatic hypotension occurred in 0.7% of lumateperone-treated patients and 0% of placebo-treated patients. The incidence of syncope was 0.2% in both groups.
  • Falls - antipsychotics may cause somnolence, postural hypotension, and motor and sensory instability which can lead to falls. Use caution in susceptible patients.
  • Body temperature dysregulation - disruption in the body's ability to reduce core temperature has been reported with antipsychotics. Use caution in patients who may be at risk of core temperature elevations (e.g. strenuous exercise, extreme heat, taking anticholinergics, dehydration).
  • Seizures - antipsychotics may increase seizure risk. Use caution in susceptible patients.
  • Cognitive and motor impairment - antipsychotics may cause sedation. Use caution before driving or performing tasks that require mental alertness.
  • Dysphagia - antipsychotics have been associated with esophageal dysmotility and aspiration. Use caution in susceptible patients.
  • Liver disease
    • Child-Pugh A: No dose adjustment necessary
    • Child-Pugh B/C: DO NOT USE
  • Kidney disease - no dose adjustment recommended by manufacturer

Lurasidone (Latuda®)

Dosage forms

Tablet
  • 20 mg
  • 40 mg
  • 60 mg
  • 80 mg
  • 120 mg

Dosing

Schizophrenia (adults)
  • Starting: 40 mg once daily
  • Maintenance: 40 - 160 mg once daily
  • Max: 160 mg once daily
  • Take with food (at least 350 calories). Food increases absorption.
  • See Drug Interactions for dosing with specific medications
Schizophrenia (13 - 17 years old)
  • Starting: 40 mg once daily
  • Maintenance: 40 - 80 mg once daily
  • Max: 80 mg once daily
  • Take with food (at least 350 calories). Food increases absorption.
  • See Drug Interactions for dosing with specific medications
Bipolar I depression (adults)
  • Starting: 20 mg once daily
  • Maintenance: 20 - 120 mg once daily
  • Max: 120 mg once daily
  • Take with food (at least 350 calories). Food increases absorption.
  • See Drug Interactions for dosing with specific medications

Generic / Price

- NO/$$$$

Pharmacokinetics

  • Half-life: 18 hours

Mechanism of action

  • Dopamine-2 receptor antagonist
  • Serotonin type 2 (5-HT2A) receptor antagonist

FDA-approved indications

  • Schizophrenia
  • Major depressive episodes associated with bipolar 1 as monotherapy or as adjunctive therapy with lithium or valproate

Side effects



Side effect Lurasidone Placebo
Extrapyramidal symptoms (80 mg dose) 26% 9%
Somnolence 22% 10%
Akathisia 15% 3%
Nausea 12% 6%
Parkinsonism 11% 5%
Weight gain (≥ 7% increase) 5.6% 4%
Other
  • Orthostatic hypotension - 1.7% with 120 mg a day
  • Hyperprolactinemia (elevated prolactin level ≥ 5 X ULN) - 3.6% of patients
  • Difficulty swallowing - incidence not well-defined
  • Priapism (erection lasting longer than 4 hours) - rare


Drug interactions

  • Lurasidone is a CYP3A4 sensitive substrate
  • CYP3A4 strong inhibitor - DO NOT COMBINE
  • CYP3A4 strong inducer - DO NOT COMBINE
  • CYP3A4 moderate inhibitor - dose of lurasidone should not exceed 40 mg a day
  • Dopamine agonists (Mirapex®, Sinemet®, etc.) - lurasidone may block the activity of dopamine agonists used in Parkinson's, RLS, etc.
  • Alpha blockers - lurasidone can block alpha receptors. It may potentiate the effects of alpha blockers.

Contraindications / Precautions

  • Poor CYP2D6 metabolizers - reduce dose by one-half
  • Elderly with dementia-related psychosis - antipsychotics may increase the risk of death in elderly patients with dementia-related psychosis. In studies lasting 10-weeks, the incidence of death was 4.5% in antipsychotic-treated patients and 2.6% in placebo-treated patients.
  • Stroke and TIA in elderly patients with dementia-related psychosis - in placebo-controlled trials, elderly patients with dementia-related psychosis who were treated with risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and TIA
  • Neuroleptic malignant syndrome (NMS)
  • Tardive dyskinesia
  • Suicide in depression - possible increase risk when starting therapy in patients ≤ 24 years old
  • Falls - antipsychotics may cause somnolence, postural hypotension, and motor and sensory instability which can lead to falls. Use caution in susceptible patients.
  • Diabetes - atypical antipsychotics have been associated with weight gain and diabetes in some patients. In trials, lurasidone had a mixed effect on blood sugars. Long-term effects are unknown. See diabetes below for ADA monitoring recommendations.
  • Cholesterol - atypical antipsychotics have been associated with increases in cholesterol in some patients. In trials, lurasidone had no significant effect on lipid parameters. Long-term effects are unknown. See cholesterol below for ADA monitoring recommendations.
  • Body temperature dysregulation - disruption in the body's ability to reduce core temperature has been reported with antipsychotics. Use caution in patients who may be at risk of core temperature elevations (e.g. strenuous exercise, extreme heat, taking anticholinergics, dehydration).
  • Leukopenia - antipsychotics have been associated with a decrease in white blood cells in some patients. Monitor CBC closely in susceptible patients.
  • Seizure - antipsychotics may increase seizure risk. Use caution in susceptible patients.
  • Orthostatic hypotension and syncope - atypical antipsychotics may cause orthostatic hypotension and syncope in some patients. Use caution in susceptible patients.
  • Cognitive and motor impairment - antipsychotics may cause sedation. Use caution before driving or performing tasks that require mental alertness.
  • Liver disease
    • Moderate to severe (Child-Pugh B/C) - do not exceed 40 mg a day
  • Kidney disease
    • CrCl 10 - 49 ml/min - do not exceed 40 mg/day

Olanzapine | Zyprexa® | Symbyax®

Dosage forms

Tablet (Zyprexa®)
  • 2.5 mg
  • 5 mg
  • 7.5 mg
  • 10 mg
  • 15 mg
  • 20 mg
Orally disintegrating tablet (Zyprexa Zydis®)
  • 5 mg
  • 10 mg
  • 15 mg
  • 20 mg
Vial (Zyprexa Relprevv®)
  • 210 mg
  • 300 mg
  • 405 mg
Symbyax®
  • Olanzapine(mg):Fluoxetine(mg)
    • 3 : 25
    • 6 : 25
    • 6 : 50
    • 12 : 25
    • 12 : 50

Dosing - Tablet and ODT

Schizophrenia (adults)
  • Starting: 5 - 10 mg once daily
  • Maintenance: 10 - 20 mg once daily
  • Max: 20 mg once daily
  • Increase dose by 5 mg/day at intervals of ≥ 1 week
  • Starting dose of 5 mg once daily is recommended in debilitated patients, patients at risk for hypotension, and slow metabolizers (e.g. nonsmoking female ≥ 65 years)
Schizophrenia (adolescents)
  • Starting: 2.5 - 5 mg once daily
  • Maintenance: 10 mg once daily
  • Max: 20 mg once daily
  • Increase dose in increments of 2.5 - 5 mg/day
Bipolar I monotherapy (adults)
  • Starting: 10 - 15 mg once daily
  • Maintenance: 5 - 20 mg once daily
  • Max: 20 mg once daily
  • Increase dose by 5 mg/day at intervals of not less than 24 hours
  • Starting dose of 5 mg once daily is recommended in debilitated patients, patients at risk for hypotension, and slow metabolizers (e.g. nonsmoking female ≥ 65 years)
Bipolar I adjunctive to lithium or valproate (adults)
  • Starting: 10 mg once daily
  • Maintenance: 5 - 20 mg once daily
  • Max: 20 mg once daily
  • Starting dose of 5 mg once daily is recommended in debilitated patients, patients at risk for hypotension, and slow metabolizers (e.g. nonsmoking female ≥ 65 years)
  • May take without regard to food
Bipolar I (adolescents)
  • Starting: 2.5 - 5 mg once daily
  • Maintenance: 10 mg once daily
  • Max: 20 mg once daily
  • Increase dose in increments of 2.5 - 5 mg/day

Dosing - Zyprexa Relprevv®

Schizophrenia (adults)
  • Dosing: 150 - 300 mg IM every 2 weeks; or 300 - 405 mg every 4 weeks
  • Dosing based on current oral olanzapine dose
  • See Relprevv® PI for dosing recommendations

Dosing - Symbyax®

Depression with Bipolar I and treatment-resistant depression (adults)
  • Starting: 6/25 mg once daily in the evening
  • Maintenance: 6/25 mg - 12/50 mg once daily
  • Max: 18/75 mg once daily
  • See fluoxetine for more
Depression with Bipolar I (10 - 17 years old)
  • Starting: 3/25 mg once daily in the evening
  • Maintenance: 6/25 mg - 12/50 mg once daily
  • Max: 12/50 mg once daily
  • See fluoxetine for more

Efficacy


Generic / Price

  • Zyprexa® - YES/$
  • Zyprexa Zydis® - YES/$
  • Symbyax® - YES/$$-$$$
  • Zyprexa Relprevv® - NO/$$$$

Other

Zyprexa®
  • May take without regard to food
Zydis®
  • Do not push tablet through foil
  • Rapidly disintegrates in mouth
  • Swallow with or without liquid
Relprevv®
  • Only available through restricted distribution program
  • To enroll, call 1-877-772-9390

Pharmacokinetics (oral)

  • Half-life: 21 - 54 hours

Mechanism of action

  • Olanzapine binds with high affinity to the following receptors: serotonin 5HT2A/2C, 5HT6, dopamine D1-4, histamine H1, and adrenergic α1 receptors. Olanzapine is an antagonist with moderate affinity binding for serotonin 5HT3 and muscarinic M1-5. Olanzapine binds with low affinity to GABAA, BZD, and β-adrenergic receptors.

FDA-approved indications

Zyprexa®
  • Schizophrenia
  • Bipolar - manic or mixed episodes
Zyprexa Relprevv®
  • Schizophrenia
Symbyax®
  • Treatment resistant depression
  • Bipolar I depression

Side effects



Side effect Zyprexa Placebo
Somnolence 29% 13%
Extrapyramidal symptoms 25% 16%
Weight gain (≥ 7% increase) 22% 3%
Insomnia 12% 11%
Dizziness 11% 4%
Fatigue 10% 9%
Constipation 9% 4%
Dry mouth 6% 1%
Orthostatic hypotension 5% 2%
Hyperprolactinemia 30% 11%
Other
  • Difficulty swallowing - incidence not well-defined
  • Priapism (erection lasting longer than 4 hours) - rare


Drug interactions

  • CYP1A2 strong inhibitors - olanzapine is a CYP1A2 sensitive substrate. CYP1A2 strong inhibitors may increase olanzapine exposure. Consider decreasing olanzapine dosage when combining.
  • CYP1A2 strong inducers - olanzapine is a CYP1A2 sensitive substrate. CYP1A2 strong inducers may decrease olanzapine exposure. Consider increasing olanzapine dosage when combining.
  • Dopamine agonists (Mirapex®, Sinemet®, etc.) - olanzapine may block the activity of dopamine agonists used in Parkinson's, RLS, etc.. Concomitant use is not recommended.
  • Alpha blockers - olanzapine blocks alpha1 receptors, and therefore, it may potentiate the blood pressure-lowering effects of alpha blockers, particularly doxazosin, prazosin, and terazosin. Use caution when combining.
  • Antihypertensive medications - olanzapine may enhance the effects of antihypertensives. Monitor blood pressure when combining and reduce antihypertensive dosage when necessary.
  • Medications with anticholinergic activity - olanzapine has anticholinergic activity, and it may potentiate the anticholinergic effects of other anticholinergic medications. Use caution when combining.
  • CNS depressants - CNS depressants, including diazepam and alcohol, may potentiate the orthostatic hypotensive effects of olanzapine. Use caution when combining.
  • OCT2 substrates - olanzapine is an OCT2 inhibitor, and it may increase exposure to OCT2 substrates
  • Omeprazole (Prilosec®) - omeprazole may increase olanzapine clearance
  • Rifampin - rifampin may increase olanzapine clearance

Contraindications / Precautions

  • Elderly with dementia-related psychosis - antipsychotics may increase the risk of death in elderly patients with dementia-related psychosis. In trials, incidence of death in elderly patients with dementia-related psychosis was 3.5% in olanzapine-treated patients and 1.5% in placebo-treated patients.
  • Stroke and TIA in elderly patients with dementia-related psychosis - in placebo-controlled trials, elderly patients with dementia-related psychosis who were treated with risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and TIA
  • Suicide - patients with schizophrenia and bipolar disorder are at increased risk for suicide. Consider the risk of intentional overdose when prescribing and limit quantity when necessary.
  • Neuroleptic malignant syndrome (NMS)
  • Tardive dyskinesia
  • Serious skin reactions - serious skin reactions, including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have been reported. Signs of DRESS include fever, rash, swollen lymph glands, facial swelling, and systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. Patients who experience these symptoms should stop olanzapine and seek immediate medical care.
  • Increase in blood sugar - atypical antipsychotics have been associated with increased blood sugars in some patients. In trials lasting at least 48 weeks, olanzapine-treated patients had an average increase in fasting blood sugar of 4.2 mg/dl. Long-term effects are unknown. See diabetes below for ADA monitoring recommendations.
  • Weight gain - olanzapine can cause weight gain in some patients. In trials lasting a median of 6 weeks, olanzapine-treated patients gained an average of 5.7 lbs (2.6 kg) compared to a loss of 0.6 lbs (0.3 kg) in placebo-treated patients.
  • Dyslipidemia - atypical antipsychotics have been associated with increased cholesterol in some patients. In trials lasting at least 48 weeks, fasting triglyceride increases ≥ 50 mg/dl and LDL increases ≥ 30 mg/dl occurred in 61% and 40% of olanzapine-treated patients, respectively. See cholesterol below for ADA monitoring recommendations.
  • Orthostatic hypotension and syncope - atypical antipsychotics may cause orthostatic hypotension and syncope in some patients. An analysis of the vital sign data from 41 studies (N=6030) in which adult patients were treated with oral olanzapine found that orthostatic hypotension was recorded in ≥ 20% of patients. Use caution in susceptible patients.
  • Falls - antipsychotics may cause somnolence, postural hypotension, and motor and sensory instability which can lead to falls. Use caution in susceptible patients.
  • Leukopenia - antipsychotics have been associated with a decrease in white blood cells in some patients. Monitor CBC closely in susceptible patients (e.g. pre-existing low WBC, history of drug-induced leukopenia).
  • Dysphagia - antipsychotics have been associated with esophageal dysmotility and aspiration. Use caution in susceptible patients.
  • Seizure - antipsychotics may increase seizure risk. Use caution in susceptible patients.
  • Cognitive and motor impairment - antipsychotics may cause sedation. Use caution before driving or performing tasks that require mental alertness.
  • Body temperature dysregulation - disruption in the body's ability to reduce core temperature has been reported with antipsychotics. Use caution in patients who may be at risk of core temperature elevations (e.g. strenuous exercise, extreme heat, taking anticholinergics, dehydration).
  • Anticholinergic effects - olanzapine has anticholinergic activity. Use caution in patients with urinary retention, prostatic hypertrophy, constipation, or a history of paralytic ileus or related conditions. In post-marketing surveillance, the risk for severe adverse reactions (including fatalities) was increased when olanzapine was taken with other anticholinergic medications.
  • Hyperprolactinemia - olanzapine blocks the dopamine D2 receptor which may cause prolactin levels to rise. Elevated prolactin levels can impair gonadal steroidogenesis in females and males leading to infertility. Galactorrhea, amenorrhea, gynecomastia, and impotence have also been reported. Long-standing hyperprolactinemia may lead to decreased bone density in female and male subjects. One-third of human breast cancers are prolactin-dependent in vitro. Theoretically, this could increase the risk of breast cancer in some patients; although, studies performed to date have not found an association between chronic administration of antipsychotics and cancer risk. In trials lasting up to 12 weeks, prolactin shifts from normal to high occurred in 30% of olanzapine-treated patients and 10.5% of placebo-treated patients.
  • Infertility - olanzapine may increase prolactin levels which may cause a reversible reduction in fertility among female patients of childbearing age
  • Liver disease
    • Mild to moderate (Child-Pugh A/B) - no dose adjustment necessary
    • Severe (Child-Pugh C) - use caution
  • Kidney disease - no dose adjustment necessary

Olanzapine + Samidorphan (Lybalvi®)

Dosage forms

Tablet
  • Olanzapine(mg):Samidorphan(mg)
  • 5 : 10
  • 10 : 10
  • 15 : 10
  • 20 : 10

Dosing

Schizophrenia (adults)
  • Starting: 5/10 - 10/10 mg once daily
  • Maintenance: 10/10 - 20/10 mg once daily
  • Max: 20/10 mg once daily
  • Increase olanzapine dose by 5 mg/day at intervals of ≥ 1 week
  • Starting dose of 5/10 mg once daily is recommended in debilitated patients, patients at risk for hypotension, and slow metabolizers (e.g. nonsmoking female ≥ 65 years)
  • May take without regard to food
Bipolar I monotherapy (adults)
  • Starting: 10/10 - 15/10 mg once daily
  • Maintenance: 5/10 - 20/10 mg once daily
  • Max: 20/10 mg once daily
  • Increase olanzapine dose by 5 mg/day at intervals of not less than 24 hours
  • Starting dose of 5/10 mg once daily is recommended in debilitated patients, patients at risk for hypotension, and slow metabolizers (e.g. nonsmoking female ≥ 65 years)
  • May take without regard to food
Bipolar I adjunctive to lithium or valproate (adults)
  • Starting: 10/10 once daily
  • Maintenance: 10/10 - 20/10 mg once daily
  • Max: 20/10 mg once daily
  • Increase olanzapine dose by 5 mg/day at intervals of ≥ 1 week
  • Starting dose of 5/10 mg once daily is recommended in debilitated patients, patients at risk for hypotension, and slow metabolizers (e.g. nonsmoking female ≥ 65 years)
  • May take without regard to food

Efficacy


Generic / Price

- NO/$$$$

Pharmacokinetics

  • Half-life (olanzapine): 35 - 52 hours
  • Half-life (samidorphan): 7 - 11 hours

Mechanism of action

  • Olanzapine binds with high affinity to the following receptors: serotonin 5HT2A/2C, 5HT6, dopamine D1-4, histamine H1, and adrenergic α1 receptors. Olanzapine is an antagonist with moderate affinity binding for serotonin 5HT3 and muscarinic M1-5. Olanzapine binds with low affinity to GABAA, BZD, and β-adrenergic receptors.
  • Samidorphan binds to the mu-, kappa-, and delta-opioid receptors. Samidorphan is an antagonist at the mu-opioid receptors with partial agonist activity at kappa- and delta-opioid receptors. Samidorphan is included to help reduce the weight gain that occurs with olanzapine therapy. Opiate antagonists suppress appetite through an unknown mechanism.

FDA-approved indications

  • Schizophrenia in adults
  • Bipolar I disorder in adults
    • Acute treatment of manic or mixed episodes as monotherapy and as adjunct to lithium or valproate
    • Maintenance monotherapy treatment

Side effects



Side effect Lybalvi
(N=134)
Placebo
(N=134)
Weight gain 19% 3%
Somnolence 9% 2%
Dry mouth 7% 1%
Headache 6% 3%
Blood insulin increase 3% 1%
Sedation 2% 0%
Dizziness 2% 1%
Neutrophil count decrease 2% 0%
  • Lybalvi contains samidorphan which is included to help suppress the weight gain that occurs with olanzapine. In a 24-week trial, Lybalvi-treated patients had an average weight gain of 4.2% compared to 6.6% in olanzapine-treated patients.


Drug interactions

  • Opiate medications - samidorphan is an opiate antagonist, and it should not be given to patients on opiate therapy or those undergoing acute opioid withdrawal. Prior to initiating Lybalvi, there should be at least a 7-day opioid-free interval from the last use of short-acting opioids, and at least a 14-day opioid-free interval from the last use of long-acting opioids. In emergency situations that require opioid therapy, Lybalvi should be discontinued, and the patient should be monitored closely. In non-emergency situations, discontinue Lybalvi at least 5 days before opioids are required and use olanzapine.
  • CYP1A2 strong inhibitors - olanzapine is a CYP1A2 sensitive substrate. CYP1A2 strong inhibitors may increase olanzapine exposure. Consider decreasing olanzapine dosage when combining.
  • CYP1A2 strong inducers - olanzapine is a CYP1A2 sensitive substrate. CYP1A2 strong inducers may decrease olanzapine exposure. Consider increasing olanzapine dosage when combining.
  • CYP3A4 strong inducers - DO NOT COMBINE. Samidorphan is a CYP3A4 sensitive substrate, and strong CYP3A4 inducers may decrease its exposure.
  • Dopamine agonists (Mirapex®, Sinemet®, etc.) - olanzapine may block the activity of dopamine agonists used in Parkinson's, RLS, etc.. Concomitant use is not recommended.
  • Alpha blockers - olanzapine blocks alpha1 receptors, and therefore, it may potentiate the blood pressure-lowering effects of alpha blockers, particularly doxazosin, prazosin, and terazosin. Use caution when combining.
  • Antihypertensive medications - olanzapine may enhance the effects of antihypertensives. Monitor blood pressure when combining and reduce antihypertensive dosage when necessary.
  • Medications with anticholinergic activity - olanzapine has anticholinergic activity, and it may potentiate the anticholinergic effects of other anticholinergic medications. Use caution when combining.
  • CNS depressants - CNS depressants, including diazepam and alcohol, may potentiate the orthostatic hypotensive effects of olanzapine. Use caution when combining.
  • OCT2 substrates - olanzapine is an OCT2 inhibitor, and it may increase exposure to OCT2 substrates
  • Omeprazole (Prilosec®) - omeprazole may increase olanzapine clearance
  • Rifampin - rifampin may increase olanzapine clearance

Contraindications / Precautions

  • Patients receiving opiate medications - samidorphan is an opiate antagonist, and it should not be given to patients on opiate therapy or those undergoing acute opioid withdrawal. Prior to initiating Lybalvi, there should be at least a 7-day opioid-free interval from the last use of short-acting opioids, and at least a 14-day opioid-free interval from the last use of long-acting opioids. In emergency situations that require opioid therapy, Lybalvi should be discontinued, and the patient should be monitored closely. In non-emergency situations, discontinue Lybalvi at least 5 days before opioids are required and use olanzapine.
  • Elderly with dementia-related psychosis - antipsychotics may increase the risk of death in elderly patients with dementia-related psychosis. In trials, the incidence of death in elderly patients with dementia-related psychosis was 3.5% in olanzapine-treated patients and 1.5% in placebo-treated patients.
  • Stroke and TIA in elderly patients with dementia-related psychosis - in placebo-controlled trials, elderly patients with dementia-related psychosis who were treated with risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and TIA
  • Neuroleptic malignant syndrome (NMS)
  • Tardive dyskinesia
  • Serious skin reactions - serious skin reactions, including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have been reported. Signs of DRESS include fever, rash, swollen lymph glands, facial swelling, and systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. Patients who experience these symptoms should stop olanzapine and seek immediate medical care.
  • Increase in blood sugar - atypical antipsychotics have been associated with increased blood sugars in some patients. In a 24-week trial that compared Lybalvi to olanzapine, 42% of Lybalvi-treated patients had an increase in HgA1C from <5.7% to 5.7 - 6.5% compared to 35% of olanzapine-treated patients. See diabetes below for ADA monitoring recommendations.
  • Weight gain - Lybalvi contains samidorphan which is included to help suppress the weight gain that occurs with olanzapine. In a 24-week trial, Lybalvi-treated patients had an average weight gain of 4.2% compared to 6.6% in olanzapine-treated patients.
  • Dyslipidemia - atypical antipsychotics have been associated with increased cholesterol in some patients. In a 4-week trial, fasting triglycerides shifted from normal to high in 14% of Lybalvi-treated patients and 4% of placebo-treated patients. See cholesterol below for ADA monitoring recommendations.
  • Orthostatic hypotension and syncope - atypical antipsychotics may cause orthostatic hypotension and syncope in some patients. In a 24-week study, rates of orthostatic hypotension were 3.7% in Lybalvi-treated patients and 0.4% in olanzapine-treated patients. Use caution in susceptible patients.
  • Falls - antipsychotics may cause somnolence, postural hypotension, and motor and sensory instability which can lead to falls. Use caution in susceptible patients.
  • Leukopenia - antipsychotics have been associated with a decrease in white blood cells in some patients. Monitor CBC closely in susceptible patients (e.g. pre-existing low WBC, history of drug-induced leukopenia).
  • Dysphagia - antipsychotics have been associated with esophageal dysmotility and aspiration. Use caution in susceptible patients.
  • Seizures - antipsychotics may increase seizure risk. Use caution in susceptible patients.
  • Cognitive and motor impairment - antipsychotics may cause sedation. Use caution before driving or performing tasks that require mental alertness.
  • Body temperature dysregulation - disruption in the body's ability to reduce core temperature has been reported with antipsychotics. Use caution in patients who may be at risk of core temperature elevations (e.g. strenuous exercise, extreme heat, taking anticholinergics, dehydration).
  • Anticholinergic effects - olanzapine has anticholinergic activity. Use caution in patients with urinary retention, prostatic hypertrophy, constipation, or a history of paralytic ileus or related conditions. In post-marketing surveillance, the risk for severe adverse reactions (including fatalities) was increased when olanzapine was taken with other anticholinergic medications.
  • Hyperprolactinemia - olanzapine blocks the dopamine D2 receptor, which may cause prolactin levels to rise. Elevated prolactin levels can impair gonadal steroidogenesis in females and males, leading to infertility. Galactorrhea, amenorrhea, gynecomastia, and impotence have also been reported. Long-standing hyperprolactinemia may lead to decreased bone density in female and male subjects. One-third of human breast cancers are prolactin-dependent in vitro. Theoretically, this could increase the risk of breast cancer in some patients; although, studies performed to date have not found an association between chronic administration of antipsychotics and cancer risk. In a 24-week trial, prolactin shifts from normal to high occurred in 32.9% of females and 22.5% of males treated with Lybalvi compared to 41.7% of females and 28.5% of males treated with olanzapine.
  • Infertility - olanzapine may increase prolactin levels which may cause a reversible reduction in fertility among female patients of childbearing age
  • Liver disease
    • Mild to moderate (Child-Pugh A/B): no dose adjustment necessary
    • Severe (Child-Pugh C): has not been studied
  • Kidney disease
    • CrCl ≥ 15 ml/min: no dose adjustment necessary
    • CrCl < 15 ml/min: not recommended

Paliperidone | Invega® | Invega Sustenna® | Invega Trinza®

Dosage forms

Extended-release tablet (Invega®)
  • 1.5 mg
  • 3 mg
  • 6 mg
  • 9 mg
Prefilled syringe (Invega Sustenna®)
  • 39 mg
  • 78 mg
  • 117 mg
  • 156 mg
  • 234 mg
Prefilled syringe (Invega Trinza®)
  • 273 mg
  • 410 mg
  • 546 mg
  • 819 mg

Dosing - Tablet

Schizophrenia/Schizoaffective disorder (adults)
  • Starting: 6 mg once daily
  • Maintenance: 3 - 12 mg once daily
  • Max: 12 mg once daily
  • Increase dose by 3 mg/day at intervals of ≥ 5 days
Schizophrenia/Schizoaffective disorder (12 - 17 years)
  • Starting: 3 mg once daily
  • Maintenance: 3 - 12 mg once daily
  • Max: 12 mg once daily
  • Only approved for schizophrenia in adolescents
  • Increase dose by 3 mg/day at intervals of > 5 days
  • Doses above 6 mg/day for patients weighing < 51 kg and 12 mg/day for patients weighing > 51 kg have not been shown to be more efficacious
Dosing in kidney disease
  • CrCl 50 - 79 ml/min
    • Starting: 3 mg once daily
    • Max: 6 mg once daily
  • CrCl 10 - 49 ml/min
    • Starting: 1.5 mg once daily
    • Max: 3 mg once daily
  • CrCl < 10 ml/min
    • Do not use

Dosing - Invega Sustenna®

Schizophrenia/Schizoaffective disorder (adults)
  • Starting: 234 mg IM on Day 1, and 156 mg IM on Day 8
  • Maintenance: 39 - 234 mg IM once a month
  • Administer first maintenance dose 5 weeks after first injection
  • The recommended maintenance dose for schizophrenia is 117 mg
  • See Sustenna PI® for more information on dosing and missed doses
Dosing in kidney disease
  • CrCl 50 - 79 ml/min
    • Dosing: Start with 156 mg on day 1 and 117 mg one week later. Administer both doses in the deltoid muscle. Thereafter, follow with monthly injections of 78 mg in either the deltoid or gluteal muscle.
  • CrCl < 50 ml/min
    • Not recommended

Dosing - Invega Trinza®

Schizophrenia/Schizoaffective disorder (adults)
  • Invega Trinza should only be used after at least 4 months of Invega Sustenna therapy
  • Start Invega Trinza when the next dose of Invega Sustenna is due
  • Invega Trinza is given once every 3 months
  • For information on missed doses, see Invega Trinza PI [sec 2]
  • The table below has the conversion rate for Invega Sustenna to Invega Trinza

Monthly Invega Sustenna dose Starting Invega Trinza dose
78 mg 273 mg
117 mg 410 mg
156 mg 546 mg
234 mg 819 mg

Dosing in kidney disease
  • CrCl 50 - 79 ml/min
    • Dosing: Dosing based on the previous dose of Invega Sustenna that the patient was stabilized on prior to initiation of Invega Trinza
  • CrCl < 50 ml/min
    • Not recommended

Generic / Price

  • Invega tablet - YES/$$$$
  • Invega Sustenna - NO/$$$$
  • Invega Trinza - NO/$$$$

Other

Invega®
  • May take without regard to food
  • Do not crush, chew, or divide tablet
  • Insoluble tablet may be seen in stool. This is normal.
Invega Sustenna®
  • Give initial 2 doses in deltoid muscle. Following doses may be given in deltoid or gluteal muscle.
  • Tolerability of oral Invega® or risperidone should be established before using
Invega Trinza®
  • Give as an IM injection in deltoid or gluteal muscle

Pharmacokinetics

Invega®
  • Half-life: 23 hours
Invega Sustenna®
  • Half-life: 25 - 49 days
Invega Trinza®
  • Half-life: 84 - 95 days

Mechanism of action

  • Dopamine-2 receptor antagonist
  • Serotonin type 2 (5-HT2A) receptor antagonist

FDA-approved indications

Invega, Invega Sustenna
  • Schizophrenia
  • Schizoaffective disorder
Invega Trinza
  • Schizophrenia

Side effects



Side effect Paliperidone Placebo
Extrapyramidal symptoms 20% 8%
Rapid heart rate 12% 7%
Headache 14% 12%
Somnolence 10% 7%
Weight gain (≥ 7% increase) 9% 5%
Akathisia 8% 4%
Orthostatic hypotension 2% 1%
Other
  • Hyperprolactinemia - similar to risperidone which is up to 87% of patients (13 - 17 years old) in some studies
  • Difficulty swallowing - incidence not well-defined
  • Priapism (erection lasting longer than 4 hours) - rare


Drug interactions

  • Drugs that prolong the QT interval - DO NOT COMBINE. Paliperidone can prolong the QT interval and should not be combined with other QT-prolonging drugs.
  • Centrally-acting drugs - paliperidone may interact with other centrally-acting drugs and increase the risk for adverse events. Use caution when combining.
  • Carbamazepine (Tegretol®) - carbamazepine is a strong inducer of CYP3A4 and P-gp. In studies, carbamazepine at a dose of 200 mg twice daily decreased the average steady-state concentration of paliperidone by 37%. Consider increasing the paliperidone dose when initiating carbamazepine and decreasing it when stopping carbamazepine.
  • Divalproex sodium (Depakote®) - in a single dose study, divalproex sodium 1000 mg caused an increase of 50% in the Cmax and area under the curve of paliperidone (single 12 mg dose). Consider reducing the dose of paliperidone when prescribing with divalproex.
  • CYP2D6 inhibitors and inducers - paliperidone is metabolized to a limited extent by CYP2D6. CYP2D6 inhibitors and inducers may affect paliperidone levels.
  • CYP3A4 strong inducers (Invega Trinza) - strong inducers of CYP3A4 may reduce Invega Trinza exposure. Invega Trinza should not be given with CYP3A4 strong inducers. If concomitant therapy is necessary, consider using paliperidone tablets.
  • P-glycoprotein (P-gp) inhibitors and inducers - Paliperidone is a P-gp substrate. P-gp inhibitors and inducers may affect paliperidone levels. Strong inducers of P-gp should not be used with Invega Trinza; if concomitant therapy is necessary, consider using paliperidone tablets.
  • Dopamine agonists (Mirapex®, Sinemet®, etc.) - paliperidone may block the activity of dopamine agonists used in Parkinson's, RLS, etc.
  • Alpha blockers - paliperidone can block alpha receptors; this may potentiate the effects of alpha blockers and increase the risk of orthostatic hypotension and syncope. Monitor orthostatic vital signs in susceptible patients when combining.

Contraindications / Precautions

  • Prolonged QT syndrome - DO NOT USE. Paliperidone may prolong the QT interval.
  • Elderly with dementia-related psychosis - antipsychotics may increase the risk of death in elderly patients with dementia-related psychosis. In studies lasting 10-weeks, the incidence of death was 4.5% in antipsychotic-treated patients and 2.6% in placebo-treated patients.
  • Stroke and TIA in elderly patients with dementia-related psychosis - in placebo-controlled trials, elderly patients with dementia-related psychosis who were treated with risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and TIA
  • Potential for GI obstruction - paliperidone comes in a non-deformable extended-release tablet. Do not use in patients who are susceptible to obstruction (e.g. esophageal motility disorders, small bowel inflammatory disease, "short gut" syndrome due to adhesions or decreased transit time, past history of peritonitis, cystic fibrosis, chronic intestinal pseudoobstruction, or Meckel's diverticulum)
  • Neuroleptic malignant syndrome (NMS)
  • Tardive dyskinesia
  • Diabetes - atypical antipsychotics have been associated with weight gain and diabetes in some patients. In trials, paliperidone had a mixed effect on blood sugars. Long-term effects are unknown. See diabetes below for ADA monitoring recommendations.
  • Hyperprolactinemia - paliperidone-induced hyperprolactinemia may suppress GnRH secretion leading to galactorrhea, amenorrhea, gynecomastia, impotence and impaired gonadal steroidogenesis in both females and males
  • Breast cancer - up to one-third of breast cancers have been shown to be prolactin-dependent in vitro. Because paliperidone raises prolactin levels, caution should be used in patients with a history of breast cancer.
  • Cholesterol - atypical antipsychotics have been associated with increases in cholesterol in some patients. In trials lasting 6 weeks, paliperidone did not have an adverse effect on lipid parameters. Long-term effects are unknown. See cholesterol below for ADA monitoring recommendations.
  • Body temperature dysregulation - disruption in the body's ability to reduce core temperature has been reported with antipsychotics. Use caution in patients who may be at risk of core temperature elevations (e.g. strenuous exercise, extreme heat, taking anticholinergics, dehydration).
  • Leukopenia - antipsychotics have been associated with a decrease in white blood cells in some patients. Monitor CBC closely in susceptible patients.
  • Seizure - antipsychotics may increase seizure risk. Use caution in susceptible patients.
  • Falls - antipsychotics may cause somnolence, postural hypotension, and motor and sensory instability which can lead to falls. Use caution in susceptible patients.
  • Orthostatic hypotension and syncope - atypical antipsychotics may cause orthostatic hypotension and syncope in some patients. Use caution in susceptible patients.
  • Cognitive and motor impairment - antipsychotics may cause sedation. Use caution before driving or performing tasks that require mental alertness.
  • Parkinson's disease or Lewy body dementia - patients with Parkinson's disease or Lewy body dementia may be especially sensitive to the effects of paliperidone. Side effects including confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and neuroleptic malignant syndrome may occur.
  • Liver disease
    • Mild to moderate (Child-Pugh A/B) - no dose adjustment necessary
    • Severe (Child-Pugh C) - has not been studied
  • Kidney disease -see Dosing

Quetiapine | Seroquel® | Seroquel XR®

Dosage forms

Tablet (Seroquel®)
  • 25 mg
  • 50 mg
  • 100 mg
  • 200 mg
  • 300 mg
  • 400 mg
Extended-release tablet (Seroquel XR®)
  • 50 mg
  • 150 mg
  • 200 mg
  • 300 mg
  • 400 mg

Dosing - Seroquel®

NOTE: Dosing below is general ranges. See the Seroquel® PI [sec 2] for specific recommendations.
Schizophrenia (adults)
  • Starting: 25 mg twice a day
  • Maintenance: 150 - 750 mg/day
  • Max: 800 mg/day
  • Give in 2 - 3 divided doses
  • Increase in increments of 50 - 100 mg/day at intervals ≥ 2 days
Schizophrenia (13 - 17 years old)
  • Starting: 25 mg twice a day
  • Maintenance: 400 - 800 mg/day
  • Max: 800 mg/day
  • Give in 2 - 3 divided doses
Bipolar mania (adults)
  • Starting: 100 mg/day
  • Maintenance: 400 - 800 mg/day
  • Max: 800 mg/day
  • Give 2 divided doses
Bipolar mania (10 - 17 years old)
  • Starting: 50 mg/day
  • Maintenance: 400 - 600 mg/day
  • Max: 600 mg/day
  • Give in 2 - 3 divided doses

Dosing - Seroquel XR®

NOTE: Dosing below is general ranges. See the Seroquel XR® PI [sec 2] for specific recommendations.
Schizophrenia (adults)
  • Starting: 300 mg once daily
  • Maintenance: 400 - 800 mg once daily
  • Max: 800 mg once daily
  • Increase in increments of 300 mg/day at intervals ≥ 1 day
Schizophrenia (13 - 17 years old)
  • Starting: 50 mg once daily
  • Maintenance: 400 - 800 mg once daily
  • Max: 800 mg once daily
Bipolar mania (adults)
  • Starting: 300 mg once daily
  • Maintenance: 400 - 800 mg once daily
  • Max: 800 mg once daily
Bipolar mania (10 - 17 years old)
  • Starting: 50 mg once daily
  • Maintenance: 400 - 600 mg once daily
  • Max: 600 mg once daily

Generic / Price

  • Seroquel® - YES/$
  • Seroquel XR® - YES/$

Other

Seroquel®
  • May take without regard to food
Seroquel XR®
  • Take without food or with a light meal (300 calories). High fat meals increase absorption (not recommended).
  • Do not crush, chew, or divide tablet

Pharmacokinetics

  • Quetiapine has an active metabolite, norquetiapine
  • Half-life (quetiapine): 7 hours
  • Half-life (norquetiapine): 12 hours

Mechanism of action

  • Dopamine-2 receptor antagonist
  • Serotonin type 2 (5-HT2) receptor antagonist

FDA-approved indications

  • Schizophrenia
  • Bipolar disorder - mania

Side effects



Side effect Quetiapine
(N=698)
Placebo
(N=347)
Somnolence 57% 15%
Dry Mouth 44% 13%
Dizziness 18% 7%
Constipation 10% 4%
Fatigue 10% 8%
Dyspepsia 7% 4%
Vomiting 5% 4%
Increased Appetite 5% 3%
Lethargy 5% 2%
Nasal Congestion 5% 3%
Other
  • Extrapyramidal symptoms - incidence is low, similar to placebo in some studies
  • Difficulty swallowing - incidence not well-defined
  • Priapism (erection lasting longer than 4 hours) - rare


Drug interactions

  • Quetiapine is a CYP3A4 sensitive substrate
  • Drugs that prolong the QT interval - DO NOT COMBINE
  • CYP3A4 strong inhibitors - quetiapine dose should be reduced to one-sixth of the original dose when taken with a CYP3A4 strong inhibitor. If the CYP3A4 strong inhibitor is discontinued, the quetiapine dose should be increased by 6-fold.
  • CYP3A4 strong inducers - quetiapine dose should be increased up to five-fold of the original dose when used in combination with a strong CYP3A4 inducer during chronic treatment (greater than 7-14 days). When the CYP3A4 inducer is discontinued, the dose of quetiapine should be reduced to the original level within 7 - 14 days.
  • Medications with anticholinergic activity - norquetiapine, an active metabolite of quetiapine, has moderate to strong anticholinergic activity, and it may potentiate the anticholinergic effect of other medications.
  • Dopamine agonists (Mirapex®, Sinemet®, etc.) - quetiapine may block the activity of dopamine agonists used in Parkinson's, RLS, etc.
  • Alpha blockers - quetiapine can block alpha receptors. It may potentiate the effects of alpha blockers.

Contraindications / Precautions

  • Prolonged QT syndrome - DO NOT USE. Quetiapine may prolong the QT interval.
  • Elderly with dementia-related psychosis - antipsychotics may increase the risk of death in elderly patients with dementia-related psychosis. In studies lasting 10-weeks, the incidence of death was 4.5% in antipsychotic-treated patients and 2.6% in placebo-treated patients.
  • Stroke and TIA in elderly patients with dementia-related psychosis - in placebo-controlled trials, elderly patients with dementia-related psychosis who were treated with risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and TIA
  • Hypothyroidism (low thyroid) - quetiapine may cause low thyroid in some patients (3 - 5% of patients)
  • Suicide in depression - possible increase risk when starting therapy in patients ≤ 24 years old
  • Neuroleptic malignant syndrome (NMS)
  • Tardive dyskinesia
  • Anticholinergic effects - norquetiapine, an active metabolite of quetiapine, has moderate to strong anticholinergic activity. Use caution in patients with urinary retention, constipation, bowel motility issues, or increased intraocular pressure, and in those who are taking other medications with anticholinergic activity. Intestinal obstruction, including fatal cases, has been reported in patients taking quetiapine with other anticholinergic drugs.
  • Diabetes - atypical antipsychotics have been associated with weight gain and diabetes in some patients. In trials, quetiapine caused mild to no elevation of blood sugars when compared to placebo. Long-term effects are unknown. See diabetes below for ADA monitoring recommendations.
  • Cholesterol - atypical antipsychotics have been associated with increases in cholesterol in some patients. In trials, more patients on quetiapine saw increases in their total cholesterol and triglycerides when compared to placebo. Long-term effects are unknown. See cholesterol below for ADA monitoring recommendations.
  • Weight gain - quetiapine may cause weight gain. In bipolar trials lasting up to 12 weeks, 21% of quetiapine-treated patients gained ≥ 7% of their body weight compared to 7% of placebo-treated patients.
  • Increases in blood pressure (children and adolescents) - quetiapine may raise blood pressure in children and adolescents. In trials with children and adolescents lasting 3 - 6 weeks, the incidence of increases at any time in systolic blood pressure (≥ 20 mmHg) was 15.2% for quetiapine-treated patients and 5.5% for placebo-treated patients. The incidence of increases at any time in diastolic blood pressure (≥ 10 mmHg) was 40.6% and 24.5%, respectively.
  • Leukopenia - neutropenia, including fatal cases, has been reported in patients taking quetiapine. White cell counts should be checked in patients presenting with unusual infections or unexplained fevers.
  • Seizure - antipsychotics may increase seizure risk. Use caution in susceptible patients.
  • Orthostatic hypotension and syncope - atypical antipsychotics may cause orthostatic hypotension and syncope in some patients. Use caution in susceptible patients.
  • Cognitive and motor impairment - antipsychotics may cause sedation. Use caution before driving or performing tasks that require mental alertness.
  • Falls - antipsychotics may cause somnolence, postural hypotension, and motor and sensory instability which can lead to falls. Use caution in susceptible patients.
  • Body temperature dysregulation - disruption in the body's ability to reduce core temperature has been reported with antipsychotics. Use caution in patients who may be at risk of core temperature elevations (e.g. strenuous exercise, extreme heat, taking anticholinergics, dehydration).
  • Serious skin reactions - serious skin reactions including drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in patients taking quetiapine
  • Liver disease
    • Seroquel® - clearance is decreased; start with 25 mg/day and increase by 25 - 50 mg/day; use caution
    • Seroquel XR® - clearance is decreased; start with 50 mg/day and increase by 50 mg/day; use caution
  • Kidney disease - no dose adjustment necessary

Risperidone | Risperdal® | Risperdal Consta® | Perseris®

Dosage forms

Tablet (Risperdal®)
  • 0.25 mg
  • 0.5 mg
  • 1 mg
  • 2 mg
  • 3 mg
  • 4 mg
Orally disintegrating tablet (Risperdal M-Tab®)
  • 0.25 mg
  • 0.5 mg
  • 1 mg
  • 2 mg
  • 3 mg
  • 4 mg
Solution (Risperdal®)
  • 1 mg/ml
  • Comes in 30 ml bottle
Vial (Risperdal Consta®)
  • 12.5 mg
  • 25 mg
  • 37.5 mg
  • 50 mg
Prefilled syringe (Perseris®)
  • 90 mg
  • 120 mg

Dosing - Risperdal®

Schizophrenia (adults)
  • Starting: 2 mg/day
  • Maintenance: 4 - 8 mg/day
  • Max: 16 mg/day
  • May be given in one or two divided doses
  • Increase dose in increments of 1 - 2 mg/day at intervals of ≥ 24 hours
  • Start low and go slow in patients at risk for orthostatic hypotension
Schizophrenia (adolescents)
  • Starting: 0.5 mg once daily
  • Maintenance: 3 mg/day
  • Max: 6 mg/day
  • May be given in one or two divided doses
  • Increase dose in increments of 0.5 - 1 mg/day at intervals of ≥ 24 hours
Bipolar mania (adults)
  • Starting: 2 - 3 mg/day
  • Maintenance: 1 - 6 mg/day
  • Max: 6 mg/day
  • May be given in one or two divided doses
  • Increase dose in increments of 1 mg per day at intervals of ≥ 24 hours
  • Start low and go slow in patients at risk for orthostatic hypotension
Bipolar mania (children and adolescents)
  • Starting: 0.5 mg once daily
  • Maintenance: 1 - 2.5 mg/day
  • Max: 6 mg/day
  • May be given in one or two divided doses
  • Increase dose in increments of 0.5 - 1 mg/day at intervals of ≥ 24 hours
Irritability in autistic disorder (children and adolescents)
  • Weight < 20 kg
    • Starting: 0.25 mg once daily for 4 days, then 0.5 mg/day
    • Maintenance: 0.5 - 3 mg/day
    • Max: 3 mg/day
    • May be given in one or two divided doses
    • Increase dose in increments of 0.25 mg/day at intervals of ≥ 14 days
    • No data is available for children weighing < 15 kg
  • Weight ≥ 20 kg
    • Starting: 0.5 mg once daily for 4 days, then 1 mg/day
    • Maintenance: 0.5 - 3 mg/day
    • Max: 3 mg/day
    • May be given in one or two divided doses
    • Increase dose in increments of 0.5 mg/day at intervals of ≥ 14 days

Dosing - Risperdal Consta®

Schizophrenia (adults)
  • Starting: 25 mg IM every 2 weeks
  • Maintenance: 25 - 50 mg IM every 2 weeks
  • Max: 50 mg IM every 2 weeks
  • Increase dose at intervals ≥ 4 weeks
  • Oral risperidone should be continued for 3 weeks after initial injection, then discontinued
Bipolar mania (adults)
  • Starting: 25 mg IM every 2 weeks
  • Maintenance: 25 - 50 mg IM every 2 weeks
  • Max: 50 mg IM every 2 weeks
  • Increase dose at intervals ≥ 4 weeks
  • Oral risperidone should be continued for 3 weeks after initial injection, then discontinued

Dosing - Perseris®

Schizophrenia (adults)
  • Dosing: 90 - 120 mg by subcutaneous injection once monthly
  • Administer in the abdomen only
  • Comes in package with 2 syringes. Drug must be mixed before injecting.
  • Must be given by healthcare professional
  • 90 mg of Perseris corresponds to 3 mg/day of oral risperidone and 120 mg corresponds to 4 mg/day of oral risperidone

Generic / Price

  • Risperdal® tablet - YES/$
  • Risperdal® M-tab - YES/$
  • Risperdal® solution - YES (60 ml)/$
  • Risperdal® Consta® - NO/$$$$
  • Perseris® - NO/$$$$

Other

Risperdal®
  • May take without regard to food
  • Store solution at room temperature
Orally disintegrating tablet
  • Once tablet is removed from blister packet, it cannot be stored. Take immediately.
  • Tablet disintegrates in mouth within seconds and can be swallowed with or without liquid
  • Do not attempt to chew or split tablet
Consta®
  • See Consta® PI for instructions on how to mix and inject

Pharmacokinetics

  • Risperidone has one, major active metabolite called 9-hydroxyrisperidone
  • The apparent half-life of risperidone is 3 hours in CYP2D6 extensive metabolizers and 20 hours in poor metabolizers. The apparent half-life of 9-hydroxyrisperidone is about 21 hours in extensive metabolizers and 30 hours in poor metabolizers.

Mechanism of action

  • Dopamine-2 receptor antagonist
  • Serotonin type 2 (5-HT2) receptor antagonist

FDA-approved indications

  • Schizophrenia
  • Bipolar mania
  • Irritability associated with autistic disorder

Side effects



Side effect Risperidone Placebo
Insomnia 32% 27%
Extrapyramidal symptoms (10 mg/day) 21% 13%
Weight gain (≥ 7% increase) 21% 3%
Anxiety 16% 11%
Sedation 10% 2%
Nausea 9% 4%
Constipation 8% 6%
Dizziness 7% 2%
Other
  • Hyperprolactinemia - up to 87% of patients (13 - 17 years old) in some studies
  • Orthostatic hypotension - 1 - 2% of patients
  • Difficulty swallowing - incidence not well-defined
  • Priapism (erection lasting longer than 4 hours) - rare


Drug interactions

  • Alpha blockers - risperidone can block alpha receptors. This may potentiate the effects of alpha blockers and increase the risk of hypotension.
  • Centrally-acting drugs and alcohol - use caution when combining risperidone with other centrally-acting drugs and alcohol. The risk for adverse neurologic effects may be increased.
  • Clozapine (Clozaril®) - chronic administration of clozapine with risperidone may decrease the clearance of risperidone
  • CYP2D6 strong inhibitors - risperidone is a CYP2D6 sensitive substrate and CYP2D6 strong inhibitors (e.g. fluoxetine, paroxetine) may increase risperidone levels. Risperidone doses should not exceed 8 mg/day when taken together.
  • CYP3A4 inducers - risperidone is a CYP3A4 sensitive substrate and CYP3A4 inducers (e.g. carbamazepine) may decrease risperidone levels. Risperidone doses may need to be increased when taken with CYP3A4 inducers, but they should not exceed twice the patient's usual dose.
  • Dopamine agonists (Mirapex®, Sinemet®, etc.) - risperidone may inhibit the effects of dopamine agonists
  • Drugs with hypotensive effects - risperidone may potentiate the hypotensive effects of other drugs that can cause hypotension. Use caution.
  • Methylphenidate - combined use of methylphenidate with risperidone may increase the risk of extrapyramidal symptoms (EPS), particularly when the dose of either drug is adjusted. Monitor for EPS symptoms when combining.
  • P-glycoprotein - risperidone is a P-glycoprotein substrate and P-glycoprotein inducers may decrease risperidone levels. Risperidone doses may need to be increased when taken with P-glycoprotein inducers, but they should not exceed twice the patient's usual dose.

Contraindications / Precautions

  • Elderly with dementia-related psychosis - antipsychotics may increase the risk of death in elderly patients with dementia-related psychosis. In studies lasting 10-weeks, the incidence of death was 4.5% in antipsychotic-treated patients and 2.6% in placebo-treated patients.
  • Stroke and TIA in elderly patients with dementia-related psychosis - in placebo-controlled trials, elderly patients with dementia-related psychosis who were treated with risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and TIA
  • Neuroleptic malignant syndrome (NMS)
  • Tardive dyskinesia
  • Diabetes - atypical antipsychotics have been associated with weight gain and diabetes in some patients. In trials, risperidone had mixed effects on blood sugars. Long-term effects are unknown. See diabetes below for ADA monitoring recommendations.
  • Cholesterol - atypical antipsychotics have been associated with increases in cholesterol in some patients. In trials, risperidone had an adverse effect on lipid parameters. Long-term effects are unknown. See cholesterol below for ADA monitoring recommendations.
  • Leukopenia - antipsychotics have been associated with a decrease in white blood cells in some patients. Monitor CBC closely in susceptible patients.
  • Seizure - antipsychotics may increase seizure risk. Use caution in susceptible patients.
  • Orthostatic hypotension and syncope - atypical antipsychotics may cause orthostatic hypotension and syncope in some patients. In trials, syncope was reported in 0.2% of risperidone-treated patients. The risk of orthostatic hypotension and syncope may be minimized by limiting the initial dose to 2 mg total (either once daily or 1 mg twice daily) in normal adults and 0.5 mg twice daily in the elderly and patients with renal or hepatic impairment. Use caution in susceptible patients (e.g. heart disease, dehydration, elderly patients with renal or hepatic impairment).
  • Cognitive and motor impairment - antipsychotics may cause sedation. Use caution before driving or performing tasks that require mental alertness.
  • Falls - antipsychotics may cause somnolence, postural hypotension, and motor and sensory instability which can lead to falls. Use caution in susceptible patients.
  • Body temperature dysregulation - disruption in the body's ability to reduce core temperature has been reported with antipsychotics. Use caution in patients who may be at risk of core temperature elevations (e.g. strenuous exercise, extreme heat, taking anticholinergics, dehydration).
  • Phenylketonuria - risperidone orally disintegrating tab contains phenylalanine
  • Parkinson's disease or Lewy body dementia - patients with Parkinson's disease or Lewy body dementia may be especially sensitive to the effects of risperidone. Side effects including confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and neuroleptic malignant syndrome may occur.
  • Liver disease (Risperdal®)
    • Severe (Child-Pugh C) - initial dose should be 0.5 mg twice a day. Increase dose in increments of 0.5 mg or less. For doses > 1.5 mg twice daily, increase in intervals of 1 week or more.
  • Liver disease (Risperdal Consta®)
    • Titrate dose with oral risperidone first. If a total daily dose of ≥ 2 mg of oral risperidone is well tolerated, an injection of 25 mg Risperdal Consta® can be administered every 2 weeks. Oral supplementation should be continued for 3 weeks after the first injection. Alternatively, a starting dose of Risperdal Consta® of 12.5 mg may be appropriate. The efficacy of the 12.5 mg dose has not been established.
  • Kidney disease
    • CrCl < 30 ml/min - initial dose should be 0.5 mg twice a day. Increase dose in increments of 0.5 mg or less. For doses > 1.5 mg twice daily, increase in intervals of 1 week or more.
  • Kidney disease (Risperdal Consta®)
    • Titrate dose with oral risperidone first. If a total daily dose of ≥ 2 mg of oral risperidone is well tolerated, an injection of 25 mg Risperdal Consta® can be administered every 2 weeks. Oral supplementation should be continued for 3 weeks after the first injection. Alternatively, a starting dose of Risperdal Consta® of 12.5 mg may be appropriate. The efficacy of the 12.5 mg dose has not been established.

Ziprasidone (Geodon®)

Dosage forms

Capsule
  • 20 mg
  • 40 mg
  • 60 mg
  • 80 mg

Dosing

Schizophrenia
  • Starting: 20 mg twice a day
  • Maintenance: 20 - 80 mg twice a day
  • Max: 80 mg twice a day
  • Increase dose at intervals of ≥ 2 days
  • Take with food. Food increases absorption.
Bipolar I
  • Starting: 40 mg twice a day
  • Maintenance: 40 - 80 mg twice a day
  • Max: 80 mg twice a day
  • Take with food. Food increases absorption.

Generic / Price

- YES/$

Pharmacokinetics (oral)

  • Half-life: 7 hours

Mechanism of action

  • Dopamine-2 receptor antagonist
  • Serotonin type 2 (5-HT2) receptor antagonist

FDA-approved indications

  • Schizophrenia
  • Bipolar I disorder
  • Agitation in schizophrenia

Side effects



Side effect Ziprasidone Placebo
Weight gain (≥ 7% increase) 16% 4%
Somnolence 14% 7%
Extrapyramidal symptoms 14% 8%
Nausea 10% 7%
Other
  • Rash - ziprasidone causes a rash in 5% of patients. Stop therapy if occurs.
  • Orthostatic hypotension - up to 1% of patients
  • Hyperprolactinemia - incidence not well-defined
  • Difficulty swallowing - incidence not well-defined
  • Priapism (erection lasting longer than 4 hours) - rare


Drug interactions

  • Drugs that prolong the QT interval - DO NOT COMBINE
  • CYP3A4 strong inhibitors and inducers - ziprasidone undergoes a small amount of metabolism by CYP3A4. Strong CYP3A4 inhibitors and inducers may affect levels.
  • Dopamine agonists (Mirapex®, Sinemet®, etc.) - ziprasidone may block the activity of dopamine agonists used in Parkinson's, RLS, etc.
  • Alpha blockers - ziprasidone can block alpha receptors. It may potentiate the effects of alpha blockers.

Contraindications / Precautions

  • Prolonged QT syndrome - DO NOT USE. Ziprasidone may prolong the QT interval.
  • Recent Heart attack - DO NOT USE. Ziprasidone may prolong the QT interval.
  • Uncompensated heart failure - DO NOT USE. Ziprasidone may prolong the QT interval.
  • Elderly with dementia-related psychosis - antipsychotics may increase the risk of death in elderly patients with dementia-related psychosis. In studies lasting 10-weeks, the incidence of death was 4.5% in antipsychotic-treated patients and 2.6% in placebo-treated patients.
  • Stroke and TIA in elderly patients with dementia-related psychosis - in placebo-controlled trials, elderly patients with dementia-related psychosis who were treated with risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and TIA
  • Neuroleptic malignant syndrome (NMS)
  • Tardive dyskinesia
  • Diabetes - atypical antipsychotics have been associated with weight gain and diabetes in some patients. In trials lasting up to 6 weeks, ziprasidone had a mixed effect on blood sugars. Long-term effects are unknown. See diabetes below for ADA monitoring recommendations.
  • Cholesterol - atypical antipsychotics have been associated with increases in cholesterol in some patients. In trials lasting up to 6 weeks, ziprasidone had a mixed effect on lipid parameters. Long-term effects are unknown. See cholesterol below for ADA monitoring recommendations.
  • Body temperature dysregulation - disruption in the body's ability to reduce core temperature has been reported with antipsychotics. Use caution in patients who may be at risk of core temperature elevations (e.g. strenuous exercise, extreme heat, taking anticholinergics, dehydration).
  • Leukopenia - antipsychotics have been associated with a decrease in white blood cells in some patients. Monitor CBC closely in susceptible patients.
  • Seizure - antipsychotics may increase seizure risk. Use caution in susceptible patients.
  • Orthostatic hypotension and syncope - atypical antipsychotics may cause orthostatic hypotension and syncope in some patients. Use caution in susceptible patients.
  • Cognitive and motor impairment - antipsychotics may cause sedation. Use caution before driving or performing tasks that require mental alertness.
  • Falls - antipsychotics may cause somnolence, postural hypotension, and motor and sensory instability which can lead to falls. Use caution in susceptible patients.
  • DRESS syndrome - severe skin reactions including DRESS syndrome have occurred in some users. DRESS syndrome is a rare, but serious skin reaction marked by rash, fever, and swollen lymph nodes.
  • Liver disease - clearance is decreased; manufacturer makes no dose adjustment recommendation
  • Kidney disease - no dose adjustment necessary



Haloperidol | Haldol® | Haldol® Decanoate

Dosage forms

Tablet
  • 0.5 mg
  • 1 mg
  • 2 mg
  • 5 mg
  • 10 mg
  • 20 mg
Solution
  • 2 mg/ml
  • Comes in 15 ml and 120 ml bottle
Vial (Haldol® decanoate)
  • 50 mg
  • 100 mg

Dosing - Oral

Psychosis (adults)
  • Starting (moderate symptoms): 0.5 - 2 mg two to three times a day
  • Starting (severe symptoms): 3 - 5 mg two to three times a day
  • Maintenance: titrate to effect
  • Max: 100 mg/day
Psychotic disorders (3 - 12 years weighing 15 - 40 kg)
  • Dosing: 0.05 mg/kg/day to 0.15 mg/kg/day
  • Daily dose may be given in 2 or 3 divided doses
  • Increase dose in increments of 0.5 mg/day at intervals ≥ 5 - 7 days
Non-psychotic behavior disorders (3 - 12 years weighing 15 - 40 kg)
  • Dosing: 0.05 mg/kg/day to 0.075 mg/kg/day
  • Daily dose may be given in 2 or 3 divided doses
  • Increase dose in increments of 0.5 mg/day at intervals ≥ 5 - 7 days
Tourette's disorder (3 - 12 years weighing 15 - 40 kg)
  • Dosing: 0.05 mg/kg/day to 0.075 mg/kg/day
  • Daily dose may be given in 2 or 3 divided doses
  • Increase dose in increments of 0.5 mg/day at intervals ≥ 5 - 7 days

Dosing - Haldol® Decanoate

Psychosis (adults)
  • Dose: 10 - 20 X the daily oral dose of haloperidol
  • Frequency: IM injection every 4 weeks
  • Max: 450 mg

Generic / Price

- YES/$ (all forms)

Mechanism of action

  • Dopamine receptor antagonist

FDA-approved indications

  • Psychotic disorders
  • Tourette's syndrome - control of tics

Side effects


NOTE: Incidence of side effects not well-defined
  • Extrapyramidal symptoms - common
  • Sedation - common
  • Weight gain - incidence not well-defined
  • Hyperprolactinemia (elevated prolactin level) - incidence not well-defined
  • Priapism (erection lasting longer than 4 hours) - rare


Drug interactions

  • Haloperidol is a CYP3A4 and CYP2D6 substrate
  • Drugs that prolong the QT interval - DO NOT COMBINE
  • CYP3A4 inducers and inhibitors - haloperidol is a CYP3A4 substrate. CYP3A4 inducers and inhibitors may affect levels
  • CYP2D6 inducers and inhibitors - haloperidol is a CYP2D6 substrate. CYP2D6 inducers and inhibitors may affect haloperidol levels.
  • CYP2D6 substrates - haloperidol is a CYP2D6 inhibitor and substrate. Haloperidol may affect other CYP2D6 substrates.
  • Anticholinergic medications - may increase side effects
  • Dopamine agonists (Mirapex®, Sinemet®, etc.) - haloperidol may block the activity of dopamine agonists used in Parkinson's, RLS, etc.
  • Epinephrine - haloperidol may block the vasopressor effects of epinephrine. An alternative vasopressor should be used in patients receiving haloperidol.

Contraindications / Precautions

  • Prolonged QT syndrome - DO NOT USE. Haloperidol may prolong the QT interval.
  • Comatose state or CNS depression - DO NOT USE
  • Parkinson's disease - DO NOT USE. Haloperidol may block the antiparkinson effects of levodopa and other dopamine agonists.
  • Dementia with Lewy bodies - DO NOT USE. Patients with Lewy body dementia may have an increased risk of adverse effects from haloperidol including severe extrapyramidal symptoms, confusion, sedation, and falls.
  • Cardiovascular disease - use with caution. Haloperidol may prolong the QT interval and increase the risk of arrhythmia.
  • Cerebrovascular disease - In controlled trials, elderly patients with dementia-related psychosis treated with some antipsychotics had an increased risk (compared to placebo) of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatalities. The mechanism for this increased risk is not known.
  • Elderly with dementia-related psychosis - antipsychotics may increase the risk of death in elderly patients with dementia-related psychosis. In studies lasting 10-weeks, the incidence of death was 4.5% in antipsychotic-treated patients and 2.6% in placebo-treated patients.
  • Cognitive and motor impairment - antipsychotics may cause sedation. Use caution before driving or performing tasks that require mental alertness.
  • Neuroleptic malignant syndrome (NMS)
  • Tardive dyskinesia
  • Falls - antipsychotics may cause somnolence, postural hypotension, and motor and sensory instability which can lead to falls. Use caution in susceptible patients.
  • Body temperature dysregulation - disruption in the body's ability to reduce core temperature has been reported with antipsychotics. Use caution in patients who may be at risk of core temperature elevations (e.g. strenuous exercise, extreme heat, taking anticholinergics, dehydration).
  • Leukopenia - antipsychotics have been associated with a decrease in white blood cells in some patients. Monitor CBC closely in susceptible patients.
  • Liver disease - manufacturer does not make recommendation
  • Kidney disease - manufacturer does not make recommendation


















Pregnancy safety studies

Risk of Major Malformations in Infants Following First-Trimester Exposure to Quetiapine, Am J Psychiatry (2018) [PubMed abstract]
  • Design: Prospective registry cohort study (N=357) among pregnant women 18 - 45 years old
  • Exposure: First-trimester exposure to quetiapine
  • Primary outcome: Major congenital malformation
  • Results:
    • Primary outcome: Quetiapine-exposed - 1.3%, Control - 1.4% (OR 0.90, 95%CI [0.15 - 5.46])
  • Findings: These data regarding the safety of fetal exposure to quetiapine in a small sample of well-characterized participants are reassuring given that the confidence interval does not exceed a fivefold increased risk of major malformations relative to psychiatric control subjects. Future analyses based on ongoing data collection will produce more precise estimates.

Antipsychotic Use in Pregnancy and the Risk for Congenital Malformations, JAMA Psychiatry (2016) [PubMed abstract]
  • Design: Cohort registry study (N=1,341,715) among women enrolled in Medicaid with a live-born infant
  • Exposure: Use of antipsychotics during the first trimester
  • Primary outcome: Major congenital malformations overall and cardiac malformations identified during the first 90 days after delivery
  • Results:
    • Congenital malformations: Not exposed - 32.7/1000 births, Atypical antipsychotic exposure - 44.5/1000 births, Typical antipsychotic exposure - 38.2/1000 births
  • Findings: Evidence from this large study suggests that use of antipsychotics early in pregnancy generally does not meaningfully increase the risk for congenital malformations overall or cardiac malformations in particular. The small increase in the risk for malformations observed with risperidone requires additional study.

Reproductive Safety of Second-Generation Antipsychotics, American Journal of Psychiatry (2015) [PubMed abstract]
  • Design: Cohort registry study (N=303) among pregnant women 18 - 45 years old
  • Exposure: Use of antipsychotics during the first trimester
  • Primary outcome: Major congenital malformations
  • Results:
    • Primary outcome: Exposed infants - 1.4%, Unexposed infants - 1.1% (OR 1.25, 95%CI [0.13 - 12.19])
  • Findings: The results suggest that it would be unlikely for second-generation antipsychotics to raise the risk of major malformations more than 10-fold beyond that observed in the general population or among control groups using other psychotropic medications. If the estimate stabilizes around the null with ongoing data collection, findings may be reassuring for both clinicians and women trying to make risk-benefit treatment decisions about using atypical antipsychotics during pregnancy. These findings are timely given the renewed focus of regulatory agencies on reproductive safety.

Antipsychotic drug use in pregnancy: high dimensional, propensity matched, population based cohort study, BMJ (2015) [PubMed abstract]
  • Design: Propensity matched cohort study (N=2042)
  • Exposure: Use of antipsychotics during the first or second trimester
  • Primary outcome: The main maternal medical outcomes were gestational diabetes, hypertensive disorders of pregnancy, and venous thromboembolism. The main perinatal outcomes were preterm birth (<37 weeks), and a birth weight <3rd or >97th centile.
  • Findings: Antipsychotic drug use in pregnancy had minimal evident impact on important maternal medical and short term perinatal outcomes. However, the rate of adverse outcomes is high enough to warrant careful assessment of maternal and fetal wellbeing among women prescribed an antipsychotic drug in pregnancy.

Aripiprazole in resistant depression

Switch to Bupropion vs Add Bupropion vs Add Antipsychotic in Resistant MDD, JAMA (2017) [PubMed abstract]
  • Design: Randomized, controlled trial (N=1522, length = 12 weeks) in patients with MDD who were failing SSRI, SNRI, or mirtazapine therapy
  • Treatment: Switch to Bupropion 300 - 400 mg/day vs Add Bupropion 300 - 400 mg/day vs Add aripiprazole 5 - 15 mg/day
  • Primary outcome: Remission during the acute treatment phase of 12 weeks
  • Results:
    • Primary outcome: Switch to Bupropion - 22%, Add Bupropion - 27%, Add Aripiprazole - 29%
  • Findings: Among a predominantly male population with MDD unresponsive to antidepressant treatment, augmentation with aripiprazole resulted in a statistically significant but only modestly increased likelihood of remission during 12 weeks of treatment compared with switching to bupropion monotherapy. Given the small effect size and adverse effects associated with aripiprazole, further analysis including cost-effectiveness is needed to understand the net utility of this approach.

Addition of Aripiprazole vs Placebo to MDD resistant to Venlafaxine (Lancet 2015) [PubMed abstract]
  • Design: Randomized, controlled trial (N=468, length = 12 weeks) in adults older than 60 with MDD who were failing venlafaxine 150 - 300 mg/day
  • Treatment: Aripiprazole (target dose 10 mg/day) vs Placebo
  • Primary outcome: Remission (defined as an MADRS score of ≤ 10 and at least 2 points below the score at the start of the randomised phase) at both of the final two consecutive visits
  • Results:
    • Primary outcome: Aripiprazole - 44%, Placebo - 29% (p=0.03)
  • Findings: In adults aged 60 years or older who do not achieve remission from depression with a first-line antidepressant, the addition of aripiprazole is effective in achieving and sustaining remission. Tolerability concerns include the potential for akathisia and Parkinsonism.



Pricing legend
  • $ = 0 - $50
  • $$ = $51 - $100
  • $$$ = $101 - $150
  • $$$$ = > $151
  • Pricing based on one month of therapy at standard dosing in an adult
  • Pricing based on information from GoodRX.com®
  • Pricing may vary by region and availability