Atypical Anti-psychotics (long-acting injectable)

Medications listed in the tables and non-FDA approved indications included in these retrospective criteria are not indicative of Texas Vendor Drug Program formulary coverage.

  • Revision history
    • Oct. 2021, Sept. 2019
  • Initially developed
    • Sept. 2017

1.1. Adults

Long-acting injectable (LAI) second generation (atypical) antipsychotics are FDA-approved drugs to treat psychiatric disorders. All of the LAI atypical antipsychotics are used to treat schizophrenia 1-13. Invega Sustenna® has an additional indication for treating schizoaffective disorder 1-5. Both Abilify Maintena® and Risperdal Consta® have an additional indication for treating bipolar I disorder 1-4, 6, 7. Invega Hafyera® was approved in September 2021 for the management of schizophrenia in adult patients, and it is administered every six months 1-4, 11. Perseris® is a monthly injection of risperidone approved for the management of schizophrenia in adults that was first approved in 2018 1-4, 13. Aristada Initio® was approved for the initiation of Aristada®, and is only given once in combination with a single 30 mg oral dose of aripiprazole 1-4, 9. Recommended treatment dosages for LAI atypical antipsychotics are summarized in Table 1 1-13.

Abilify Maintena® dosages must be modified in patients prescribed CYP3A4 or CYP2D6 inhibitors, or in those patients identified as CYP poor metabolizers. Abilify Maintena® should be avoided in patients prescribed CYP3A4 inducers concurrently 1-4, 6. Recommended Abilify Maintena® dosages when prescribed concurrently with CP450-modifying medications are summarized in Table 2 1-4, 6.

Aristada® dosages must be modified in patients prescribed CYP3A4 or CYP2D6 inhibitors as well as CYP3A4 inducers concurrently. Aristada Initio® only comes in one dosage strength, and it should be avoided in patients who are known CYP2D6 poor metabolizers or taking strong CYP3A4 inhibitors, strong CYP2D6 inhibitors, or strong CYP3A4 inducers 1-4, 8, 9. Recommended Aristada® dosages when prescribed concurrently with CP450-modifying medications are summarized in Table 3 1-4, 8, 9.

Table 1: Adult LAI Atypical Antipsychotic Recommended Dosages

Treatment Indication Drug Name Available Dosage Strengths Maximum Recommended Dosage
Schizophrenia, bipolar I disorder (maintenance therapy) Aripiprazole (Abilify Maintena®) 300 mg, 400 mg intramuscular (IM) injection 400 mg IM once monthly
Schizophrenia Aripiprazole lauroxil (Aristada®, Aristada Initio®) 441 mg, 662 mg, 675 mg, 882 mg, 1064 mg IM injection 1064 mg IM every two months
Schizophrenia Olanzapine (Zyprexa® Relprevv ™) 210 mg, 300 mg, 405 mg IM injection 300 mg IM every two weeks or 405 mg every 4 weeks
Schizophrenia in patients who have been treated on Invega Sustenna for at least four months or Invega Trinza for at least one three month cycle Paliperidone palmitate (Invega Hafyera®) 1,092 mg, 1,560 mg IM injection 1,560 mg IM every 6 months
Schizophrenia, schizoaffective disorder Paliperidone palmitate (Invega Sustenna®) 39 mg, 78 mg, 117 mg, 156 mg, 234 mg IM injection 234 mg IM once monthly
Schizophrenia in patients who have been treated on Invega Sustenna® for at least four months Paliperidone palmitate (Invega Trinza®) 273 mg, 410 mg, 546 mg, 819 mg IM injection 819 mg IM once every 3 months
Schizophrenia Risperidone (Perseris®) 90 mg, 120 mg IM injection 120 mg IM every month
Schizophrenia, bipolar I disorder (maintenance therapy) Risperidone (Risperdal Consta®) 12.5 mg, 25 mg, 37.5 mg, 50 mg IM injection 50 mg IM every 2 weeks

Table 2: Cytochrome P450-Associated Dosage Changes for Aripiprazole (Abilify Maintena®) (Adults)

Factors Dosage Adjustment
Abilify Maintena® 300 mg intramuscular administration  
Strong CYP3A4 or CYP2D6 inhibitor (greater than 14 days) Reduce to 200 mg
CYP3A4 and CYP2D6 inhibitor together (greater than 14 days) Reduce to 160 mg
CYP3A inducer (greater than 14 days) Avoid use
Abilify Maintena® 400 mg intramuscular administration  
Strong CYP3A4 or CYP2D6 inhibitor (greater than 14 days) Reduce to 300 mg
CYP3A4 and CYP2D6 inhibitor together (greater than 14 days) Reduce to 200 mg
CYP3A inducer (greater than 14 days) Avoid use
Abilify Maintena® in CYP2D6 poor metabolizers  
Known CYP2D6 poor metabolizers Reduce to 300 mg
Known CYP2D6 poor metabolizer taking a CYP3A4 inhibitor Reduce to 200 mg

Table 3: Cytochrome P450-Associated Dosage Changes for Aripiprazole Lauroxil (Aristada® & Aristada Initio®) (Adults)

Factors Dosage Adjustment
Strong CYP3A inhibitor Reduce Aristada® dose to the next lowest strength; if patient is taking 441 mg, no dosage adjustment required
Strong CYP2D6 inhibitor Reduce Aristada® dose to next lowest strength; if patient is taking 441 mg, no dosage adjustment required
Known CYP2D6 poor metabolizer taking a strong CYP3A inhibitor If patient is taking 662 or 882 mg, reduce the dose to 441 mg; if patient is taking 441 mg, no dosage adjustment required
Known CYP2D6 poor metabolizer taking a strong CYP2D6 inhibitor No dose adjustment needed
Both a strong CYP2D6 inhibitor and CYP3A inhibitor Avoid using in patients who are taking 662 or 882 mg; if patient is taking 441 mg, no dosage adjustment needed
CYP3A4 inducers No dose adjustment is needed for the 662 mg or 882 mg dosages; if patient is taking 441 mg, increase dose to 662 mg

1.2. Pediatrics

Safety and efficacy of LAI atypical antipsychotics for use in children younger than 18 years of age have not been established 1-14. The Psychotropic Medication Utilization Parameters for Children and Youth in Texas Public Behavioral Health (6th Version) does not provide dosing recommendations for long-acting injectable atypical antipsychotics 14.

2. Duration of Therapy

If the patient is tolerating the LAI atypical antipsychotic, then there is no basis for limiting treatment length for approved psychiatric disorders as schizophrenia, schizoaffective disorder, and bipolar I disorder are chronic, lifelong diseases 1-13.

3. Duplicative Therapy

Co-administration of two or more LAI atypical antipsychotics is not justified due to limited additional therapeutic benefit and increased risk of adverse effects 1-13.

Patient profiles containing concomitant prescriptions for two or more LAI atypical antipsychotics will be reviewed.

4. Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens which may result in clinically significant drug-drug interactions. Drug-drug interactions considered clinically relevant for LAI atypical antipsychotics are summarized in Table 6. Only those drug-drug interactions classified as clinical significance level 1 or those considered life-threatening which have not yet been classified will be reviewed 1-13.

Table 6: Select LAI Atypical Antipsychotic Drug-Drug Interactions

Target Drug Interacting Drug Interaction Recommendation Clinical Significance Level
Aripiprazole Citalopram Increased risk of QT prolongation and serotonin syndrome because aripiprazole is a partial agonist of 5-HT1A and citalopram is a selective serotonin reuptake inhibitor Avoid use Major (DrugReax) 2-major(CP)
Aripiprazole Strong CYP3A4 inhibitors (e.g., clarithromycin, ketoconazole) Increased risk of aripiprazole overexposure because aripiprazole is metabolized by CYP3A4 Monitor patient closely and adjust aripiprazole dosages as needed Major (DrugReax) 3-moderate (CP)
Long-acting injectable atypical antipsychotics (LAI AAs) CNS depressants Increased risk of respiratory and central nervous system depression due to additive pharmacologic effects Use cautiously together; observe patients for enhanced CNS adverse effects Major (DrugReax) 3-moderate (CP)
LAI AAs Metoclopramide Increased risk of extrapyramidal reactions or neuroleptic malignant syndrome Avoid use Contraindicated (DrugReax) 1-severe,2-major (CP)
LAI AAs QT interval- prolonging medications (e.g. posaconazole) Increased risk of QT interval prolongation Avoid use; if combined use necessary, administer cautiously together and monitor closely     Contraindicated (DrugReax) 1-severe,2-major,3-moderate (CP)
Olanzapine Agents that lower seizure threshold (e.g. clomipramine) Increased seizure risk because psychotropic drugs may reduce the seizure threshold Use caution when administered concomitantly Major (DrugReax) 3-moderate (CP)
Atypical antipsychotics CYP3A4 and CYP1A2 inducers (e.g. carbamazepine) Concomitant use can lead to decreased serum concentrations of atypical antipsychotics Monitor treat efficacy and adjust atypical antipsychotic dosages as needed Major (DrugReax) 2-major (CP)
Olanzapine (CYP1A2 substrate) CYP1A2 inhibitor (e.g. fluvoxamine) Increased olanzapine serum concentrations Monitor patient closely and adjust olanzapine dosages as needed Major (DrugReax) 2-major (CP)
Risperidone Serotonergic agents (e.g. linezolid) Increased risk of serotonin syndrome Monitor patients for serotonin syndrome Major (DrugReax) 2-major (CP)
Risperidone, Olanzapine Lithium Increased extrapyramidal symptoms; encephalopathy and brain damage have occurred in case reports due to unknown mechanism Monitor patients closely for symptoms and monitor lithium levels Major (DrugReax) 3-moderate (CP)

5. References

  1. IBM Micromedex® DRUGDEX® (electronic version). IBM Watson Health, Greenwood Village, Colorado, USA. Available at: https://www-micromedexsolutions-com.libproxy.uthscsa.edu/ (cited:  September 21, 2021).
  2. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2021. Available at:  http://clinicalpharmacology-ip.com.ezproxy.lib.utexas.edu/. Accessed September 21, 2021.
  3. Facts and Comparisons eAnswers [database online]. Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2021; September 21, 2021.
  4. American Society of Health-System Pharmacists. 2021. AHFS Drug Information® - 2021st Ed. Bethesda, MD. American Society of Health-System Pharmacists®. STAT!Ref Online Electronic Medical Library. Available at: https://online.statref.com/document/cQfe8yqMRNqgSGqm4Qo8Qj. Accessed September 15, 2021.
  5. Paliperidone palmitate extended-release injection suspension (Invega® Sustenna®) package insert. Janssen Pharmaceuticals, August 2021.
  6. Aripiprazole intramuscular extended-release injection (Abilify Maintena®) package insert. Otsuka America Pharmaceutical, Inc., September 2021.
  7. Risperidone long-acting injection (Risperdal Consta®) package insert. Janssen Pharmaceuticals, Inc., February 2021.
  8. Aripiprazole lauroxil intramuscular extended-release injection (Aristada®) package insert. Alkermes, Inc., March 2021.
  9. Aripiprazole lauroxil intramuscular extended-release (Aristada Initio®) package insert. Alkermes, Inc., March 2021.
  10. Olanzapine extended release injectable suspension (Zyprexa® Relprevv™) package insert. Eli Lilly and Company, May 2021.
  11. Paliperidone palmitate extended-release injection suspension (Invega Hafyera®) package insert. Janssen Pharmaceuticals, August 2021.
  12. Paliperidone palmitate extended release suspension (Invega Trinza®) package insert. Janssen Pharmaceuticals, August 2021.
  13. Risperidone long-acting injection (Perseris®) package insert. Indivior Inc., December 2019.
  14. The Parameters Workgroup of the Psychiatric Executive Formulary Committee, Health and Specialty Care Division, Texas Health and Human Services Commission. Psychotropic medication utilization parameters for children and youth in Texas public behavioral health (6th version). (June 2019) Available at: https://hhs.texas.gov/sites/default/files/documents/doing-business-with-hhs/provider-portal/facilities-regulation/psychiatric/psychotropic-medication-utilization-parameters.pdf. Accessed September 21, 2021. 
  15. Correll CU, Citrome L, Haddad PM, et al. The use of long-acting injectable antipsychotics in schizophrenia: evaluating the evidence. J Clin Psychiatry. 2016;77(suppl 3):1-24.
  16. Llorca PM, Abbar M, Courtet P, et al. Guidelines for the use and management of long-acting injectable antipsychotics in serious mental illness. BMC Psychiatry. 2013;13:340.