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Home , Aripiprazole, Cariprazine, Lumateperone, Mesoridazine, Molindone, Ziprasidone

County of Santa Clara Behavioral Health Services Practice Guidelines

ANTIPSYCHOTICS AGENTS – ATYPICAL

A. FDA-Approved Indications for Adults (Documentation Required)

1. - treatment-resistant () 2. Reduction in risk of recurrent suicidal behavior in Schizophrenia or (Clozapine) 3. - depressive or acute manic episodes (, immediate- release (IR)/extended-release (XR)) 4. Bipolar Disorder - depressive episodes (Cariprazine, , /, Quetiapine IR/XR) 5. Bipolar Disorder Maintenance: • Monotherapy: , , Cariprazine, Olanzapine, , • Adjunctive treatments ( or Depakote): Aripiprazole, Asenapine, Quetiapine IR/XR, Ziprasidone 6. Agitation with Schizophrenia or Bipolar Disorder: intramuscular (IM) formulations (Aripiprazole, Olanzapine), Ziprasidone for Schizophrenia ONLY 7. Treatment of Agitation in Schizophrenia: Aripiprazole and Olanzapine 8. Major Depressive Disorder Adjunctive treatment: Aripiprazole, , Quetiapine XR 9. Treatment Resistant (Olanzapine/Fluoxetine) 10. Schizoaffective Disorder ()

B. FDA-Approved Indications for Children/Adolescents (Documentation Required)

1. Schizophrenia • Aripiprazole, Risperidone, Quetiapine IR/XR, Lurasidone, Olanzapine (13-17 y.o.) • Paliperidone (12-17 y.o.) 2. Bipolar disorder (acute manic/mixed episodes) • Aripiprazole, Risperidone, Quetiapine IR/XR, Asenapine (10-17 y.o.) • Olanzapine (13-17 y.o.) 3. Bipolar Disorder (depressive episodes) • Lurasidone, Olanzapine/Fluoxetine (10-17 y.o.) 4. Treatment of irritability associated with Autistic Disorder, including symptoms of aggression towards others, deliberate self-injuriousness; temper tantrums, and quickly changing moods • Risperidone (5-17 y.o.) • Aripiprazole (6-17 y.o.) 5. Tourette’s • Aripiprazole (6-18 y.o.)

C. Non-FDA Approved Common Uses (Documentation Required)

1. Psychotic Depression 2. Augmentation in Anxiety Disorders, Sleep Disorder 3. Pervasive Developmental Disorders, Behavioral Disturbances, and 4. Augmentation in disorders and Tourette’s Syndrome 5. Substance-Induced

Section I, Page 1 of 26, Revised 12/2020 County of Santa Clara Behavioral Health Services Medication Practice Guidelines

6. Specific Movement Disorders e.g., Huntington’s Chorea and Parkinson’s Disease 7. Personality Disorder Symptoms 8. Severe Agitation and Aggressive outbursts in children and adolescents

D. Minimal Documentation (Documentation Required)

• All standard outpatient & inpatient requirements

E. Dosing Information (Documentation Required) (Refer to Medication Maximum Daily Dose (MDD) and Tables 1 & 2)

1. “As needed” dosing of :

• Should be minimized, given lack of evidence for efficacy • Documentation should include rationale for using antipsychotics instead of standard, alternative treatments.

2. Use of Quetiapine for sleep disturbance: In the absence of mood or psychotic symptoms, the use of Quetiapine <150 mg for >60 days is discouraged and requires documentation of specific rationale. Documentation should include list of prior trials of pharmacological and non-pharmacological agents and the outcome, implementation of healthy sleep hygiene and must document discussion of risk vs. benefit in context of metabolic syndrome.

3. Applicable to Abilify Maintena® (Aripiprazole) extended-release injectable , for IM use ONLY:

• Prior to starting Abilify Maintena, Aripiprazole naïve patients require up to two weeks of oral Aripiprazole to establish tolerability. (Note: The elimination t1/2 of oral aripiprazole is about 75 hours. Since take about 4-5 half-lives to reach steady state, oral aripiprazole will reach steady state in approximately 12.5 to 15.5 days.)

• After the first Abilify Maintena , continue with oral aripiprazole or other antipsychotics for two weeks to maintain therapeutic concentration during initiation of therapy.

• If patients experience adverse reactions with the 400 mg, consider decreasing the dosage to 300 mg once monthly.

• Dosage adjustment needed for 2D6 poor metabolizer and/or with 3A4 inhibitors (see PI for details).

4. Applicable to Aristada® () extended-release injectable suspension, for IM use ONLY:

• For patients naïve to aripiprazole, establish tolerability with oral aripiprazole prior to initiating treatment with Aristada.

• Two options with initiating Aristada:

Section I, Page 2 of 26, Revised 12/2020 County of Santa Clara Behavioral Health Services Medication Practice Guidelines

o Aristada Initio: Give one 30 mg dose of PO aripiprazole and one 675 mg Aristada Initio injection with the first Aristada injection OR o PO Aripiprazole: Give 21 consecutive days of PO aripiprazole with the first Aristada injection

Total Daily Dose of PO Aripiprazole to Aristada PO Aripiprazole IM Aristada 10 mg/day 441 mg q month 15 mg/day 662 mg q month 882 mg q6 weeks 1064 mg q2 months ≥20 mg/day 882 mg q month

• Dosage adjustments are required for A. Known CYP2D6 poor metabolizers and B. For patients taking CYP3A4 inhibitors, CYP2D6 inhibitors, or CYP3A4 inducers for more than 2 weeks (See prescriber information (PI) for more details).

• For patients with both strong CYP3A4 and strong CYP2D6, avoid 662 mg, 882 mg, or 1064 mg doses of Aristada

• DO NOT substitute Aristada Initio for Aristada

5. Applicable to Invega Sustenna® (Paliperidone Palmitate) extended-release injectable suspension, for IM use ONLY:

• For patients who have never taken oral paliperidone or oral or injectable risperidone, it is recommended to establish tolerability with oral paliperidone or oral risperidone prior to initiating treatment with Invega Sustenna®.

• Upon initiation of therapy with Invega Sustenna®, cross coverage with oral paliperidone or risperidone is not necessary.

• Invega Sustenna is not recommended for patients with moderate-to-severe renal impairment (CrCl < 50 mL/min).

• For patients with mild renal impairment (CrCl ≥ 50 mL/min to < 80 mL/min), administer 156 mg on day 1 of treatment and 117 mg one week later (both administered in the deltoid muscle). Continue with monthly 78 mg injections in either the gluteal or deltoid muscle.

6. Applicable to Invega Trinza® (3-month Paliperidone Palmitate) extended-release injectable suspension, for IM use ONLY:

• Invega Trinza should be used only after the patient has been adequately treated with the 1-month Invega Sustenna IM for at least four months.

• Invega Trinza should be administered once every 3 months.

Section I, Page 3 of 26, Revised 12/2020 County of Santa Clara Behavioral Health Services Medication Practice Guidelines

Last Dose of Invega Sustenna Following Invega Trinza Dose 78 mg 273 mg 117 mg 410 mg 156 mg 546 mg 234 mg 819 mg

• Invega Trinza is not recommended for patients with moderate-to-severe renal impairment (CrCl < 50 mL/min).

• For patients with mild renal impairment (CrCl ≥ 50 mL/min to < 80 mL/min), adjust dosage and stabilize the patient on Invega Sustenna then transition to Invega Trinza using the above conversion.

7. Applicable to Risperdal Consta® (Risperidone) LAI, for IM use ONLY:

• For patients who have never taken oral risperidone, it is recommended to establish tolerability with oral risperidone prior to initiating treatment with Risperdal Consta.

• Oral risperidone (or another antipsychotic medication) should be given with the first injection of Risperidal Consta and continued for 3 weeks (and then discontinued) to ensure that adequate therapeutic plasma concentrations are maintained prior to the main release phase of risperidone from the injection site.

• Dose increases of Risperdal Consta should not be made more often than 4 weeks. Clinical effects of each increased dose titration adjustment should not be anticipated sooner than 3 weeks after each injection.

8. Applicable to Perseris® (Risperidone) for extended-release injectable suspension, for subcutaneous (SQ) use ONLY:

• No loading dose or oral supplementation recommended.

• Prior to starting Perseris, establish tolerability with oral risperidone in risperidone- naïve patients.

• Patients who are on stable oral risperidone doses lower than 3 mg/day or higher than 4 mg/day may not be candidates for Perseris.

• Perseris is administered monthly by abdominal subcutaneous injection ONLY.

• Perseris is available in 90 mg and 120 mg syringes and need to be refrigerated and brought to room temperature for 15 minutes prior to mixing. (Note: When mixing the powder and liquid syringe, “1 cycle” of mixing occurs after transferring the contents of the liquid syringe into the powder syringe AND BACK from the powder syringe into the liquid syringe. Pre-mixing requires 5 gentle cycles, while thorough mixing requires an additional 55 cycles; the mixing can be more vigorous within the 55 cycles than when pre-mixing.)

Section I, Page 4 of 26, Revised 12/2020 County of Santa Clara Behavioral Health Services Medication Practice Guidelines

• Perseris 90 mg is expected to produce a plasma level similar to that of 3 mg/day of oral risperidone and Perseris 120 mg equates to 4 mg/day of oral risperidone.

F. Duration of Use/Medication Changes (Documentation Required)

• Inpatient and Outpatient: Document rational for all dosage or medication changes in each progress note.

G. Polypharmacy (Documentation Required)

1. Documentation regarding failed monotherapy must include specifics such as: dosage, duration of therapy and the clinical response (see purpose section of medication guideline for patients that are currently on polypharmacy i.e. at the time of transfer).

2. Use of more than one antipsychotic agent beyond the 90 days cross titration period requires the following documentation:

• That a risk/benefit analysis was performed and discussed with the patient

• The rationale for not attempting to taper or discontinue the polypharmacy regimen every 6-month period

H. Standard Laboratory and Examination Requirements (Documentation Required) (Refer to Table 4)

1. For Inpatient: Basic laboratory studies on admission 2. For Outpatient: (See Lab Monitoring); Upon initiation of treatment, unless recent studies obtained elsewhere are documented, the following baseline studies are required (Refer to Table 4)

• There is an increased risk of myelosuppression with all antipsychotic agents especially in patients who are concomitantly on other myelosuppressive drugs i.e. (CBZ) and valproic acid (VPA). It is recommended to monitor more closely by ordering more frequent Complete Blood Counts (CBC) with differentials.

3. Applicable to Quetiapine ONLY: • Consider eye examination for cataracts at initiation of treatment or shortly thereafter and at 6-month intervals during chronic treatment

4. Applicable to Clozapine ONLY (Refer to Prescriber Information): • Complete baseline CBC with differential (absolute neutrophil count (ANC)) prior to start date • However, only ANC needs to be monitored & reported to Risk Evaluation and Mitigation Strategy (REMS) to rule out neutropenia. • For general population i.e. those without benign ethnic neutropenia (BEN), interrupt treatment if neutropenia is suspected to be clozapine-induced for ANC less than 1,000 cells per microliter and 500 cells per microliter for those with BEN. • Although re-challenging patients with clozapine-induced severe neutropenia is not recommended, patients may now be re-challenged if the prescriber determines that

Section I, Page 5 of 26, Revised 12/2020 County of Santa Clara Behavioral Health Services Medication Practice Guidelines

the risk of psychiatric illness is greater than the risk of recurrent severe neutropenia (refer to FDA safety bulletin for more details). • Substantial drops in ANC do not require action unless the patient experiences neutropenia. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety- communication-fda-modifies-monitoring-neutropenia-associated-schizophrenia- medicine o Vital signs: blood pressure (BP), pulse and weight o Consultation with a neurologist for patients with a history of seizure or intracranial disease • During Clozapine treatment: ANC monitoring weekly from initiation to 6 months. Then every 2 weeks from 6 to 12 months and every 4 weeks after 12 months.

5. Consider additional or more frequent monitoring whenever there is a change in patient’s mental or physical status.

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I. Black Box Warnings (Document Assessment) (Refer to Table 5)

1. Elderly patients with -related psychosis treated with antipsychotic drugs are at an increased risk of death.

2. ARIPIPRAZOLE, BREXPIPRAZOLE, CARIPRAZINE, LURASIDONE, OLANZAPINE/FLUOXETINE, QUETIAPINE IR/XR, ONLY

• Children, adolescents, and young adults up to age 24 taking for Major Depressive Disorder and other psychiatric disorders are at increased risk of suicidal thinking and behavior.

3. CLOZAPINE ONLY

• Because of a significant risk of agranulocytosis, a potential life threatening adverse effect, Clozapine should be reserved for the use in (1) treatment of severely ill patients with schizophrenia who failed to show an acceptable response to adequate courses of standard antipsychotic drug treatment, or (2) for reducing the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at risk for reexperiencing suicidal behavior.

4. ZYPREXA RELPREVV ONLY

• Post-Injection Delirium/Sedation Syndrome—Adverse events with signs and symptoms consistent with olanzapine overdose—sedation (including coma) and/or delirium, have been reported following injections of Zyprexa Relprevv. Zyprexa Relprevv must be administered in a registered healthcare facility with ready access to emergency response services. After each injection, patients must be observed at the healthcare facility by a healthcare professional for at least 3 hours. Because of this risk, Zyprexa Relprevv is available only through a restricted distribution program called Zyprexa Relprevv Patient Care Program and requires prescriber, healthcare facility, patient, and pharmacy enrollment.

J. Absolute Contraindications (Documentation Required) Note: Contraindication includes known hypersensitivity to the desired drug or any of its components (for risperidone or paliperidone, this includes hypersensitivity to either medication).

1. Applicable to Asenapine ONLY: • Severe hepatic impairment (Child-Pugh C)

2. Applicable to Lurasidone ONLY: • Concomitant use with a strong 3A4 inducer (refer to Table 6) • Concomitant use with a strong 3A4 inhibitor (refer to Table 6)

3. Applicable to Olanzapine/Fluoxetine (Symbyax®) ONLY: • Use of monoamine oxidase inhibitors (MAOIs); in addition, o Do not use MAOIs ≤5 weeks of discontinuing Symbyax® o Do not use Symbyax® ≤14 days of stopping a MAOI • Use of or (risk of QT prolongation); in addition, do not use thioridazine ≤5 weeks of discontinuing Symbyax®.

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• Inpatient: Treatment with linezolid or intravenous

4. Applicable to Ziprasidone ONLY: • Known history of QT prolongation (should be discontinued in patients who have persistent QTc >500 msec) • Recent acute myocardial infarction • Uncompensated heart failure • Other medications that have demonstrated QT prolongation

K. Warning/Precautions & Relative Contraindications (associated with all atypicals, unless otherwise noted) (Refer to Table 5 for Black Box Warnings, & Nursing Mother)

1. Use with caution in:

• The elderly, in the presence of cardiovascular disease and seizure disorders • In patients with suspected hepatic disorder (monitor clinically and measure transaminase periodically) • In patients with narrow angle glaucoma, prostatic hypertrophy (may result in urinary retention) • Elderly patients with dementia related psychosis: increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack) reported with Olanzapine, Aripiprazole and Risperidone.

2. Monitor if QT interval exceed 420 msec and discontinue drug if patient is symptomatic or if QT interval exceed 500 msec. Patients with hypokalemia or hypomagnesemia may also be at risk.

3. Cigarette smoking is reported to induce the metabolism and decrease the plasma level of Clozaril and Zyprexa.

4. Agitation, aggression, delirium, worsening of psychosis, diaphoresis and abnormal movements associated with rapid Clozapine or Quetiapine withdrawal (suggested to taper clozapine by 25-100mg / week and quetiapine by 50-200 mg / week)

5. Confusion, disturbed concentration, disorientation (more common with high doses or in the elderly)

6. Lower seizure threshold. (Note: With clozapine—seizures have been associated with the use of clozapine. Dose seems to be an important predictor of seizure, with a greater likelihood at higher clozapine doses.)

7. . (Note: With clozapine—orthostatic hypotension, bradycardia with or without syncope, can occur. Rarely, collapse can be profound, and be accompanied by respiratory and/or cardiac arrest. Orthostatic hypotension is more likely to occur in initial titration in association with rapid dose escalation.)

8. is common with most second-generation antipsychotics. Long term data is limited with Ziprasidone or Aripiprazole, moderate risk is seen with Quetiapine and risperidone, and high risk is seen with Clozapine and olanzapine. Weight gain may predispose to coronary artery disease, , and obstructive sleep apnea

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9. Metabolic syndrome, also called syndrome, consists of disturbed glucose metabolism, , hyperlipidemia, and hypertension

10. Neuroleptic malignant syndrome – rare disorder characterized by muscular rigidity, tachycardia, hyperthermia, altered consciousness, autonomic dysfunction, and increase in creatine phosphokinase (CPK)— can occur with any class of antipsychotic agent, at any dose, and at any time (increased risk in hot weather). Other risk factors include polypharmacy, organic syndromes, mood disorders, dehydration, low serum sodium, exhaustion, and agitation

11.

12. Leukopenia, Neutropenia and Agranulocytosis have been reported with all antipsychotics.

13. Pregnancy and Nursing Mother (See Table 5)

14. Applicable to Clozapine ONLY:

• Eosinophilia—Assess for organ involvement (e.g. pancreatitis, hepatitis, colitis, nephritis, myocarditis). Discontinue clozapine if these occur.

• Hepatotoxicity—Can be fatal. Discontinue treatment if transaminase elevations or hepatitis combined with other symptoms occur.

• Gastrointestinal Hypomotility with Severe Complications—If constipation is identified, prompt treatment and close monitoring is recommended.

• Analysis of post marketing safety databases suggested that Clozapine is associated with an increased risk of fatal myocarditis, cardiomyopathy, and mitral valve incompetence, especially during, but not limited to, the first month of therapy. Cardiomyopathy signs and symptoms include exertional dyspnea, fatigue, orthopnea, paroxysmal nocturnal dyspnea, and peripheral edema.

• Fever should be evaluated to rule out the possibility of an underlying infectious process or the development of agranulocytosis

• Pulmonary embolism, consider in those present with deep vein thrombosis, acute dyspnea, chest pain, or with other respiratory signs and symptoms

• toxicity: glaucoma, gastrointestinal, and prostate

• Use caution with: ▪ Untreated hypertension or tachycardia ▪ History of orthostatic hypotension ▪ History of any serious physical illness in the prior month ▪ Any agent with significant potential for bone marrow suppression or agranulocytosis, e.g. carbamazepine ▪ History of poor follow-through with frequent mandatory lab testing

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15. Applicable to Asenapine ONLY: The use of Saphris® (Asenapine Maleate) has been associated with serious type 1 hypersensitivity reactions which may include , angioedema, low blood pressure, rapid heart rate, swollen tongue, difficulty breathing, wheezing, or rash. In several cases, these reactions occurred after the first dose. Healthcare professionals are encouraged to counsel patients who are receiving the drug about how to recognize the signs and symptoms of a serious allergic reaction.

16. Applicable to Aripiprazole and Brexipiprazole ONLY: Compulsive or Uncontrollable urges to gamble, binge eat, shop, and have sex have been reported with Aripiprazole (Abilify, Abilify Maintena, Aristada, and generics) and Brexipiprazole. Such urges were reported to have stopped after dosage reduction or discontinuation • https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety- communication-fda-warns-about-new--control-problems-associated-mental- health (Aripiprazole)

17. Applicable to Olanzapine and Ziprasidone ONLY: • Olanzapine and ziprasidone have been linked to a severe condition known as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). DRESS may start as a rash that can spread to all parts of the body. It can include fever, swollen lymph nodes, and a swollen face. It causes a higher-than-normal eosinophil count that can cause inflammation or swelling. DRESS can result in injury to organs, including the , kidneys, lungs, heart, or pancreas and can lead to death. DRESS is a potentially fatal drug reaction with a mortality rate of up to 10%. The FDA recommends that physicians immediately stop treatment with Olanzapine and ziprasidone if DRESS is suspected and consider systemic corticosteroids. (Please see the FDA Advisory for more details • https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety- communication-fda-warns-about-rare-serious-skin-reactions-mental-health-drug (Olanzapine) • https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety- communication-fda-reporting-mental-health-drug-ziprasidone-geodon-associated- rare#:~:text=The%20U.S.%20Food%20and%20Drug,other%20parts%20of%20the% 20body. (Ziprasidone)

18. Applicable to Paliperidone ONLY: Obstructive symptoms may develop in patients with gastrointestinal disease.

19. Applicable to Quetiapine ONLY: • Cataracts (reported incidence of 0.005%): Changes in lens have been observed in patients on long-term treatment with quetiapine. • Increase in blood pressure in adolescents and children – monitor BP when starting treatment, and periodically during treatment.

20. Applicable to Risperdal Consta® ONLY: • Use caution in patients at risk for aspiration pneumonia, as esophageal dysmotility and aspiration can occur • Increased sensitivity in patients with dementia with Lewy bodies and Parkinson’s disease have been reported (symptoms include extra-pyramidal symptoms, motor

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impairment, mental status changes, and features consistent with neuroleptic malignant syndrome).

L. and Drug-Drug Interactions (Refer to Table 6)

M. Pregnancy & Nursing Mother (Refer to Table 5)

N. Adverse Effects a. Serious Adverse Effects (Refer to Table 7) b. Common Adverse Effects (Refer to Table 8)

Attachments: Table 1: FDA-Approved Indications & Applicable Daily Dosing for Adults Table 2: FDA-Approved Indications & Applicable Daily Dosing for Children/Adolescents Table 3: Atypicals Drug Formulations & Dosing Requirements Table 4: APA Monitoring Guidelines Table 5: Atypicals Black Box Warnings, Pregnancy & Nursing Mother Table 6: Pharmacokinetics and Drug-Drug Interactions Table 7: Atypicals Serious Adverse Effects Table 8: Atypicals Common Adverse Effects

References: 1. Eugene Barrett, MD & et al, 2004 Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes, Diabetes Care, Vol. 27, Number 2: 596-601, 2/2004. 2. www.Epocrates.com 3. www.MicroMedex.com 4. FDA Package Insert for each respective Atypical Antipsychotic Medication 5. FDA Drug Safety 6. http://www.accessdata.fda.gov/scripts/cder/rems 7. http:///www.fda.gov/drugs/drugsafety/ucm461853.htm 8. http://www.medscape.com/viewarticle/855225 9. http://www.fda.gov/Drugs/DrugSafety/ucm498662.htm#

Refer to appendix for standardized treatment algorithms including Texas Medication Algorithm. Refer to appendix for American Diabetic Association Guidelines for use of atypical antipsychotics. Medication Practice Guideline Appendix section is available online @ www.sccmhd.org Rev. 6-2012

Section I, Page 12 of 26, Revised 12/2020 County of Santa Clara Behavioral Health Services Medication Practice Guidelines Table 1: FDA-Approved Indications & Applicable Daily Dosing (mg) unless specified, for Adults Schizophrenia/ Agitation with : manic Agitation with Bipolar Disorder: Treatment Resistant Schizophrenia: Treatment- SAD Reduction in Risk of FDA Approved Indicationsa schizophrenia or bipolar (acute and/or Schizophrenia SAD MDD, adjunct schizophrenia (IM) depressive Depression Resistant Recurrent Suicidal disorder (IM) maintenance) Behavior 15-30 (acute and maintenance monotherapy) 9.75-30 10-30 10-30 2-15 (acute and maintenance adjunct to lithium or Aripiprazole (Abilify®)b ) 400 mg IM qmonth 400 mg IM qmonth Aripiprazole (Abilify Maintena®)c (maintenance monotherapy) 441-882 qmonth or 882 q6wks; Aripiprazole Lauroxil (Aristada®) max 1064 q2 months 10-20 (acute and maintenance monotherapy) 10-20 10-20 (acute adjunct to lithium or Asenapine (Saphris®)d valproate) Brexpiprazole (Rexulti®) 1-4 0.5-3 3-6 1.5-3 1.5-6 Cariprazine (Vraylar®) (acute monotherapy) Clozapine (Clozaril®) 12.5-900 12.5-900 (Fanapt®)d 12-24 (Caplyta®) 42 Lurasidone (Latuda®) 20-120 40-160 10-15 (acute monotherapy or 10-30 adjunct to lithium or 5/20 (fluoxetine) 5-10 5/20 (fluoxetine) Olanzapine (Zyprexa®) + divalproex, and Zydis® maintenance) 150-300 q2wks to 300-405 Olanzapine (Relprevv IM®)e q4wks Olanzapine/Fluoxetine 6/25 to 12/50 6/25 to 18/50 (Symbyax®) Paliperidone (Invega®) 6-12 6-12

78-234 q4wks (monotherapy or adjunct to 39-234 q4wks mood stabilizers & Paliperidone Palmitate antidepressants) (Sustenna IM®) Paliperidone Palmitate 273-819 q3months (Invega Trinza IM®) 100-800d (acute monotherapy or adjunct to lithium or 50-300 50-750d divalproex, and Quetiapine IR (Seroquel IR®) maintenance) 300-800 (acute monotherapy or adjunct to lithium or 50-300 300-800 50-300 divalproex, and Quetiapine XR (Seroquel XR®) maintenance) 2-6 (acute monotherapy or 2-16 adjunct to lithium or Risperidone (Risperdal®) divalproex) Risperidone SQ (Perseris®) 90-120 qmonth 25-50 q2wks (maintenance monotherapy 25-50 q2wks Risperidone or adjunct to lithium or (Risperdal Consta IM®)c divalproex) 80-160d (acute monotherapy or 10-40 40-160d,f maintenance adjunct to Ziprasidone (Geodon®) lithium or divalproex) Bolded agents reflect formulary status at SCVHHS. a References: Prescribing Information (PI), Epocrates, Micromedex b Abilfy is considered non-formulary on SCVH&HS Formulary Effective 12/01/2011. c When initiating treatment, overlap with oral counterpart or other antipsychotics x2 weeks (aripiprazole) or x3 weeks (risperidone). d Usually given in divided doses (e.g. "80-160" is given as 40 mg BID - 80 mg BID) e Zyprexa Relprevv: Due to the need for rigorous monitoring, SCCMH department does not support the use of Relprevv in its outpatient programs. f Per Ziprasidone prescribing information (10/2020): "Safety and efficacy has been demonstrated in doses up to 100 mg twice daily." Section I, Page 13 of 26, Revised 12/2020 County of Santa Clara Behavioral Health Services Medication Practice Guidelines

Table 2: FDA-Approved Indications & Applicable Daily Dosing (mg) unless specified, for Children/Adolescents Bipolar Disorder: both Bipolar Disorder: acute Bipolar Disorder: Irritability with autistic FDA Approved Indicationsa depressive/acute manic Schizophrenia Tourettes's manic/mixed episodes depressive episodes disorderb episodes 2-30 child/adol 10-17 yo 2-10 mg (<50 kg) (monotherapy or adjunct to 2-30 adol 13-17 yo 2-15 child/adol 6-17 yo 2-20 mg (≥50 kg) Aripiprazole (Abilify®) c lithium or valproate) child/adol 6-18 yo 5-20 child/adol 10-17 yo Asenapine (Saphris®)d (monotherapy) Lurasidone (Latuda®) 20-80 child/adol 10-17 yo 40-80 adol 13-17 yo 2.5-10 adol 13-17 yo (acute monotherapy or 2.5/20 (fluoxetine) 2.5-10 adol 13-17 yo adjunct to lithium or child/adol 10-17 yo valproate, and maintenance) Olanzapine (Zyprexa®) + Zydis® 3/25 to 12/50 Olanzapine/Fluoxetine (Symbyax®) child/adol 10-17 yo 3-6 mg (<51 kg) 3-12 mg (≥51 kg) Paliperidone (Invega®) child/adol 12-17 yo 50-600 child/adol 10-17 yo d 50-800 adol 13-17 yo Quetiapine IR (Seroquel IR®) (acute monotherapy) 50-600 child/adol 10-17 yo 50-800 adol 13-17 yo Quetiapine XR (Seroquel XR®) (acute monotherapy) 0.25-3 (weight <20 kg) 0.5-6 child/adol 10-17 yo 0.5-6 adol 13-17 yo 0.5-3 (weight ≥20 kg) (acute monotherapy) Risperidone (Risperdal®) child/adol 5-17 yo

Bolded agents reflect formulary status at SCVHHS. a Reference: Prescribing Information (PI), Epocrates, Micromedex b Irritability includes symptoms of aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing moods. c Abilfy is considered non-formulary on SCVH&HS Formulary Effective 12/01/2011. d Usually given in divided doses (e.g. "80-160" is given as 40 mg BID - 80 mg BID)

Section I, Page 14 of 26 Revised 12/2020 County of Santa Clara Behavioral Health Services Medication Practice Guidelines Table 3: Atypicals Drug Formulations & Dosing Requirements1-2 Formulations Dosing Requirements (T) Orally Oral Long IM Affected Requires Dosing Frequency Capsule (C), or Disintegrating Acting with Titration Sublingual (SL) Tablet (mg) (mg/mL) Injectable Respect (mg) (mg) to Food Aripiprazole PO: Daily T: 2, 5, 10, 15, Discmelt®: 9.75 mg/ (Abilify®) 1 IM: Wait ≥2 hours 20, 30 10, 15 1.3mL between doses Aripiprazole (Abilify Maintena®) 300, 400 qmonth

Aripiprazole Lauroxil (Aristada Initio®) 675 x1

Aripiprazole Lauroxil qmonth, 882 mg q6 441, 662, (Aristada®) weeks, or 1064 mg q2 882, 1064 months Asenapine (Saphris®) SL: 2.5, 5, 10 Xa BID Brexpiprazole T: 0.25, 0.5, 1, X Daily (Rexulti®) 2, 3, 4 Cariprazine C: 1.5, 3, 4.5, 6 Xb Daily (Vraylar®) Clozapine Fazaclo®: (Clozaril®, T: 25, 50, 100, 12.5, 25, 100, 50 X Daily or BID FazaClo®), 200 150, 200 Versacloz®) Iloperidone (Fanapt®) T: 1, 2, 4, 6, 8, X BID 10, 12 Lumateperone C: 42 Xc Daily (Caplyta®) Lurasidone (Latuda®) T: 20, 40, 60, Xd Daily 80, 120 Olanzapine PO: Daily T: 2.5, 5, 7.5, Zydis®: 10 mg IM: Wait 2-4 hours (Zyprexa®) 10, 15, 20 5, 10, 15, 20 between doses Olanzapine 150 mg q2 weeks, 300 mg q4 weeks, 210 mg (Zyprexa Relprevv®) 210, 300, q2 weeks, 405 mg q4 405 weeks, 300 mg q2 weeks Olanzapine/Fluoxetine C: 3/25, 6/25, Daily (Symbyax®) 6/50, 12/50 Paliperidone T: 1.5, 3, 6, 9 Daily (Invega ER®) Paliperidone 39, 78,

(Invega Sustenna®) 117, 156, qmonth 234 Paliperidone 273, 410, q3 months (Invega Trinza®) 546, 819 Quetiapine T: 25, 50, 100, X BID or QHS (Seroquel IR®) 200, 300, 400

Quetiapine XR T: 50, 150, 200, Xe X Daily (Seroquel XR®) 300, 400

Risperidone T: 0.25, 0.5, 1, M-TAB®: 0.5, 1 X Daily or BID (Risperdal®) 2, 3, 4 1, 2, 3, 4 Risperidone SQ (Perseris®) 90, 120 qmonth

Risperidone 12.5, 25, q2 weeks (Risperdal Consta®) 37.5, 50 Ziprasidone PO: BID f (Geodon®) C: 20, 40, 60, 80 20 mg/mL X X IM: Wait 2-4 hours between doses a Asenapine – Eating and drinking should be avoided for 10 minutes after administration. References b Cariprazine – Dose titration required for bipolar . 1. Prescribing Information c Lumateperone – Take with food (no recommendation for calorie amount/fat content). 2. Lincoln, J., Stewart, M. E., & Preskorn, S. H. (2010). How Sequential Studies Inform Drug d Lurasidone – Take with food (≥350 calories). Development: Evaluating the Effect of Food Intake on Optimal of e Quetiapine XR – Take without food or with a light meal (~300 calories). Ziprasidone. Journal of Psychiatric Practice, 16(2), 103-114. f Ziprasidone – Take with food (≥500 calories2). doi:10.1097/01.pra.0000369971.64908.dc

Section I, Page 15 of 26, Revised 12/2020

County of Santa Clara Behavioral Health Services Medication Practice Guidelines Table 4: APA Monitoring Guidelines1 Baseline or Initial Assessments Frequency of Follow-Up Physical Status & Physical Conditions Vital Signs • HR As clinically indicated • BP (including temperature) Body Weight & Height • Body Weight

• Height • BMI Every visit x6 months and at least quarterly thereafter Pregnancy • Pregnancy Test for women of childbearing potential Hematology • CBC (including ANC) Blood Chemistries • Electrolytes • Function As clinically indicated • LFTs • TSH Drug Toxicology • Drug toxicology screen, if clinically indicated Imaging & Genetic Testing • If indicated based on examination or history Specific Treatment Side Effects Diabetes • Fasting Blood Glucose (A1c) • Diabetes Risk Factors Hyperlipidemia • Lipid Panel Metabolic Syndrome • Determine if metabolic syndrome criteria are met (≥3 of the risk factors): • Waist circumference >102 cm (men) and >88 cm (women) At 4 months after starting a new treatment, and at • TG ≥ 150 mg/dL or drug treatment for elevated TG least annually thereafter • HDL-C <40 mg/dL (men) or <50 mg/dL (women) or drug treatment for reduced HDL • SBP ≥ 130 mmHg and/or DBP ≥85 mmHg or on antihypertensive treatment for HTN • FBG ≥ 100 mg/dL or drug treatment for elevated BG QTc prolongation EKG before treatment with • • EKG with significant change in dose, or with • Iloperidone addition of other medications that can affect QTc • Pimozide interval in patients with elevated baseline QTc • Thioridazine intervals or with cardiac risk factors • Ziprasidone Or in the presence of cardiac risk factors Hyperprolactinemia • Symptoms of hyperprolactinemia At each visit until stable, then yearly if treated with an antipsychotic known to increase • Prolactin level, if indicated based on clinical history If indicated based on clinical history Antipsychotic-Induced Movement Disorders • Clinical assessment of EPS (and use of structured instrument Assessment with a structured instrument at least if movements are present) every 6 months in patients at high risk of TD and at least every 12 months in other patients (and if new onset or exacerbation of preexisting movements is detected at any visit) References: 1. Association, A. P. (2020). The American Psychiatric Association Practice Guideline for the Treatment of Patients With Schizophrenia. doi:10.1176/appi.books.9780890424841 Section I, Page 16 of 26, Revised 12/2020 County of Santa Clara Behavioral Health Services Medication Practice Guidelines Table 5: Atypicals Black Box Warnings, Pregnancy & Nursing Mother1-2 Black Box Warnings (BBW)

ALL MEDICATIONS LISTED BELOW Increased mortality in elderly patients with dementia -related psychosis

*Increased suicidality risk in children/adolescents ≤ 24 years old.

Medication Pregnancy Category Nursing Mother (NM) Aripiprazole (Abilify®)* May cause extrapyramidal and/or withdrawal Limited data from published literature report the presence of aripiprazole in human breast milk, symptoms in neonates with third trimester at relative infant doses ranging between 0.7% to 8.3% of the maternal weight-adjusted dosage. exposure There are reports of poor weight gain in breastfed infants exposed to aripiprazole and reports of inadequate milk supply in lactating women taking aripiprazole.

The development and health benefits of should be considered along with the mother’s clinical need for aripiprazole and any potential adverse effects on the breastfed infant from aripiprazole or from the underlying maternal condition. Asenapine (Saphris®) May cause extrapyramidal and/or withdrawal Lactation studies have not been conducted to assess the presence of asenapine in human milk, symptoms in neonates with third trimester the effects of asenapine on the breastfed infant, or the effects of asenapine on milk production. exposure Asenapine is excreted in rat milk.

The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for asenapine and any potential adverse effects on the breastfed infant from asenapine or from the underlying maternal condition. Brexpiprazole (Rexulti)* May cause extrapyramidal and/or withdrawal Lactation studies have not been conducted to assess the presence of brexpiprazole in human symptoms in neonates with third trimester milk, the effects of brexpiprazole on the breastfed infant, or the effects of brexpiprazole on exposure milk production.

Brexpiprazole is present in rat milk.

The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for brexpiprazole and any potential adverse effects on the breastfed infant from brexpiprazole or from the underlying maternal condition. Cariprazine (Vraylar®)* Based on animal data, may cause fetal harm. Lactation studies have not been conducted to assess the presence of cariprazine in human milk, Neonates exposed to antipsychotic drugs during the effects on the breastfed infant, or the effects on milk production. the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms Cariprazine is present in rat milk. following delivery The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for cariprazine and any potential adverse effects on the breastfed infant from cariprazine or from the underlying maternal condition. Clozapine (Clozaril®) There are no adequate or well-controlled studies Clozapine is present in human milk. of clozapine in pregnant women. Additional BBW: Because of the potential for serious adverse reactions in nursing infants from Clozapine, a 1. Agranulocytosis (Severe Neutropenia)

Section I, Page 17 of 26, Revised 12/2020 County of Santa Clara Behavioral Health Services Medication Practice Guidelines Table 5: Atypicals Black Box Warnings, Pregnancy & Nursing Mother1-2 2. Seizures Consider the risk of exacerbation of psychosis decision should be made whether to discontinue nursing or to discontinue the drug, taking into 3. Myocarditis, Cardiomyopathy, and Mitral when discontinuing or changing treatment with account the importance of the drug to the mother. Valve Incompetence antipsychotic medications during pregnancy and 4. Other adverse cardiovascular and postpartum. Neonates exposed to antipsychotic respiratory effects, including orthostatic drugs during the third trimester of pregnancy are hypotension, collapse, respiratory and/or cardiac arrest at risk for extrapyramidal and/or withdrawal symptoms following delivery Iloperidine (Fanapt®) May cause extrapyramidal and/or withdrawal Advise not to breast feed. symptoms in neonates with third trimester exposure Lumateperone (Caplyta®) May cause extrapyramidal and/or withdrawal Breastfeeding not recommended. symptoms in neonates with third trimester exposure Lurasidone (Latuda®)* May cause extrapyramidal and/or withdrawal Lactation studies have not been conducted to assess the presence of lurasidone in human milk, symptoms in neonates with third trimester the effects on the breastfed infant, or the effects on milk production. exposure Lurasidone is present in rat milk.

The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for lurasidone and any potential adverse effects on the breastfed infant from lurasidone or from the underlying maternal condition. Olanzapine (Zyprexa®) May cause extrapyramidal and/or withdrawal Olanzapine is present in human milk. There are reports of excess sedation, irritability, poor (Olanzapine IM) symptoms in neonates with third trimester feeding and (tremors and abnormal muscle movements) in infants exposure exposed to olanzapine through breast milk. Additional BBW for Zyprexa Relprevv®: 1. Patients are at risk for severe sedation There is no information on the effects of olanzapine on milk production. (including coma) and/or delirium after each injection and must be observed for at The developmental and health benefits of breastfeeding should be considered along with the least 3 hours in a registered facility with mother’s clinical need for olanzapine and any potential adverse effects on the breastfed child ready access to emergency response services. Because of this risk, Zyrexa from olanzapine or from the mother’s underlying condition Relprevv is available only through restricted distribution program called Zyrexa Relprevv Patient Care Program, and requires prescriber, healthcare facility, patient, and pharmacy enrollment. Olanzapine/Fluoxetine (Symbyax)* SSRI use, particularly later in pregnancy, may Safety and efficacy of Symbyax® for the treatment of bipolar I depression in patients under 10 increase the risk for persistent pulmonary years of age have not been established. Safety and efficacy of Symbyax® for treatment hypertension and symptoms of poor adaptation resistant depression in patients under 18 years of age have not been established (respiratory distress, temperature instability, feeding difficulty, hypotonia, irritability, tremor) in the neonate. Olanzapine may cause extrapyramidal symptoms and/or withdrawal symptoms in neonates with third trimester exposure. Paliperidone (Invega®) May cause extrapyramidal and/or withdrawal Limited data from published literature report the presence of paliperidone in human breast symptoms in neonates with third trimester milk.

Section I, Page 18 of 26, Revised 12/2020 County of Santa Clara Behavioral Health Services Medication Practice Guidelines Table 5: Atypicals Black Box Warnings, Pregnancy & Nursing Mother1-2 exposure There is no information on the effects on the breastfed infant, or the effects on milk production; however, there are reports of sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) in breastfed infants exposed to paliperidone’s parent compound, risperidone.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for paliperidone and any potential adverse effects on the breastfed child from paliperidone or from the mother’s underlying condition Quetiapine (Seroquel®)* May cause extrapyramidal and/or withdrawal Limited data from published literature report the presence of quetiapine in human breast milk symptoms in neonates with third trimester at relative infant dose of <1% of the maternal weight-adjusted dosage. There are no consistent exposure adverse events that have been reported in infants exposed to quetiapine through breast milk.

There is no information on the effects of quetiapine on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for quetiapine and any potential adverse effects on the breastfed child from quetiapine or from the mother’s underlying condition. Risperidone (Risperdal®) May cause extrapyramidal and/or withdrawal Limited data from published literature reports the presence of risperidone and its metabolite, symptoms in neonates with third trimester 9-hydroxyrisperidone, in human breast milk at relative infant dose ranging between 2.3% and exposure 4.7% of the maternal weight-adjusted dosage. There are reports of sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) in breastfed infants exposed to risperidone.

There is no information on the effects of risperidone on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for risperidone and any potential adverse effects on the breastfed child from risperidone or from the mother’s underlying condition. Ziprasidone (Geodon®) May cause extrapyramidal and/or withdrawal Limited data from a published case report indicate the presence of ziprasidone in human milk. symptoms in neonates with third trimester Although there are no reports of adverse effects on a breastfed infant exposed to ziprasidone exposure via breast milk, there are reports of excess sedation, irritability, poor feeding, and extrapyramidal symptoms (tremors and abnormal muscle movements) in infants exposed to other atypical antipsychotics through breast milk.

There is no information on the effects of ziprasidone on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ziprasidone and any potential adverse effects on the breastfed child from ziprasidone or from the mother's underlying condition. References: 1. Prescribing Information 2. Association, A. P. (2020). The American Psychiatric Association Practice Guideline for the Treatment of Patients With Schizophrenia. doi:10.1176/appi.books.9780890424841

Note: Bolded agents reflect formulary status at SCVMC

Section I, Page 19 of 26, Revised 12/2020 County of Santa Clara Behavioral Health Services Medication Practice Guidelines

Table 6: Pharmacokinetics & Drug-Drug Interactions1-4

Agent Brand Metabolism; CYP (Substrate) t1/2 (hr) Comments First Generation Chlorpromazine Thorazine® 2D6 (major), 1A2/3A4 Biphasic – initial 2 hours; terminal 30 hours • Use with caution in renal (not dialyzable) and hepatic impairment Prolixin® 2D6 4.4-16.4 • Contraindicated in hepatic impairment Fluphenazine decanoate • Use with caution in renal impairment Haldol® 2D6/3A4 (major), 1A2, 14-37 glucuronidation 21 (haloperidol decanoate) Loxitane® 1A2/2D6/3A4 (minor) Biphasic – 5 hours; terminal 19 hours • Pgp inhibitor Moban® 2D6 1.5 • Use with caution in hepatic impairment Trilafon® 2D6 (major), Perphenazine: 9-12 • Active metabolite (responsible for 70% of activity) 1A2/3A4/2C9/2C19 (minor) 7-hydroxyperphenazine: 10-19 • Contraindicated in liver damage • Use with caution in renal impairment Pimozide Orap® 1A2, 2D6, 3A4 55 • Use with caution in renal and hepatic impairment Thioridazine Mellaril® 2D6 (major), 2C19 21-24 • Moderate 2D6 inhibitor • Metabolite: (2x as potent as thioridazine) • Use with caution in hepatic impairment

Thiothixene Navane® 1A2 34 Stelazine® 1A2 3-12 • Contraindicated in hepatic disease Second Generation • Aripiprazole Abilify® 2D6, 3A4 Aripiprazole: 75 • Active metabolite: dehydro-aripiprazole Aristada® Dehydro-aripiprazole: 94 • No dose adjustments for mild-to-severe renal impairment (GFR 15-90 Abilify Maintena® 2D6 poor metabolizers: 146 mL/min) or mild-to-severe hepatic function (Child-Pugh score between 5-15)

Maintena® Factors Aripiprazole PO Dose 29.9 (300 mg) - 46.5 days (400 mg) - after q4 week Adjustments gluteal administrations Known 2D6 Poor Metabolizers Administer ½ of usual dose Aristada® Known 2D6 Poor Metabolizers & Administer ¼ of usual dose 53.9-57.2 days – q monthly, q6 week, and q2 Strong 3A4 Inhibitors Strong 3A4 or 2D6 inhibitors Administer ½ of usual dose month injections Strong 3A4 and 2D6 inhibitors Administer ¼ of usual dose Strong 3A4 inducers Double usual dose over 1-2 weeks

Factors Maintena® Dose Adjustments if P450 modulators are added for > 14 days 2D6 Poor Metabolizers 200 mg Patients taking Abilify Maintena 400 mg Strong 3A4 or 2D6 Inhibitor 300 mg 3A4 and 2D6 Inhibitor 200 mg 3A4 Inducers Avoid Use Patients taking Abilify Maintena 300 mg Strong 3A4 or 2D6 Inhibitor 200 mg 3A4 and 2D6 Inhibitor 160 mg 3A4 Inducers Avoid Use

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County of Santa Clara Behavioral Health Services Medication Practice Guidelines

Table 6: Pharmacokinetics & Drug-Drug Interactions1-4 Factors Aristada® Dose Adjustments if P450 modulators are added for > 14 days Strong 3A4 Inhibitor Reduce Aristada dose to next lower strength (but no adjustments if taking 441 mg, if tolerated) Poor 2D6 metabolizers: Reduce dose to 441 mg from 662 mg, 882 mg, or 1064 mg (but no adjustments if taking 441 mg, if tolerated) Strong 2D6 Inhibitor Reduce Aristada dose to next lower strength (but no adjustments if taking 441 mg, if tolerated) Poor 2D6 metabolizers: No dose adjustment required Strong 3A4 and 2D6 Inhibitor Avoid use if patients taking 662 mg, 882 mg, or 1064 mg (but no adjustments if taking 441 mg, if tolerated) 3A4 Inducer No dose adjustment for 662 mg, 882 mg, or 1064 mg dose; increase 441 mg dose to 662 mg.

Asenapine Saphris® 1A2 (major) and 24 • Weak 2D6 inhibitor glucuronidation, 2D6/3A4 • Intake of ~2-5 minutes after asenapine administration caused decrease (minor) in asenapine exposure; Avoid drinking and eating 10 minutes after administration. • No dose adjustments for mild-to-severe renal impairment (GFR 15-90 mL/min) or mild-to-moderate hepatic impairment (Child-Pugh A and B) • Contraindicated in severe hepatic impairment (Child-Pugh C) • If taking (2D6 substrate and inhibitor), reduce paroxetine dose by ½ Brexpiprazole Rexulti® 2D6, 3A4 91 • Moderate-to-severe hepatic impairment (Child-Pugh B or C) or CrCl <60 mL/min: o MDD max dose: 2 mg/day o Schizophrenia max dose: 3 mg/day Factors Brexipiprazole Dose Adjustments Known 2D6 Poor Metabolizers & Administer ¼ of usual dose Strong/moderate 3A4 Inhibitors Strong 3A4 or 2D6 inhibitors Administer ½ of usual dose Strong/moderate 2D6 and 3A4 Administer ¼ of usual dose inhibitors Strong 3A4 inducers Double usual dose and further adjust based on clinical response

Cariprazine Vraylar® 3A4 (major), 2D6 2-4 days • CrCl <30 mL/min and severe hepatic impairment (Child-Pugh C): not recommended Factors Cariprazine Dose Adjustments Strong 3A4 Inhibitors Administer ½ of usual dose 3A4 Inducers Not recommended

Section I, Page 21 of 26, Revised 12/2020

County of Santa Clara Behavioral Health Services Medication Practice Guidelines

Table 6: Pharmacokinetics & Drug-Drug Interactions1-4 Clozapine Clozaril® 1A2 (major), 4-66 (steady state 12 hours) • Active metabolite: N-desmethyl-clozapine 2C19/2C9/2D6/3A4 • Cigarette smoke can induce 1A2 (cannabis can induce 1A2; consider dose adjustment when patient stops or resumes smoking) Factors Clozapine Dose Adjustments Strong 1A2 Inhibitors Administer 1/3 of usual dose Strong 3A4 Inducers Not recommended Discontinuation of 3A4 or 1A2 Consider reducing clozapine dose Inducers (e.g. tobacco smoke) when 3A4 or 1A2 inducers are discontinued

Iloperidone Fanapt® 2D6 (major), 3A4 Extensive metabolizers • Use with caution in moderate hepatic impairment Iloperidone: 18 • Not recommended in severe hepatic impairment P88: 26 Factors Iloperidone Dose Adjustments Strong 2D6 or 3A4 Inhibitors Reduce dose P95: 23 Poor metabolizers Iloperidone: 33 P88: 37 P95: 31 Lumateperone Caplyta® UGT1A1, 3A4, 2C8, 1A2 18 hours (IV administration) • Administer without food (a high-fat meal with lumateperone can lower mean Cmax by 33% and increases AUC by 9%) • Not recommended in moderate-to-severe hepatic impairment (Child-Pugh B or Child-Pugh C) Factors Lumateperone Dose Adjustments 3A4 Inducers Avoid concomitant use Moderate or strong 3A4 Inhibitor Avoid concomitant use

Lurasidone Latuda® 3A4 Lurasidone: 18-40 • Weak 3A4 inhibitor ID-14283: 7.5-10 • Administer with food (≥350 calories) (administration with food increases AUC ~2x and Cmax ~3x) • Active metabolite: ID-14283, ID-14326 • CrCl < 50 mL/min: Initial dose 20 mg; max dose 80 mg • Moderate-to-severe hepatic impairment (Child-Pugh B or C): o Child-Pugh B: Initial dose 20 mg; max dose 80 mg o Child-Pugh C: Initial dose 20 mg; max dose 40 mg Factors Lurasidone Dose Adjustments Strong 3A4 Inhibitors Avoid concomitant use Moderate 3A4 Inhibitors Administer ½ of usual dose Strong 3A4 Inducers Avoid concomitant use Moderate 3A4 Inducers Increase dose

Olanzapine Zyprexa® 1A2 (major), 2D6, PO: 30 hours • Use with caution in hepatic impairment Relprevv® glucuronidation Relprevv: 30 days • Not removed by dialysis • Cigarette smoke can induce 1A2 (cannabis can induce 1A2; consider dose adjustment when patient stops or resumes smoking) • See package insert for specific dose adjustments regarding drug-drug interactions Paliperidone Invega® Pgp, ABCB1, 2D6, 3A4 Paliperidone: 23 • No dose adjustments in mild-to-moderate hepatic impairment, and not studied Sustenna® Renal impairment (CrCl <80 mL/min): 24-51 in severe hepatic impairment. Trinza® • Renal impairment: o CrCl < 10 mL/min: Not recommended for use

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County of Santa Clara Behavioral Health Services Medication Practice Guidelines

Table 6: Pharmacokinetics & Drug-Drug Interactions1-4 Sustenna® 39-234 mg o CrCl 10-49 mL/min: max dose 3 mg/day 25-49 days o CrCl 50-79 mL/min: max dose 6 mg/day Factors Paliperidone Dose Adjustments Trinza® 273-819 mg Strong 3A4 and Pgp Inducer May consider increasing 84-95 days (deltoid injection) paliperidone PO dose (avoid 118-139 days (gluteal injection) concomitant use in Sustenna® and Trinza®)

Divalproex sodium See package insert

Quetiapine Seroquel® 3A4 (major), 2D6 Quetiapine: 6-7 • Active metabolite: Norquetiapine Seroquel XR® Norquetiapine: 12 • IR: Can be taken with or without food • XR: Administer without food or with a light meal (~300 calories), (a light meal had no significant effect on AUC or Cmax of quetiapine) • Hepatic impairment: o IR: Initial dose 25 mg/day, increase by 25-50 mg/day to effective dose o ER: Initial dose 50 mg/day, increase by 50 mg/day to effective dose Factors Quetiapine Dose Adjustments Strong 3A4 Inhibitors Administer 1/6 of usual dose Strong 3A4 Inducers Administer ≤5x of usual dose with chronic treatment (>7-14 days) of strong 3A4 Inducers Discontinuation of strong 3A4 Reduce quetiapine dose by 5x within Inducers 7-14 days of 3A4 inducer discontinuation

Risperidone Risperdal® 2D6 (major), 3A4, Pgp, N- Risperidone: 3-20 • Weak 2D6 inhibitor Perseris® dealkylation 9-hydroxyrisperidone: 21-30 • Active metabolite: 9-hydroxyrisperidone Risperdal Consta® • Renal impairment: o CrCl ≥30 mL/min: Reduce dose o CrCl <30: Start at 0.5 mg BID, increase by ≤0.5 mg BID, may increase total dosage to >1.5 mg BID at 1 week or more • Hepatic impairment: Perseris®: 9-11 days o Child-Pugh A or Child-Pugh B: reduce dose o Child-Pugh C: Start at 0.5 mg BID, increase by ≤0.5 mg BID, may Consta®: 3-6 days increase total dosage to >1.5 mg BID at 1 week or more • See package insert for specific dose adjustments regarding drug-drug interactions Ziprasidone Geodon® 1A2/3A4 (minor) PO: 7 • Active metabolites: benzisothiazole sulfoxide and benzisothiazole sulfone IM: 2-5 • Administer with food (≥500 calories without regard to fat content, 3 absorption is increased ≤2x with food) • Ziprasidone not removed by dialysis • Use with caution in hepatic impairment. • IM ziprasidone contains cyclodextrin – use with caution in renal impairment • See package insert for specific dose adjustments regarding drug-drug interactions

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County of Santa Clara Behavioral Health Services Medication Practice Guidelines

Table 6: Pharmacokinetics & Drug-Drug Interactions1-4 Common DDI Offenders* 3A4 2D6 1A2 Pgp Inducers Inhibitors Inhibitors Inducers Inhibitors Inhibitors Weak Allopurinol (↑ digoxin AUC ≥1.25x) 200 mg Clobazam Clarithromycin Inhibitor: Verapamil ↑ substrate† AUC ≥1.25 to <2x Labetalol Ritonavir Inducer: Sertraline ↓ substrate† AUC ≥20% to <50% Moderate Phenobarbital Ciprofloxacin Oral (↑ digoxin AUC ≥2x with co-administration) Diltiazem Rifampin contraceptives Amiodarone Inhibitor: Fluconazole Ritonavir 800 mg ↑ substrate† AUC Fluvoxamine Smoking Clarithromycin ≥2 to <5x Verapamil Ritonavir Some HIV medications & antifungals Inducer: ↓ substrate† AUC ≥50% to <80% Strong Carbamazepine Clarithromycin Fluvoxamine Phenytoin Grapefruit juice Fluoxetine Inhibitor: Rifampin Paroxetine ↑ substrate† AUC St. John’s wort Some HIV ≥5x medications & antifungals Inducer: ↓ substrate† AUC ≥80% *Not a comprehensive list of all potential drug-drug interactions; please refer to the desired drug’s prescribing information for additional details and dosage adjustments, as necessary. †According to the FDA, these area under the curve (AUC) changes are applicable to “sensitive” substrates; not all antipsychotics are “sensitive” substrates and yield the specific degree of AUC changes; please refer to the desired drug’s prescribing information for additional details and dosage adjustments, as necessary.

References: 1. Prescribing Information 2. Association, A. P. (2020). The American Psychiatric Association Practice Guideline for the Treatment of Patients With Schizophrenia. doi:10.1176/appi.books.9780890424841 3. Lincoln, J., Stewart, M. E., & Preskorn, S. H. (2010). How Sequential Studies Inform : Evaluating the Effect of Food Intake on Optimal Bioavailability of Ziprasidone. Journal of Psychiatric Practice, 16(2), 103-114. doi:10.1097/01.pra.0000369971.64908.dc 4. Center for Drug Evaluation and Research. (n.d.). Table of Substrates, Inhibitors and Inducers. Retrieved December 01, 2020, from https://www.fda.gov/drugs/drug-interactions- labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers

Section I, Page 25 of 26, Revised 12/2020

County of Santa Clara Behavioral Health Services Medication Practice Guidelines

Table 7: Atypicals Serious Adverse Effects1-2 Seizures QTc Syncope & Tardive Leukopenia, Other ADRs (relative risk) prolongation Orthostatic Dyskinesia Neutropenia, (relative risk) Hypotension (relative risk) Agranulocytosis (relative risk) First Generation Antipsychotics Chlorpromazine ++ +++ +++ +++ X Fluphenazine + ++ + +++ X Haloperidol + ++ + +++ X Loxapine + ++ ++ ++ X Molindone + ++ + ++ X Perphenazine + ++ ++ ++ X Pimozide +++ +++ + +++ X Thioridazine ++ +++ +++ + X • Pigmentary retinopathy • Avoid use if concomitant use of drugs that inhibit 2D6 or prolong the QTc interval, or if QTc interval is >450 msec Thiothixene +++ ++ + +++ X Trifluoperazine + ++ + ++ X Second Generation Antipsychotics Aripiprazole + + + + X • Impulse control disorders Asenapine + ++ ++ ++ X • Oral hypoesthesia Brexpiprazole + ++ + + X • Impulse control disorders Cariprazine + ++ + + X (Late-occurring ADRs—monitor several weeks after starting) Clozapine +++ ++ +++ + X Possible • Paralytic ileus • Severe Constipation • Fever with initiation Infrequent/Rare • Myocarditis and Cardiomyopathy • Severe Neutropenia Iloperidone + +++ +++ + X • Dose-related ↑SCr in some patients • Priapism Lumateperone X Lurasidone + + + ++ X Olanzapine ++ ++ ++ + X • DRESS Paliperidone + ++ ++ ++ X • GI obstruction Quetiapine ++ ++ ++ + X • Cataracts (lens changes) Risperidone + ++ ++ ++ X • Reported intraoperative floppy iris syndrome Risperdal Consta® • Priapism • Thrombotic Thrombocytopenia Purpura (TTP) Ziprasidone + +++ ++ + X • DRESS References: 1. Prescribing Information 2. Association, A. P. (2020). The American Psychiatric Association Practice Guideline for the Treatment of Patients With Schizophrenia. doi:10.1176/appi.books.9780890424841

Section I, Page 25 of 26, Revised 12/2020 County of Santa Clara Behavioral Health Services Medication Practice Guidelines

Table 8: Atypicals Common Adverse Effects1 Weight Gain & Hyper- Prolactin Anticholinergic Orthostatic EPS/TD Sedation Diabetes cholesterolemia Elevation Side Effects Hypotension Mellitus

Chlorpromazine ++/++ + ++/+++ + +++ +++ +++

Fluphenazine* ++/+ + +++/+++ +++ + + +

Haloperidol* ++/+ + +++/+++ +++ + + +

Loxapine +/+ + ++/++ ++ ++ + ++

Molindone +/+ + ++/++ ++ ++ + +

Perphenazine ++/+ + ++/++ ++ ++ ++ ++

Pimozide +/+ + +++/+++ +++ + + +

Thioridazine ++/+ + +/+ ++ +++ +++ +++

Thiothixene +/+ + +++/+++ +++ + + +

Trifluoperazine ++/+ + ++/++ ++ + ++ +

Aripiprazole* +/+ + ++/+ + + + +

Asenapine ++/++ ++ ++/++ ++ ++ + ++

Brexpiprazole +/+ ++ +/+ ++ + + +

Cariprazine ++/+ + +/+ + ++ ++ +

Clozapine +++/+++ +++ +/+ + +++ +++ +++

Iloperidone ++/++ + +/+ ++ ++ + +++

Lurasidone +/++ ++ ++/++ ++ ++ + +

Olanzapine* +++/+++ +++ +/+ ++ +++ ++ ++

Paliperidone* ++/+ ++ ++/++ +++ + + ++

Quetiapine ++/++ +++ +/+ + +++ ++ ++

Risperidone* ++/++ + ++/++ +++ ++ + ++

Ziprasidone +/+ + +/+ ++ ++ + ++ *Injectable formulations may have injection-site reactions as a potential adverse effect.

References: 1. Association, A. P. (2020). The American Psychiatric Association Practice Guideline for the Treatment of Patients With Schizophrenia. doi:10.1176/appi.books.9780890424841

Section I, Page 26 of 26, Revised 12/2020