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Criteria for Outpatient Use Guidelines

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Atypical Antipsychotics

[Criteria developed, February 1997; Revised, March 1998; March 1999; April 2000; April 2001; April 2002; May 2003; October 2006; December 2006; March 2007; May 2010; June 2010]

Information on indications for use or diagnosis is assumed to be unavailable. All criteria may be applied retrospectively; prospective application is indicated with [*].

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1.* Dosage

Adults
Oral atypical antipsychotics are FDA-approved for use in schizophrenia, bipolar I disorder, bipolar disorder with mixed episodes, depressive episodes associated with bipolar disorder, bipolar mania, schizoaffective disorder, agitation associated with schizophrenia or bipolar mania, adjunctive therapy in major depressive disorder, and treatment-resistant schizophrenia. Maximum recommended adult doses for atypical antipsychotics are summarized in Table 1. Dosages exceeding these recommendations will be reviewed.

TABLE 1
Atypical Antipsychotics - Maximum Recommended Doses
DRUG MAXIMUM DOSE
Aripiprazole (Abilify®, Abilify Discmelt®) oral tablets, disintegrating tablets: 30 mg once daily
oral solution: 25 mg/day as a single dose
Asenapine (Saphris®) sublingual tablet: 20 mg/day, in two divided doses
Clozapine (Clozaril®, FazaClo®) 900 mg/day, as single dose, or in two or three divided doses
Iloperidone (Fanapt®) 24 mg/day
Olanzapine (Zyprexa®, Zyprexa Zydis®) 20 mg/day, as a single dose
Paliperidone (Invega®) 12 mg/day
Quetiapine (Seroquel®, Seroquel XR®) immediate-release: 800 mg/day, in two or three divided doses
extended-release: 800 mg/day, as a single dose
Risperidone (Risperdal®, Risperdal M-TAB®, generics) 8 mg/day*
Ziprasidone (Geodon®) 200 mg/day, in two divided doses

* doses up to 16 mg/day have demonstrated efficacy in clinical trials; however, doses of 4 to 8 mg/day tended to produce the maximal effect.

Combination therapy with the atypical antipsychotic, olanzapine, and the selective serotonin re-uptake inhibitor, fluoxetine, is FDA-approved for the management of depressive episodes associated with bipolar I disorder and treatment-resistant depression. Doses exceeding the maximum adult recommended doses summarized in Table 2 will be reviewed.

Table 2
Atypical Antipsychotics (Combination Therapy) – Adult Maximum Recommended Doses
DRUG MAXIMUM DOSE
Olanzapine/ fluoxetine (Symbyax®) olanzapine 18 mg/ fluoxetine 75 mg once daily

Pediatrics
Risperidone has been FDA-approved to manage symptoms of irritability in autistic children > 5 years of age and adolescents, and has recently gained FDA-approved indications for bipolar mania in children and adolescents 10 to 17 years of age and schizophrenia in adolescents 13 to 17 years of age.  Aripiprazole has received recent FDA approval for management of schizophrenia in adolescents 13 to 17 years of age, bipolar disorder with or without psychotic features in children 10 to 17 years of age, and irritability associated with autistic disorder in children 6 to 17 years of age.  Olanzapine has been granted FDA approval for bipolar disorder and schizophrenia in adolescents 13 years of age and older, while quetiapine received FDA approval for acute treatment of bipolar disorder mania episodes in children and adolescents 10 to 17 years of age and schizophrenia management in adolescents 13-17 years of age.  Asenapine, clozapine, iloperidone, paliperidone, and ziprasidone are not recommended for use in pediatric patients as safety and efficacy have not been established in this patient population.  Atypical antipsychotic pediatric dosages are summarized in Table 3.

Table 3
Atypical Antipsychotics – Pediatric Maximum Recommended Dosages
DRUG MAXIMUM RECOMMENDED DOSE
Aripiprazole 10-17 years of age:  30 mg once daily (oral tablets, disintegrating tablets); 25 mg once daily (oral solution)
6-9 years of age: 15 mg/day as a single dose
Olanzapine bipolar disorder, schizophrenia (13 to 17 years of age):  20 mg once daily
Quetiapine* manic episodes associated with bipolar disorder-acute treatment (10 to 17 years of age):  600 mg daily, in 2 to 3 divided doses*
schizophrenia (13 to 17 years of age):  800 mg daily, in 2 to 3 divided doses*
Risperidone bipolar mania (10-17 years of age), schizophrenia (13-17 years of age):  6 mg daily
irritability in autistic disorder:   < 20 kg:  1 mg/day; > 20 kg:  2.5 mg/day; > 45 kg:  3 mg/day

*immediate-release tablets only

2. Duration of Therapy

Atypical antipsychotics are indicated for use in the management of schizophrenia and psychotic disorders. Therefore, there is no basis for limiting treatment duration with these atypical antipsychotics as these agents are utilized in the management of chronic disorders.

3.* Duplicative Therapy

Combined therapy with multiple antipsychotic medications has been evaluated in patients with treatmentresistant
schizophrenia. Open studies, case reports, and clinical trials have observed favorable results following concurrent therapy with either atypical antipsychotics plus conventional antipsychotic agents, or clozapine in conjunction with an additional atypical antipsychotic in clozapine-refractory patients. Further controlled trials are necessary to identify patients and circumstances in which combination therapy should be utilized as well as risks and benefits of concurrent therapy.

Neuroleptics should be used concomitantly during transitional periods lasting up to four weeks when switching patients to a different antipsychotic agent.

4.* Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens which may result in clinically significant drug-drug interactions.

Drug interactions considered clinically relevant for atypical antipsychotics are summarized in Table 4.  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:

Table 4
Drug-Drug Interactions for Atypical Antipsychotics
TARGET DRUG INTERACTING DRUG INTERACTION RECOMMENDATIONS CLINICAL SIGNIFICANCE
atypical antipsychotics (AA) metoclopramide potential for increased extrapyramidal symptoms (EPS) and neuroleptic malignant syndrome (NMS) as metoclopramide may also cause EPS and, rarely, NMS combination contraindicated by metoclopramide manufacturer; if combination necessary, monitor for signs/symptoms of EPS or NMS-discontinue metoclopramide if symptoms develop contraindicated (DrugReax)
1-severe (Clinical Pharmacology)
atypical antipsychotics antihypertensive agents potential for enhanced antihypertensive effects due to AA-associated alpha1-adrenergic receptor antagonism use cautiously together; monitor for amplified hypotensive effects 3-moderate (Clinical Pharmacology)
atypical antipsychotics CNS depressants potential for additive CNS effects use cautiously together; observe patients for enhanced CNS adverse effects 3-moderate (Clinical Pharmacology)
clozapine myelopsuppressive (antineoplastic) drugs potential for additive bone marrow suppressive effects concurrent administration contraindicated 1-severe (Clinical Pharmacology)
clozapine carbamazepine increased risk of additive bone marrow-suppressing effects, including agranulocytosis avoid concurrent use; choose alternative anticonvulsant major (DrugReax)
4 (DIF)
2-major (Clinical Pharmacology)
clozapine drugs affecting seizure threshold (e.g., tramadol) increased seizure risk as clozapine decreases seizure threshold avoid drug combination if possible; if combination necessary, closely monitor patients for seizure activity and discontinue therapy as indicated major (DrugReax)
2-major (Clinical Pharmacology)
clozapine, iloperidone, olanzapine, paliperidone, quetiapine, risperidone, ziprasidone levodopa, dopamine agonists AA other than aripiprazole may antagonize levodopa, dopamine agonist antiparkinsonian activity by blocking dopamine (D2) receptors administer concurrently cautiously; monitor for loss of levodopa, dopamine agonist therapeutic effect moderate (DrugReax)
2-major (Clinical Pharmacology)
asenapine, iloperidone, paliperidone, quetiapine, ziprasidone QTc interval-prolonging medications  potential for increased cardiotoxicity (e.g., torsades de pointes, cardiac arrest) due to additive QT interval prolongation avoid concurrent use; if combination necessary, closely monitor cardiac function; discontinue therapy in patients with QTc measurements > 500 msec major (DrugReax)
1 (DIF)
1-severe, 2-major (Clinical Pharmacology)
clozapine, olanzapine CYP1A2 inducers (e.g., carbamazepine**, phenobarbital, phenytoin, ritonavir*, rifampin) potential for reduced clozapine, olanzapine serum concentrations and worsening of psychosis monitor clozapine, olanzapine efficacy in patients; adjust doses as necessary when CYP1A2 inducer added, deleted, or changed to therapeutic regimen moderate (Drug Reax)
1, 2, 4 (DIF)
2-major (Clinical Pharmacology)
asenapine, clozapine, olanzapine CYP1A2 inhibitors (e.g., fluvoxamine) potential for decreased AA clearance, increased AA serum concentrations and enhanced pharmacologic/adverse effects (seizures, hypotension) as clozapine, olanzapine metabolized by CYP1A2 if drug combination necessary, used reduced clozapine dosages and closely monitor for adverse events moderate (DrugReax)
1 (DIF)
2-major (Clinical Pharmacology)
aripiprazole, clozapine, iloperidone, quetiapine, ziprasidone CYP3A4 inhibitors (e.g., ketoconazole, ritonavir*) potential for decreased AA clearance, increased AA serum concentrations, and enhanced pharmacologic/adverse effects as AAs metabolized by CYP3A4 monitor for enhanced AA pharmacologic/adverse effects and adjust doses as necessary moderate (DrugReax)
2 (DIF)
2-major, 3-moderate (Clinical Pharmacology)
aripiprazole, clozapine, olanzapine, quetiapine, risperidone, ziprasidone CYP3A4 inducers (e.g., carbamazepine**, phenytoin) potential for significant reductions in AA plasma concentrations (by as much as 50%) due to enhanced AA hepatic microsomal metabolism monitor AA efficacy in patients; adjust doses as necessary when CYP3A4 inducer added, deleted, or changed to therapeutic regimen moderate (DrugReax)
2, 3, 4 (DIF)
3-moderate (Clinical Pharmacology)
aripiprazole, asenapine, iloperidone CYP2D6 inhibitors (e.g., quinidine, select SSRIs, ritonavir) potential for decreased AA clearance and increased AA serum concentrations and enhanced pharmacologic/adverse effects as AAs metabolized by CYP2D6 monitor for enhanced AA pharmacologic/adverse effects and adjust doses as necessary (recommended to reduce aripiprazole, iloperidone doses by 50% when administered in conjunction with CYP2D6 inhibitor) moderate (DrugReax)
2 (DIF)
2-major, 3-moderate (Clinical Pharmacology)

*Ritonavir inhibits clozapine metabolism through CYP3A4 inhibition, but induces olanzapine metabolism through CYP1A2 enzyme induction. 
**Carbamazepine induces olanzapine metabolism through CYP1A2 enzyme induction and induces clozapine metabolism through CYP3A4 induction.

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Prepared by: Drug Information Service, The University of Texas Health Science Center at San Antonio, and the College of Pharmacy, The University of Texas at Austin.