Atypical Antipsychotics Step Therapy And

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Atypical Antipsychotics Step Therapy and

Quantity Limit Criteria Program Summary

This step therapy program applies to Commercial, GenPlus, NetResults A series, NetResults F series and Health Insurance Marketplace.

OBJECTIVE The intent of the Atypical Antipsychotic Step Therapy (ST) program is to encourage the use of cost-effective generic atypical antipsychotic agents over brand atypical antipsychotic agents and to accommodate for use of brand atypical antipsychotic agents when generic atypical antipsychotic agents cannot be used due to previous trial, documented intolerance, FDA labeled contraindication, or hypersensitivity. The criteria for Abilify and Abilify Discmelt encourage the use of cost-effective generic atypical antipsychotic agents or generic FDA approved agents for Tourette’s Disorder, and accommodate for the use of Abilify and Abilify Discmelt when generic atypical antipsychotic agents or generic FDA approved Tourette’s Disorder agents cannot be used due to previous trial, documented intolerance, FDA labeled contraindication, or hypersensitivity. The use of these agents for the off-label use “dementia- related psychosis” will be accommodated for shorter approval timeframes, due to concerns with safety of their use in the dementia population and based on published regulations and guidelines. The program also allows for continuation of therapy if a patient has been previously stabilized on the requested brand atypical antipsychotic. All dosage forms of the brand atypical antipsychotics listed will be included as targets in the step therapy program.

TARGET DRUGS Abilify® (aripiprazole)a Abilify Discmelt® (aripiprazole)a Abilify Maintena™ (aripiprazole) Aristada™ (aripiprazole lauroxil injection) Clozaril® (clozapine)a Fanapt® (iloperidone) FazaClo®, clozapine ODTa,b (clozapine) Geodon® (ziprasidone)a Invega® (paliperidone)a Invega® Sustenna™ (paliperidone) Invega Trinza™ (paliperidone injection) Latuda® (lurasidone) Rexulti® (brexpiprazole) Risperdal® (risperidone)a Risperdal® M-Tab® (risperidone)a Risperdal® Consta® (risperidone) Saphris® (asenapine) Seroquel® (quetiapine)a Versacloz™ (clozapine) Vraylar™ (cariprazine) Zyprexa® (olanzapine)a Zyprexa® Zydis® (olanzapine)a Zyprexa® Relprevv™ (olanzapine) a – generic available; not a target in step therapy program b – MSC M product available; included as target in step therapy program

PRIOR AUTHORIZATION CRITERIA FOR APPROVAL Brand Atypical Antipsychotics will be approved when ONE of the following is met: 1. The patient is requesting Abilify OR Abilify Discmelt for Tourette’s Disorder AND ONE of the following: a. The patient’s medication history includes the use of haloperidol OR pimozide in the past 90 days OR b. The patient has a documented intolerance, FDA labeled contraindication, or hypersensitivity to either generic haloperidol OR pimozide OR 2. The patient’s medication history includes use of a generic atypical antipsychotic agent in the past 90 days OR 3. There is documentation that the patient is currently using the requested brand atypical antipsychotic agent OR 4. The prescriber states the patient is using the requested brand atypical antipsychotic agent AND is at risk if therapy is changed OR 5. The patient has a documented intolerance, FDA labeled contraindication, or hypersensitivity to at least one generic atypical antipsychotic agent

Length of approval: for dementia-related psychosis: 3 months for initial approval; 6 months for renewals for all other indications: 12 months

NOTE: If Quantity Limit program also applies, please refer to Quantity Limit documents.

FDA APPROVED INDICATIONS AND DOSAGE1-10,20-23,28,31,32,38,39,45

Agent Dosing Ranges

Recurrent

(acute (acute

Schizophrenia (acute) Schizophrenia (maintenance) Schizoaffective (acute) Acute agitation Resistant Schizophrenia Risk of suicidalbehavior BPD manic/mixed) BPD depressive) BPD (maintenance) Autism (irritability) MDD Tourette’s Disorder Doses/Day – 1 dose/day Schizophrenia and BPD (mania): Start 10-15 mg/day; maximum 30 mg/day. MDD (adjunctive): Start 2-5 mg/day. Range: 2-15 mg/day. Autism: Start 2 mg/day, increase if needed. Range: 5-15 mg/day. Abilify, Acute agitation (IM): 9.75 mg aripiprazole ‡ (recommended dose); range is ✓ bc c (tablet, ✓ ✓ ✓ ✓ ✓ ✓ ✓ 5.25 – IM solution, 15 mg. Safety of total daily dose injection) >30 mg or dosing interval <2 hours not evaluated. 1. Tourette’s Disorder: Patients < 50 kg – initial 2 mg/day, recommended 5 mg/day, maximum 10 mg/day Patients > 50 kg – initial 2 mg/day, recommended 10 mg/day, maximum 20 mg/day Doses/Day – 1 dose/day Schizophrenia and BPD (mania): Start 10-15 mg/day; maximum 30 mg/day. MDD (adjunctive): Start 2-5 Abilify mg/day. Range: 2-15 mg/day. Discmelt ‡ Autism: Start 2 mg/day, increase bc c (oral ✓ ✓ ✓ ✓ ✓ ✓ ✓ if needed. Range: 5-15 mg/day. disintegratin 2. Tourette’s Disorder: g tablet) Patients < 50 kg – initial 2 mg/day, recommended 5 mg/day, maximum 10 mg/day Patients > 50 kg – initial 2 mg/day, recommended 10 mg/day, maximum 20 mg/day

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Agent Dosing Ranges

Recurrent

(acute (acute

Schizophrenia (acute) Schizophrenia (maintenance) Schizoaffective (acute) Acute agitation Resistant Schizophrenia Risk of suicidalbehavior BPD manic/mixed) BPD depressive) BPD (maintenance) Autism (irritability) MDD Tourette’s Disorder Tolerability should be established with oral aripiprazole prior to starting treatment with Abilify Maintena. The recommended starting/maintenance dose of Abilify Abilify Maintena is 400 mg Maintena monthly (no sooner than 26 aripiprazole days after the previous ✓ (extended- injection). After the first release injection, continue treatment injection) with oral aripiprazole or other oral antipsychotic for 14 consecutive days. If there are adverse reactions with the 400 mg dosage, consider reducing the dosage to 300 mg once monthly. 441 mg, 662 mg, or 882 mg per month; or 882 mg every 6 weeks. Aristada (aripiprazole ✓ lauroxil injection)

Clozaril, Doses/Day – 2-3 divided doses FazaClo Start 12.5 mg once or twice daily, clozapine‡ titrate up to 300-450 mg/day over ✓ ✓ (tablet, oral two weeks, then up to maximum disintegrat- 600-900 mg/day, based on ing tablet) response. Fanapt Doses/Day – 2 divided doses iloperidone Start 1 mg twice daily, titrate to (tablet) ✓* 12 mg twice daily over 7 days; control of symptoms delayed due to titration. Target dose: 12-24 mg/day.

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Agent Dosing Ranges

Recurrent

(acute (acute

Schizophrenia (acute) Schizophrenia (maintenance) Schizoaffective (acute) Acute agitation Resistant Schizophrenia Risk of suicidalbehavior BPD manic/mixed) BPD depressive) BPD (maintenance) Autism (irritability) MDD Tourette’s Disorder Doses/Day – 2 divided doses Schizophrenia: Start 20 mg twice daily; titrate up to 80 mg Geodon twice daily. BPD (mania): Start 40 mg twice ziprasidone‡ ✓ c ✓* ✓ ✓ ✓ daily. Range: 40-80 mg twice (capsule, IM daily. injection) Acute agitation (IM): 10 mg every 2 hours; 20 mg every 4 hours; up to maximum of 40 mg/day. Invega Doses/Day – 1 dose/day paliperidone‡ Start 6 mg/day (tab); range 3-12 (extended- ✓ ✓ ✓ mg/day (maximum). release tablet) Invega Tolerability should be Sustenna established with oral paliperidone paliperidone or oral risperidone (ER inj - IM) prior to initiating Invega Sustenna. 3. Initially, 234 mg on day 1 and ✓ ✓ 156 mg one week later. Recommended monthly maintenance dose is 117 mg; may benefit from lower or higher doses. Recommended range 39 mg to 234 mg based on tolerability/efficacy. Invega 4. 273-829 mg once every 3 months Trinza ✓ paliperidone (injection) Doses/Day 1 dose/day Schizophrenia: Start at 40 Latuda mg/day; Maximum recommended lurasidone ✓ ✓ dose 160 mg/day. (tablet) BPD (depression): Start at 20 mg/day; Maximum recommended dose 120 mg/day MDD: Start at 0.5-0.1 mg/day; Rexulti Recommended at 2 mg/day; Maximum of 3 mg/day brexpiprazole ✓ ✓ ✓c Schizophrenia: 1 mg/day; (tablet) Recommended at 2-4 mg/day; Maximum of 4 mg/day

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Agent Dosing Ranges

Recurrent

(acute (acute

Schizophrenia (acute) Schizophrenia (maintenance) Schizoaffective (acute) Acute agitation Resistant Schizophrenia Risk of suicidalbehavior BPD manic/mixed) BPD depressive) BPD (maintenance) Autism (irritability) MDD Tourette’s Disorder Doses/Day 1-2 divided doses Schizophrenia: Start 2 mg/day; Risperdal Effective dose range: 4-16 risperidone‡ mg/day. (tablet, oral BPD (mania): Start 2-3 mg/day; ✓ ✓ ✓ ✓ disintegrat- Effective dose range: 1-6 mg/day. Autism: Start 0.25 – 0.5 mg/day; ing tablet, target dose 0.5 – 1 mg/day. solution) Effective dose range 0.5-3 mg/day. (autism dosing is weight based) Tolerability should be established with oral risperidone prior to starting treatment with Risperdal Consta. Give oral risperidone (or other antipsychotic) with Risperdal first Risperdal Consta injection Consta and continue for 3 weeks (then ✓ ✓ ✓ ✓ risperidone stop oral). (LA inj - IM) Dosed 25 mg IM every 2 weeks. If no response, may use 37.5 mg or 50 mg. Maximum is 50 mg IM every 2 weeks. Do not make upward dose adjustment more frequently than every 4 weeks. Doses/Day – 2 divided doses Schizophrenia: Start and target Saphris dose is 5 mg twice daily. asenapine ✓ ✓ ✓ b,c BPD Adults: Start and target (sublingual dose 5-10 mg twice daily. tablet) BPD Pediatrics: Starting dose of 2.5 mg twice daily with target dose of 2.5-10 mg twice daily Doses/Day - 2 divided doses Schizophrenia: Start 25 mg twice daily and titrate up to 300- 400 mg/day Range: 150-750 Seroquel mg/day. c quetiapine‡ ✓ ✓ ✓ ✓ ✓ BPD (mania): Titrate from 100 (tablet) mg to, 400 mg on first 4 days. Range: 400-800 mg/day. BPD (depression): Start 50 mg; titrate to recommended dose 300 mg.

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Agent Dosing Ranges

Recurrent

(acute (acute

Schizophrenia (acute) Schizophrenia (maintenance) Schizoaffective (acute) Acute agitation Resistant Schizophrenia Risk of suicidalbehavior BPD manic/mixed) BPD depressive) BPD (maintenance) Autism (irritability) MDD Tourette’s Disorder Doses/Day – 1 dose/day Schizophrenia: Start 300 mg/day. Range: 400-800 mg/day. Seroquel BPD (mania): Start with 300 mg XR and 600 mg on days 1 and 2, quetiapine‡ respectively. Then range of 400- ✓ ✓ ✓ ✓ ✓ c ✓ c (extended- 800 mg/day. BPD (depression): Start 50 mg; release titrate to recommended dose 300 tablet) mg. MDD (adjunctive): Start 50 mg (days 1 & 2); then 150 mg (days 3 & 4). Range: 150-300 mg/day. Doses/Day – in divided doses Versacloz Start 12.5 mg once or twice daily, clozapine titrate up to 300-450 mg/day over ✓ ✓ (oral two weeks, then up to maximum 900 mg/day, in 100 mg suspension) increments once or twice weekly, based on response. Doses/Day - 1 dose/day Schizophrenia: Vraylar Start: 1.5 mg/day cariprazine ✓ ✓ Range: 1.5-6 mg/day (capsule) Acute Manic Mixed BPD: 5. Start: 1.5 mg/day Range: 3-6 mg/day Doses/Day – 1 dose/day Schizophrenia: Start 5-10 mg once daily. Target 10 mg/day. Zyprexa BPD (mania): Start 10-15 mg olanzapine‡ once daily. (tablet, oral ✓ ✓ ✓ ✓ ✓ a ✓b ✓a BPD (depression) and disintegrat- IM Treatment resistant MDD: Start ing tablet, 5 mg olanzapine w/ 20 mg injection) fluoxetine once daily. Acute agitation (IM): 10 mg Maximum 3 doses 2 to 4 hours apart.

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Agent Dosing Ranges

Recurrent

(acute (acute

Schizophrenia (acute) Schizophrenia (maintenance) Schizoaffective (acute) Acute agitation Resistant Schizophrenia Risk of suicidalbehavior BPD manic/mixed) BPD depressive) BPD (maintenance) Autism (irritability) MDD Tourette’s Disorder Tolerability should be established with oral olanzapine prior to treatment Zyprexa with Zyprexa Relprevv Relprevv ✓ ✓ Dose range is 150 mg to 300 olanzapine mg IM every 2 weeks or 405 (ER inj -IM) mg IM every 4 weeks. Doses > 300 mg every 2 weeks or 405 mg every 4 weeks not studied. Dosing chart in PI. MDD=major depressive disorder BPD=bipolar disorder a= adjunctive with fluoxetine b= monotherapy c= adjunctive d= associated with schizophrenia or BPD e= age >5 *Iloperidone and ziprasidone may have greater capacity to prolong QT/QTc interval compared to other antipsychotic drugs. Whether ziprasidone or iloperidone will cause torsade de pointes or increase rate of sudden death is not yet known. ‡ Generics available

CLINICAL RATIONALE Schizophrenia Previous guidelines in the United States, Europe, and the United Kingdom recommended atypical antipsychotics as first-line treatment for schizophrenia, primarily because they were thought to carry a lower potential risk of extrapyramidal side effects. However, updated evidence from systematic reviews and clinical trials suggests that choosing the most appropriate drug and formulation for an individual may be more important than the drug group. These guidelines now reflect less of a preference for one group of antipsychotics over another, acknowledging that all antipsychotics have adverse effects.11-14,24,33,34

The initial choice of antipsychotic medication or the decision to switch to a new antipsychotic should be made on an individual basis, considering prior treatment response, side effect experience; adherence history; relevant medical history, risk factors; individual medication side effect profile; and long-term treatment planning. Generally, antipsychotic medications other than clozapine and olanzapine, are recommended as first-line treatment for persons with schizophrenia experiencing their first acute positive symptom episode.14

Second-generation (atypical) antipsychotics are now used more commonly than first- generation drugs, even though controlled trials have failed to demonstrate a clear advantage in efficacy with the newer drugs, except for clozapine and possibly olanzapine. Clozapine can be effective for psychotic symptoms in patients not responding to other drugs, and appears to be more effective vs other antipsychotics in decreasing the risk of suicide. Although clozapine is the most effective antipsychotic drug, it is reserved for refractory disease due to its potential hematologic toxicity and strict monitoring requirements. Olanzapine may have some slight advantages over other drugs in efficacy, but its adverse effects on weight and metabolism may

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© Copyright Prime Therapeutics LLC. 11/2016 All Rights Reserved be unacceptable for long term use. Other second-generation anti psychotics are not clearly more effective than first-generation drugs, but they have a lower risk of tardive dyskinesia. Some patients who do not respond to one antipsychotic may respond to another. Long-acting injectable antipsychotics may be useful when adherence is a problem.15

Bipolar Disorder Lithium is generally the drug of choice for maintenance treatment of bipolar disorder. Lamotrigine may be used to prevent recurrent depressive episodes. Lithium, valproate, and second-generation antipsychotics are similarly effective for treatment of mania. Quetiapine or a combination of olanzapine and fluoxetine are effective for treatment of depression in patients with bipolar disorder.15

Atypical antipsychotics are less likely to produce extrapyramidal side effects than typical antipsychotics used at conventional doses, which is of particular significance in bipolar disorder because of an apparently greater risk of motor side effects, including tardive dyskinesia.17

The Canadian Network for Mood and Anxiety Treatments (CANMAT)/International Society for Bipolar Disorders (ISBD)- Bipolar Disorder (2013) guideline recommends the following.39 . First line treatment for acute mania (monotherapy): lithium, divalproex, divalproex ER, olanzapine (caution metabolic effects), risperidone, quetiapine, quetiapine XR, aripiprazole, ziprasidone, asenapine, paliperidone ER. Adjunctive therapy with lithium or divalproex: risperidone, quetiapine, olanzapine, aripiprazole, asenapine. . First line treatment for acute bipolar depression (monotherapy): lithium, lamotrigine, quetiapine, quetiapine XR. Combination therapy: lithium or divalproex + SSRI (except paroxetine), olanzapine + SSRI (except paroxetine), lithium + divalproex, lithium or divalproex + bupropion. The management of a bipolar depressive episode with antidepressants remains complex. The clinician must balance the desired effect of remission with the undesired effect of switching. . First line treatment for maintenance therapy of bipolar disorder (monotherapy): lithium, lamotrigine (limited efficacy in preventing mania), divalproex, olanzapine (caution metabolic effects), quetiapine, risperidone LAI (for prevention mania), aripiprazole (for prevention mania). Adjunctive therapy with lithium or divalproex: quetiapine, risperidone LAI (for prevention mania), aripiprazole (for prevention mania), ziprasidone (for prevention mania).

The World Federation of Societies of Biological Psychiatry (WFSBP, 2012) states it is not possible to give an overall recommendation for long-term treatment of bipolar disorder. Different scenarios have to be examined separately: prevention of mania, depression, or an episode of any polarity, both in acute responders and in patients treated de novo. Treatment might differ in bipolar II patients or rapid cyclers, as well as in special subpopulations. Several medications are preventive against new manic episodes, whereas the current state of research into the prevention of new depressive episodes is less satisfactory. Lithium continues to be the substance with the broadest base of evidence across treatment scenarios. Agents with good evidence and good benefit/risk ratios include aripiprazole, lamotrigine, lithium, and quetiapine. Risperidone and olanzapine are considered to have good evidence with moderate risk/benefit ratios.35

Depression Guidelines do not consider antipsychotics as a first line treatment of major depressive disorder without psychosis. However, they suggest that psychotic depression typically responds better to the combination of an antipsychotic and an antidepressant medication rather than either component alone, although some research has shown comparable responses for antidepressive treatment or antipsychotic treatment alone.18

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© Copyright Prime Therapeutics LLC. 11/2016 All Rights Reserved Aripiprazole, quetiapine XR, olanzapine, and brexpiprazole are FDA approved as adjunctive treatment for treatment resistant depression. An SSRI, SNRI, bupropion, or mirtazapine is first-line treatment of major depression. Most clinicians begin with an SSRI. When an adequate trial of an SSRI produces little to no response, another antidepressant can be tried, or two antidepressants from different classes can be combined. Augmentation with antipsychotic drugs may be helpful when the response to antidepressant agents is inadequate, but adverse effects (e.g., weight gain, extrapyramidal symptoms) can occur. 40

The British Association of Psychopharmacology (2015) states adding a second agent may be considered if there is partial/insufficient response on current antidepressant, there is good tolerability of current antidepressant, and switching antidepressants has been unsuccessful. Establish the safety of the proposed combination. Choose the combinations with the best evidence base first. Consider adding quetiapine, aripiprazole or lithium as first-line add on treatments. 41

Autism Practice Parameters-American Academy of Child and Adolescent Psychiatry (AACAP, 2014) suggest pharmacotherapy may be offered when there is a specific target symptom or comorbid condition, potentially increasing patient ability to profit from educational and other interventions, and allow less restrictive environments through management of severe and challenging behaviors. Frequent targets for pharmacologic intervention include associated comorbid conditions (e.g., anxiety, depression) and other features (e.g., aggression, self- injurious behavior, hyperactivity, inattention, compulsive-like behaviors, repetitive or stereotypic behaviors, and sleep disturbances). Various considerations (e.g., adverse effects) should inform pharmacologic treatment. Risperidone and aripiprazole have been FDA approved for the treatment of irritability (e.g., physical aggression, severe tantrum behavior) associated with autism. There is a growing body of controlled evidence for pharmacologic intervention. The guideline provides a summary chart of medications supported by RCTs for use in children with autism spectrum disorder (ASD), including target symptoms, ages, dosing, potential adverse effects, and outcomes. 13 . Antipsychotics supported by RCTs showing positive effects on various target symptoms in ASD include aripiprazole, haloperidol, olanzapine, and risperidone. . Combining medication with parent training is moderately more efficacious than medication alone for decreasing serious behavioral disturbance and modestly more efficacious for adaptive functioning. Individuals with ASD may be nonverbal, so treatment response is often judged by caregiver report and observation of specific behaviors. Although this may help document the effectiveness of the selected medication, an overall goal of treatment is to facilitate the child’s adjustment and engagement with educational intervention.

A review (2013) on pharmacotherapy of core symptoms of autism (e.g., impaired social interaction and communication, presence of restricted and repetitive behaviors) considered atypical antipsychotics as agents that are “possibly efficacious”. Results suggest that atypical antipsychotics (e.g., risperidone, aripiprazole) may have a modest effect on the core symptoms of autism. Most studies recruited children specifically for irritability, so it is unclear if effects on the core symptoms of autism would be observed in children without irritability. In these samples, perceived improvements in the core symptoms may simply reflect some improvement in irritability. No study has evaluated the core symptoms as a primary outcome. Finally, the side effects associated with the atypical antipsychotics (e.g., weight gain and somnolence) may override the modest potential improvement in the core symptoms.16

An Agency for Healthcare Research and Quality (AHRQ, 2012) comparative effectiveness review found risperidone and aripiprazole are the best-studied medications in treatment of autism. Each agent has >2 RCTs showing improvement in challenging behaviors (e.g.,

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© Copyright Prime Therapeutics LLC. 11/2016 All Rights Reserved emotional distress, aggression, self-injury). Hyperactivity and noncompliance also showed significant improvement, but were not primary target behaviors in these studies. Repetitive behavior showed improvement with both risperidone and aripiprazole. Both drugs have side effects limiting use for patients with severe impairment or risk of injury. Strength of evidence was moderate for risperidone, high for aripiprazole, and insufficient for serotonin reuptake inhibitors (fluoxetine, citalopram), stimulants, and most other medical interventions.30

Dementia-Related Psychosis (off-label use) Concerns have emerged in recent years regarding the safety of both atypical and typical classes of antipsychotic medications when used in the elderly dementia population. In June 2008, the FDA warned healthcare professionals that both typical and atypical antipsychotics are associated with an increased risk of death in elderly patients being treated for dementia- related psychosis. As a result, a Black Box Warning on increased risk of mortality in these patients appears on the product labeling of all atypical and typical antipsychotic drugs.27

The APA Practice Guideline for Treatment of Patients with Alzheimer’s disease and Other Dementias25 and the NICE guidelines on dementia26 currently recommend that nonpharmacologic interventions be attempted before a trial of antipsychotic drug therapy and that the interventions attempted be guided by the patient’s level of distress and the risk to the patients and caregiver. In addition, the FDA states that physicians who prescribe antipsychotics to elderly patients with dementia-related psychosis should discuss the risk of increased mortality with their patients, patients’ families, and caregivers.27

The APA Guideline Watch (2014) states new evidence indicates that antipsychotics provide weak benefits for the treatment of psychosis and agitation in patients with dementia. Adverse effects of antipsychotics include sedation, metabolic effects, and cognitive impairment. For many patients with Alzheimer’s disease, antipsychotics can be tapered and discontinued without significant signs of withdrawal or return of behavioral symptoms. 42

Antipsychotic drug therapy generally is reserved for patients who have severe symptoms or when associated agitation, combativeness, or violent behavior puts the patient or others in danger. Current evidence indicates that the atypical antipsychotics can provide modest improvement in behavioral manifestations; some evidence suggests that efficacy may be better for psychosis than for other manifestations. Antipsychotic efficacy appears to be similar among available agents and therefore the choice of agent should be based on adverse effect profile and other patient considerations; to minimize adverse effects, the lowest possible effective dose should be used.25-27

Tourette’s Disorder A review (2015) on treatment of Tourette’s syndrome suggests alpha-2 agonists (clonidine and guanfacine) are less effective than antipsychotics but are usually recommended as initial pharmacotherapy due to low side effects. Atypical neuroleptics (aripiprazole or risperidone) are typically used if the alpha-2 agonists are ineffective or intolerable. 44

Canadian Guidelines for Pharmacotherapy of Tic Disorders (2012) provide strong recommendations for use of clonidine and guanfacine (children only) for the treatment of tics. They provide weak recommendations for use of pimozide, haloperidol, fluphénazine, metoclopramide (children only), risperidone, aripiprazole, olanzapine, quetiapine, ziprasidone, topiramate, baclofen (children only), botulinum toxin injections, tetrabenazine, and cannabinoids (adults only) for the treatment of tics. While evidence supports efficacy of many antipsychotics for treatment of tics, the high rates of side effects associated with these medications resulted in only weak recommendations for these drugs. 43

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© Copyright Prime Therapeutics LLC. 11/2016 All Rights Reserved The American Academy of Child & Adolescent Psychiatry and the European Child and Psychiatry guideline state that atypical antipsychotics are effective in Tourette’s Disorder (TD). At the time the guidelines were published, no atypical antipsychotics were FDA approved, and only haloperidol and pimozide had been approved for TD. However, most clinicians use atypical antipsychotics prior to the two approved agents. The guidelines found that risperidone is the most well studied non-FDA labeled atypical antipsychotic for the treatment of TD. Risperidone was found to be at least as effective as clonidine, haloperidol, and pimozide; with less frequent and severe side effects. The most common adverse reaction with risperidone therapy was mild to moderate sedation. No clinically significant extrapyramidal symptoms were observed. Ziprasidone showed efficacy compared to placebo in one randomized controlled trial.36-37 However, ECG screenings are recommended if ziprasidone treatment is considered.36 Olanzapine was studied in several open-label trials and 1 double-blind crossover study with pimozide. Although olanzapine was shown to be effective, weight gain was observed. Due to the metabolic effects, olanzapine, it is not recommended as a first line medication for TD.36-37 Quetiapine has also shown efficacy in TD in small scale studies with the most common side effects being sedation and weight gain.37

Aripiprazole atypical antipsychotic is FDA approved for the treatment of TD. The most common adverse effects when used for TD in pediatric patients age 6-18 were sedation, somnolence, nausea, headache, nasopharyngitis, fatigue, and increased appetite. Safety and effectiveness of aripiprazole in pediatric patients with TD were established in one 8 week (aged 7 to 17) and one 10 week trial (aged 6 to 18) in 194 pediatric patients. Depending on the strength, aripiprazole showed an improved difference of - 5.3 to -9.9 decrease in Yale Global Tic Severity Scale Total Tic Score compared to placebo. Maintenance efficacy in pediatric patients has not been systematically evaluated. 6

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