Criteria for Outpatient Use Guidelines

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[Developed, January 2007; Revised, March 2007, May 2007, July 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
Quetiapine, a dibenzothiazepine antipsychotic agent, is FDA-approved for treating manic and mixed episodes of bipolar disorder, major depressive disorder when used as adjunctive therapy to antidepressants, and schizophrenia.^1,2 Recommended quetiapine dosages are summarized in Table 1.

Table 1
Quetiapine Dosage Recommendations for Adults

DIAGNOSIS	USUAL DOSAGE RANGE	MAXIMUM RECOMMENDED DOSAGE
Bipolar disorder treatment: depression	IR:  300-600 mg/day ER:  300 mg/day	600 mg/day
Bipolar disorder treatment: mania	IR, ER:  400-800 mg/day	800 mg/day
Bipolar disorder maintenance	IR, ER: 400-800 mg/day	800 mg/day
Major depressive disorder, adjunctive therapy	ER:  150-300 mg/day	300 mg/day
Schizophrenia	IR:  150-750 mg/day; ER:  400-800 mg/day	800 mg/day

IR = immediate-release; ER = extended-release

While not FDA-approved, quetiapine has been evaluated in managing adult insomnia utilizing doses < 150 mg/day in the literature with some benefit.  Measurements commonly used to assess insomnia treatment effectiveness include sleep period time (SPT; the duration of time from sleep onset to final awakening), total sleep time (TST; the difference of time between SPT and the time spent awake), and sleep efficiency (SE;   the ratio of TST compared to the amount of time spent in bed).⁶   Patient-   reported outcomes are also often assessed.  The Spiegel Sleep Questionnaire (SSQ) is comprised of 7 items that are each scored from 1 to 5, with higher scores indicating positive outcomes.⁷ The Insomnia Severity Index scale (ISI) is a tool used to measure a patient’s perception of his or her insomnia.  This instrument also consists of 7 items, but each item is scored from 0 to 4.  Higher scores correlate with more severe insomnia.⁸ Clinical evidence of low-dose quetiapine use for insomnia is exhibited in Table 2.

Table 2
Quetiapine Studies/Case Reports for the Treatment of Insomnia

Study	Population	Design	Intervention	Outcomes
Cohrs et al6	14 patients: •healthy males •age: 18 – 65 years	Study Design:  DB, PC,  R, crossover, single-center study Duration: 3 consecutive nights, 4 days apart	Quetiapine: 25 mg one hour before bedtime 100 mg one hour before bedtime Control: placebo	Under standard sleep laboratory conditions: 25 mg: significant differences for SPT, TST, and SE compared to placebo 100 mg: significant difference for SPT compared to placebo Under Acoustic Stress:* 25 mg: significant differences for SPT, TST,  and SE compared to placebo 100 mg: significant differences at SPT, TST and SE compared to placebo
Juri et al9	14 patients: •male and female •Parkinson’s disease	Study Design: open-label study Duration: 12 weeks	Quetiapine: initial dose: 12.5 mg at bedtime dose adjusted according to response and tolerance mean dose: 31.9 mg at bedtime at week 12	Sleep Latency: decrease of 82 ± 65.4 vs 28.6 ± 22.7 minutes from baseline (p <0.05) no correlation between response and dose of levodopa or dopamine agonist Safety: two patients withdrew because of restless leg symptoms which subsided after quetiapine discontinuation two patients reported increased diurnal sleepiness no reports of orthostatic symptoms or significant changes in blood pressure
Fernando et al10	1 patient: •34 year-old male •insomnia secondary to chronic back pain	Study Design: case report	Quetiapine: titrated up to 200 mg at bedtime	Observations: improved quality of sleep improved sleep latency
Sokolski et al11	1 patient: •42 year-old white male •25 year history of      major depression •insomnia exacerbated by phenelzine use	Study Design: case report	Quetiapine: initial dose: 6.25 mg at bedtime dose increased by 6.25 mg every 3 - 4 days until reached 25 mg at bedtime later increased to 37.5 mg at bedtime max dose:  50 mg at bedtime	Observations: insomnia dramatically improved patient slept 6 - 7 hours per night without interruption Safety: only reported adverse event was morning sedation; patient gradually habituated patient continued on phenelzine and quetiapine for more than 1 year with no report of adverse events
Wiegand et al12	18 patients: •primary insomnia	Study Design: open-label pilot study Duration: 6 weeks	Quetiapine: initial dose: 25 mg at bedtime increased to 50 mg at bedtime (n = 7) increased to 75 mg at bedtime (n = 1)	Objective Sleep Parameters: significant improvements in TST and SE initial improvements observed at 2 weeks and continued throughout study period sleep onset latency  was not significantly reduced no test variable showed a decline from baseline over the study period Safety: reports of xerostomia and morning sedation (frequency not defined) no reports of severe adverse events
Terán et al13	52 patients: •drug abusers in    detoxification process •insomnia as primary withdrawal symptom •included both     outpatients and inpatients	Study Design: retrospective study follow-up period of at least 60 days	Quetiapine: median dose: 50 mg at bedtime mean dose: 62.35 mg at bedtime range: 22 mg - 225 mg at bedtime	Change in SSQ: 75% improvement from baseline (p <0.001) greatest improvement in mean score occurred in first week (p < 0.001) benzodiazepine use decreased from baseline (83% vs 22.6% of patients) Safety: well tolerated no patients dropped out due to adverse events xerostomia most common adverse event (n=18; 34.5%)
Pasquini et al14	6 patients: females localized breast cancer receiving tamoxifen	Study Design: case series Duration: 6 weeks	Quetiapine: initial dose: 25 mg one hour before bedtime max dose: 100 mg one hour before bedtime	Efficacy: swift improvement in insomnia in 5/6 patients patients moved from the moderate ISI category (score of 15 to 21)      to absence of insomnia effect maintained after 6 weeks Safety: weight gain (n=2) dizziness (n=1)
Cates et al15	43 patients: male and female psychiatric patients 19 – 65 years old receiving at least one other psychotropic medication mean BMI = 31	Study Design: retrospective study	Quetiapine: mean initial dose: 109.3 mg ± 47.3 per day mean final dose: 120.3 mg ± 58.6 per day most common regimen: 100 mg hs mean duration: 11.1 months ± 8.2	Efficacy: Primary Outcome: changes in weight, BMI, and waist circumference compared to baseline mean weight gain of 4.9 lb over approximately 11 months statistically significant increase in weight (p = 0.037) statistically significant increase in BMI (p = 0.048) increase in waist circumference not statistically significant male mean increase in weight: 10.5 lb ± 15.6 (p = 0.009) male mean increase in BMI: 1.3 points ± 2.1 (p = 0.016)     Secondary Outcome: (compared to baseline) correlation of metabolic changes with patient and treatment variables no significant  differences were found

DB = double-blind; PC = placebo-controlled; R = randomized; SPT = sleep period time; TST = total sleep time; SE = sleep efficiency; SSQ = Spiegel Sleep Questionnaire; BMI = body mass index; ISI = Insomnia Severity Index scale
*Acoustic Stress = staccato piano tones ranging in pitch and tone intensity played in short spurts during the 8 hour bedtime period (duration: 4-5 seconds; interval: 30 – 90 seconds)

Based on available clinical evidence, low-dose quetiapine may be beneficial for adult patients suffering from insomnia.^6-16  Quetiapine not only improved the quantity of sleep, by increasing TST and SE, but also the quality of sleep, by increasing patient-reported outcomes.  The most commonly reported adverse events have been xerostomia, morning sedation, and weight gain.  Reports of weight gain despite the use of low quetiapine doses may predispose some patients to the metabolic disturbances (e.g., diabetes, dyslipidemia) associated with second generation antipsychotic (SGA) use.¹⁵

Although the evidence provided seems promising, the long-term efficacy of low-dose quetiapine treatment for insomnia has yet to be demonstrated in larger, randomized, controlled trials. Additional safety data are also needed before quetiapine can be prescribed with confidence for insomnia patients. Until strong evidence is established, low-dose quetiapine should be used with caution for the off-label treatment of insomnia, especially when other FDA-approved agents for insomnia are available.

A recent comparative effectiveness review published by the Agency for Healthcare Research and Quality (AHRQ) evaluating physician prescribing patterns for atypical antipsychotics found that physicians are prescribing atypical antipsychotics to patients for unapproved uses such as depression, dementia, posttraumatic stress disorder, and obsessive-compulsive disorder with minimal benefit.  Quetiapine studies for depression and obsessive- compulsive disorder using doses < 150 mg/day were available for evaluation in the AHRQ review; the        strength of evidence used to determine the efficacy of quetiapine in depression was low, and moderate in obsessive-compulsive disorder.¹⁷

Quetiapine doses < 150 mg/day are not routinely recommended.  However, elderly patients (defined as 65 years of age and older) and debilitated patients may not tolerate higher initial quetiapine doses due to decreased oral quetiapine clearance. Slower titration schedules using doses of 25-50 mg/day until clinical response is achieved are necessary to avoid adverse events.1-5 Some patients have been managed with doses as low as 25 mg to 50 mg/day for psychosis and bipolar disorder.^18-20 Quetiapine is not FDA-approved for use in doses lower than 150 mg/day, except in elderly and debilitated patients, and will be reviewed.

Pediatrics
Currently there is no FDA-approved indication for low-dose quetiapine use (150 mg/day or less) in the pediatric population. According to the most recently updated package insert, quetiapine is indicated for the treatment of schizophrenia in adolescents (age 13-17) and bipolar disorder in children and adolescents (age 10-17); however, the dosing ranges for these indications are 400-800 mg/day and 400-600 mg/day, respectively.² Data have been published that address quetiapine safety and efficacy for the treatment of various conditions in the pediatric population, and some of the patients included were taking quetiapine doses of 150 mg/day or less. Summary details of these       publications can be found in Table 3.

Evidence suggests that quetiapine use in children for a variety of indications including conduct disorder, attention-deficit/hyperactivity disorder (ADHD), bipolar disorder, and other psychoses may be beneficial as monotherapy in some situations and as combination therapy in others. Although most trials used a mean dose greater than 300 mg/day, all studies presented in Table 3 included doses of 150 mg/day or less as part of the range that participants received.^21-30   Based on the trials collectively, using quetiapine in patients younger than 18 years of age resulted in significantly improved scores on many of the psychiatric evaluations. Although the average doses in the trials were over 150 mg/day, efficacy does not seem to be limited to higher quetiapine doses.^21-30 However, many of these trials had several limitations that are important to consider. All trials were open-label trials, included a very small number of participants, and were relatively short in duration. Only one trial was randomized, and most did not have a comparator or control group.^27-30

While efficacy results seem promising from these trials, there are important adverse effects associated with quetiapine use in children. Weight gain, other metabolic changes, and sedation/somnolence are well known adverse effects associated with quetiapine use, and were frequently reported by trial participants.^27-30 It is especially important to understand the detrimental effects these events would    have on a school-aged child. Moreno et al³¹ published a trial examining the metabolic effects of quetiapine and other second generation antipsychotic (SGA) medications on children being treated for bipolar disorder as well as other psychotic and nonpsychotic disorders. This study found that after three months of treatment with a SGA, over 70% of patients experienced abnormal weight gain. Due to the frequency of weight gain and sedation occurring with SGA use, Penzner et al³² studied the effect of co-prescribing a stimulant, which can cause weight loss and insomnia, to neutralize the adverse effects of the antipsychotic. Investigators found no significant differences in body composition and metabolic profiles between SGA-treated patients managed concurrently with or without stimulants.

Low-dose quetiapine treatment for children with various psychotic or behavioral disorders has been beneficial in some cases.   However, possible adverse events that may negatively impact health and quality of life need to be considered before treatment initiation.

Table 3
Quetiapine Dosages in Pediatric Patients

STUDY	AGE	QUETIAPINE DOSE	DISEASE STATE
Stathis et al21	15 to 17 years of age (6 cases – mean age 16.7 yrs)	dose range 50 mg -200 mg/day (mean dose: 133 mg)	Posttraumatic stress disorder
Findling et al22 (2006)	6-12 years of age (mean age 8.9 yrs)	range 75mg -300 mg/day (median dose: 150 mg/day; mean dose: 4.4 mg/kg/day)	Conduct disorder
Marchand et al23	4-17 years of age (mean age 10.8 yrs)	dose range 100 mg -1000 mg/day (mean dose: 407 + 230 mg/day)	Bipolar disorder
Findling et al24 (2004)	12-17 years of age (mean age 14.6 + 2.3 yrs)	mean maximum total daily dose range 100 mg - 450 mg/day (overall mean dose: 291.7 mg/day)	Autistic disorder
Mukaddes et al25	8-16 years of age (mean age 11.4 + 2.4 yrs)	dose range 50 mg -100 mg/day (mean dose: 72.9 mg  + 22.5 mg/day)	Tourette’s disorder
Tufan26	17-year-old-female	100 mg/day in divided doses (plus sertraline 50 mg/day)	Autism; pervasive developmental disorder with mental retardation and self-injurious behavior
Arango et al27	12-18 years of age	dose range 73.2 mg – 992.4 mg/day (mean dose:  532.8 mg/day)	Schizophrenia; bipolar disorder
Findling et al28 (2007)	6-12 years of age	dose range 75 mg-350 mg/day (mean dose at study end: 158.3 mg/day) (methylphenidate administered adjunctively in majority of patients)	Conduct disorder
Duffy et al29	13-20 years of age	throughout study: dose range 64.4 mg – 617.4 mg/day (mean dose:  340.9 mg/day) at study end: dose range 27.3 mg – 561.9 mg/day (mean dose: 294.6 mg/day)	Bipolar disorder
Kronenberger et al30	12-16 years of age	dose range 120.2 mg – 538.2 mg/day (mean dose: 329.2 mg/day) (given in conjunction with methylphenidate)	ADHD*-combined type and disruptive behavior disorder with conduct disorder

*ADHD = attention deficit hyperactivity disorder

2. Duration of Therapy

Low-dose quetiapine (< 150 mg/day) is only FDA-approved as part of a drug titration schedule to aid patients in getting to the target quetiapine dosage goal (see Table 1).  Therefore, quetiapine dosages < 150 mg/day should not be prescribed for more than 30 days, except in elderly and debilitated patients. Quetiapine dosages < 150 mg/day prescribed for greater than 30 days, except in elderly and debilitated patients, are not recommended and will be reviewed.

3.* Drug-Drug Interactions

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

Drug-drug interactions considered clinically relevant for quetiapine 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^{4, 33, 34}
Quetiapine Drug-Drug Interactions

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)
quetiapine	CYP3A4 inhibitors (e.g., ketoconazole, ritonavir)	potential for decreased quetiapine clearance, increased quetiapine serum concentrations, and enhanced pharmacologic/adverse effects as quetiapine metabolized by CYP3A4	monitor for enhanced quetiapine pharmacologic/adverse effects and adjust doses as necessary	moderate (DrugReax) 2 (DIF) 2-major, 3-moderate (Clinical Pharmacology)
Quetiapine	CYP3A4 inducers (e.g., carbamazepine, phenytoin)	potential for significant reductions in quetiapine plasma concentrations (by as much as 50%) due to enhanced quetiapine hepatic microsomal metabolism	monitor quetiapine 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)
Quetiapine	levodopa, dopamine agonists	Quetiapine 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)
Quetiapine	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)

 

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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.