Criteria for Outpatient Use Guidelines
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Sedative/Hypnotics
[Developed, January 1995; Revised, November 1996; November 1997; November 1998; December 1999; October 2000; November 2001; October 2002; December 2003; July 2006; August 2006; November 2006; May 2010 ]
Information on indications for use or diagnosis is assumed to be unavailable. All criteria may be applied retrospectively; prospective application is indicated with [*].
1.* Dosage
Adults
Maximum recommended daily doses for sedative/hypnotics in adults, including the elderly population, are summarized in Table 1. Prescribed dosages exceeding these recommendations will be reviewed.
| DRUG | < 65 YEARS | > 65 YEARS |
|---|---|---|
| Benzodiazepines: Estazolam (generics) | 2mg | 2 mg* |
| Benzodiazepines: Flurazepam (generics) | 30 mg | 15mg* |
| Benzodiazepines: Quazepam (Doral®) | 30 mg | 15mg* |
| Benzodiazepines: Temazepam (Restoril®, generics) | 30 mg | 15mg* |
| Benzodiazepines: Triazolam (Halcion®, generics) | 0.5 mg | 0.25mg* |
| Barbiturates++: Butabarbital (Butisol®, generics) | 120 mg | 120mg* |
| Barbiturates: Mephobarbital (Mebaral®) | 600 mg | 600mg* |
| Barbiturates: Phenobarbital | 400 mg | 400mg* |
| Barbiturates: Secobarbital (Seconal®, generics) | 200 mg | 200mg* |
| Miscellaneous Nonbarbiturates: Chloral hydrate (generics) | 2000 mg | 2000 mg |
| Miscellaneous Nonbarbiturates: Eszopiclone (Lunesta®) | 3 mg | 2mg |
| Miscellaneous Nonbarbiturates: Ramelteon (Rozerem®) | 8 mg | 8mg |
| Miscellaneous Nonbarbiturates: Zaleplon (Sonata®) | 20 mg | 10mg |
| Miscellaneous Nonbarbiturates: Zolpidem (Ambien®, Ambien CR®) immediate-release: | 10 mg | 5 mg |
| Miscellaneous Nonbarbiturates: Zolpidem (Ambien®, Ambien CR®) extended-release: | 12.5 mg
|
6.25 mg |
*While the daily dose recorded is the maximum recommended dose assigned to the drug listed, in elderly patients (patients > 65 years of age) sedative/hypnotic dosages should be reduced if possible, as these patients are more sensitive to the pharmacologic effects.
++No longer considered acceptable drug class to manage insomnia as safer agents (i.e., benzodiazepines) are available
In the elderly, short- and intermediate-acting benzodiazepines (e.g., temazepam, triazolam) are preferred, as long-acting benzodiazepines (e.g., flurazepam, quazepam) are associated with increased sedation and an increased risk of falls and fractures in this patient population.
The appropriate sedative/hypnotic dose for debilitated patients is the same as that prescribed in elderly patients for most sedative/hypnotic agents. However, estazolam 0.5 mg is used in small, debilitated patients, a dose lower than that recommended for elderly patients.
Quazepam dosages for elderly patients should be reduced to the lowest possible dose in one to two days, if possible.
Patients with hepatic insufficiency do not clear zolpidem doses as readily as patients with normal hepatic function. A 5 mg zolpidem immediate-release dose or 6.25 mg extended-release dose is recommended in these patients.
Eszopiclone doses greater than 2 mg daily are not recommended in patients with severe hepatic impairment, as eszopiclone is significantly hepatically metabolized and serum concentrations may increase significantly in this patient population.
Pediatrics
Safety and efficacy of most benzodiazepines as sedative/hypnotics, eszopiclone, ramelteon, zaleplon, or zolpidem in pediatric patients have not been established. Flurazepam is FDA-approved for use to manage insomnia in adolescents 15 years of age and older. Chloral hydrate and barbiturates may be used in pediatric patients for short-term management of insomnia (< 2 weeks) and/or to provide sedation prior to nonpainful therapeutic or diagnostic procedures. Dosage recommendations for barbiturates and chloral hydrate for pediatric patients are summarized in Table 2.
| DRUG | RECOMMENDED DOSAGE |
|---|---|
| Barbiturates: Butabarbital | Preoperative sedation: 2-6 mg/kg; maximum 100 mg/dose Sedation maintenance: 2 mg/kg/dose orally three times daily |
| Barbituates: Mephobarbital (Mebaral®) | Sedation: 16-32 mg orally 3-4 times daily |
| Barbiturates: Phenobarbital | Sedation: 6 mg/kg/day, in three divided doses |
| Benzodiazepines: Flurazepam | Insomnia: Adolescents 15 years and older: 15 mg orally at bedtime |
| Miscellaneous Nonbarbiturates: Chloral hydrate | Insomnia: 50 mg/kg/day; maximum 1 g/dose Procedural Sedation: 20-25 mg/kg/dose orally Sedation: 8 mg/kg three times daily orally; maximum 500 mg/dose |
2. Duration of Therapy
In adults, insomnia is classified based on symptom duration. Periods of sleep difficulty lasting from one to three nights are classified as transient insomnia, periods lasting three nights to one month are classified as short-term insomnia, while chronic or long-term insomnia represents sleep difficulties exceeding one month. Acute, transient insomnia is due to minor situational, familial, and/or occupational stress and is managed primarily by teaching patients to re-establish normal sleep-wake patterns. Short-term insomnia is precipitated by events such as divorce, job loss, health concerns, or prescription medications and may be managed by behavioral techniques, lifestyle changes, and, if necessary, short-term pharmacologic therapy. Long-term insomnia may be associated with medical or psychiatric illness (e.g., mood and anxiety disorders, asthma, chronic pain, and gastroesophageal reflux) as well as a variety of prescribed medications, although approximately 50% of patients may develop chronic insomnia due to psychophysiological characteristics. Chronic insomnia with a psychophysiologic component is characterized by a marked overconcern about the inability to fall asleep. A definitive diagnosis of the specific cause for long-term insomnia is necessary before a treatment plan can be delineated. Sedative/hypnotics are generally reserved for use in those patients with insomnia in whom secondary causes of insomnia have been evaluated and managed or in whom sleep hygiene practices have failed. Ideally, sedative/hypnotics are not routinely recommended for the management of chronic insomnia. However, in certain circumstances, these agents may be administered in conjunction with nonpharmacologic therapy in the lowest effective dose several times per week for no more than 1 to 3 months to minimize tolerance and dependence. Chronic insomnia without underlying medical or psychiatric disease can be managed most effectively with a benzodiazepine or nonbenzodiazepine hypnotic used concurrently for a finite time period with daily behavioral therapy. Hypnotics should typically be dosed intermittently once every two to three nights to avoid tolerance and dependence. However, eszopiclone and ramelteon have been approved for use in the long-term management of sleep onset and/or sleep maintenance insomnia, while zolpidem extended-release has been approved for use in managing insomnia without a limit to treatment duration.
Zolpidem immediate-release prescribed quantities should not exceed a one month supply.
Barbiturates are indicated for short-term treatment of insomnia as these agents appear to lose effectiveness in sleep induction and maintenance after 2 weeks.
Sedative/hypnotic treatment regimens lasting longer than four months in adult patients will be reviewed.
In pediatric patients, sedative/hypnotics are primarily used to alleviate anxiety and/or pain associated with painful or nonpainful but threatening procedures. Due to an increased incidence of deaths associated with chloral hydrate use prior to or following a diagnostic or therapeutic procedure in pediatric patients, the American Academy of Pediatrics recommends that chloral hydrate should only be administered to pediatric patients in a health care facility with close supervision and appropriate monitoring.
3.* Duplicative Therapy
The concurrent use of two or more sedative/hypnotics is not recommended. Additional therapeutic benefit is not appreciated when several sedative/hypnotics are administered in combination. Patient profiles containing concurrent prescriptions for multiple sedative/hypnotics will be reviewed.
The concurrent use of sedative/hypnotics and other sedative/CNS depressant drugs, including antihistamines, other barbiturates, narcotics, anesthetics, and other benzodiazepines, is not recommended.
4.* Drug-Drug Interactions
Patient profiles will be assessed to identify those drug regimens which may result in clinically significant drug-drug interactions.
The following drug-drug interactions are considered clinically relevant for sedative/hypnotics. Only those drug-drug interactions identified as clinical significance level 1 or those considered life-threatening which have not yet been classified will be reviewed:
| TARGET DRUG | INTERACTING DRUG | INTERACTION | RECOMMENDATIONS | CLINICAL SIGNIFICANCE |
|---|---|---|---|---|
| barbiturates (BARB) | anticoagulants | BARB induction of warfarin metabolic clearance (CYP3A4) with potential for decreased warfarin clinical effects | avoid combination, if possible; closely monitor INR when BARB therapy added, discontinued or changed; addition of warfarin to chronic BARB regimen more tolerable | moderate (DrugReax) 1 Drug Interaction Facts (DIF) 2-major (Clinical Pharmacology) 2 (Hansten & Horn) |
| barbiturates | cyclosporine | BARB induction of cyclosporine metabolic clearance (CYP3A4) with potential for reduced cyclosporine clinical effects | avoid concurrent therapy, if possible; if combination necessary, monitor for cyclosporine immunosuppressive efficacy; monitor cyclosporine serum concentrations when BARB therapy added, discontinued, or changed | 4 (DIF) 2-major (Clinical Pharmacology) 3 (Hansten & Horn) |
| barbiturates | oral contraceptives (OC) | BARB induction of estrogen/progestin hepatic metabolic clearance with potential for decreased OC clinical effects and risk of contraceptive failure | OCs with higher ethinyl estradiol dosages (e.g., 50 mcg) to increase contraceptive efficacy may be necessary; second contraceptive method recommended to prevent unwanted pregnancy | 2 (DIF) 3-moderate (Clinical Pharmacology) 3 (Hansten & Horn) |
| barbiturates | voriconazole | BARB induction, especially long-acting BARBs (mephobarbital, phenobarbital), of voriconazole metabolic clearance (CYP3A4) with potential for decreased voriconazole clinical effects | voriconazole contraindicated for use with long-acting BARBs; use cautiously with short-acting BARBs and monitor clinical effects | contraindicated (DrugReax) 1 (DIF) 1-severe (Clinical Pharmacology) |
| chloral hydrate (CH) | anticoagulants | potential increased bleeding risk due to displacement of warfarin from binding sites by CH metabolite, trichloroacetic acid; effect usually transient and small | monitor INR during first few days of CH therapy or when therapy is discontinued or changed; may substitute benzodiazepine (BZD) for CH (no significant interactions between BZD and warfarin) | moderate (DrugReax) 3 (DIF) 4-low (Clinical Pharmacology) 3 (Hansten & Horn) |
| chloral hydrate | QTc interval-prolonging agents | increased risk of cardiovascular adverse effects, including torsades de pointes, with concurrent administration as CH can prolong QTc interval | administer cautiously together, if at all; observe for adverse effects if combination utilized | contraindicated, major (DrugReax) |
| eszopiclone | CYP3A4 inducers (e.g., rifampin, phenytoin, carbamazepine) | induction of eszopiclone metabolic clearance (CYP3A4) with potential for decreased eszopiclone clinical effects | monitor patients for decreased eszopiclone efficacy; consider hypnotic agent not metabolized by CYP3A4 | moderate (DrugReax) 3-moderate (Clinical Pharmacology) 3 (Hansten & Horn) |
| eszopiclone | CYP3A4 inhibitors (e.g., ketoconazole, protease inhibitors, macrolides) | potential for increased eszopiclone serum concentrations and enhanced pharmacologic/adverse effects | monitor patients for enhanced eszopiclone effects; adjust doses as necessary | moderate (DrugReax) 3-moderate (Clinical Pharmacology) |
| oxidatively metabolized BZDs (e.g., estazolam, quazepam, triazolam) | imidazole antifungals (e.g., itraconazole, ketoconazole) | potential for increased serum concentrations and enhanced pharmacologic/adverse effects in oxidatively metabolized BZDs (metabolized by CYP3A4) as imidazole antifungals inhibit CYP3A4 | adjunctive therapy with imidazole antifungals and oxidatively metabolized BZD contraindicated; BZD metabolized by glucuronidation (e.g., temazepam) may be acceptable alternative | contraindicated (DrugReax) 2 (DIF) 1-severe (Clinical Pharmacology) itraconazole: 2; ketoconazole: 3 (Hansten & Horn) |
| oxidatively metabolized BZDs (e.g., estazolam, quazepam, triazolam) | macrolides | potential for increased serum concentrations and enhanced pharmacologic/adverse effects in oxidatively metabolized BZDs (metabolized by CYP3A4) as macrolides inhibit CYP3A4 | adjunctive therapy with macrolides and oxidatively metabolized BZD not recommended; BZD metabolized by glucuronidation (e.g., temazepam) may be acceptable alternative; azithromycin may be macrolide alternative (not metabolized by CYP3A4) | moderate (DrugReax) triazolam: 2 (DIF) triazolam: 2-major; estazolam, quazepam: 3-moderate (Clinical Pharmacology) 3 (Hansten & Horn) |
| oxidatively metabolized benzodiazepines (e.g., estazolam, quazepam, triazolam) | nefazodone | potential for increased serum concentrations and enhanced pharmacologic/adverse effects(e.g., prolonged sedation, excessive hypnotic effects) in oxidatively metabolized BZDs (metabolized by CYP3A4) as nefazodone potently inhibits CYP3A4 | adjunctive therapy with nefazodone and oxidatively metabolized BZD contraindicated; BZD metabolized by glucuronidation (e.g., temazepam) may be acceptable alternative | contraindicated (DrugReax) 3 (DIF) 1-severe (Clinical Pharmacology) |
| oxidatively metabolized BZDs (e.g., estazolam, quazepam, triazolam) | NNRT inhibitors | potential for altered serum concentrations and pharmacologic effects in oxidatively metabolized BZDs (metabolized by CYP3A4); delavirdine, efavirenz inhibit CYP3A4 and magnify oxidative BZD pharmacologic/ adverse effects, while nevirapine induces oxidative BZD metabolism and diminishes pharmacologic effects | adjunctive therapy with NNRT inhibitors and oxidatively metabolized BZD contraindicated; BZD metabolized by glucuronidation (e.g., temazepam) may be acceptable alternative | contraindicated (DrugReax) 2 (DIF) 1-severe (Clinical Pharmacology) |
| oxidatively metabolized BZDs (e.g., estazolam, quazepam, triazolam) | protease inhibitors | potential for increased serum concentrations and enhanced pharmacologic/adverse effects (e.g., severe sedation, respiratory depression) in oxidatively metabolized BZDs (metabolized by CYP3A4) as protease inhibitors inhibit CYP3A4 | adjunctive therapy with protease inhibitors and oxidatively metabolized BZD contraindicated; BZD metabolized by glucuronidation (e.g., temazepam) may be acceptable alternative | contraindicated (DrugReax) 1 (DIF) 1-severe (Clinical Pharmacology) 3 (Hansten & Horn) |
| oxidatively metabolized BZDs (e.g., estazolam, quazepam, triazolam) | triazole antifungals (e.g., fluconazole, voriconazole) | potential for increased serum concentrations and enhanced pharmacologic/adverse effects in oxidatively metabolized BZDs (metabolized by CYP3A4) as triazole antifungals inhibit CYP3A4 | adjunctive therapy with triazole antifungals and oxidatively metabolized BZD not recommended; BZD metabolized by glucuronidation (e.g., temazepam) may be acceptable alternative | major (DrugReax) 2 (DIF) 3-moderate (Clinical Pharmacology) fluconazole: 2; voriconazole: 3 (Hansten & Horn) |
| ramelteon | antifungal agents (triazoles or imidazoles) | potential for increased ramelteon serum concentrations and increased clinical/adverse effects due to CYP2C9 inhibition by triazole antifungals (e.g., fluconazole, voriconazole) or CYP3A4 inhibition by imidazole antifungals (e.g., itraconazole, ketoconazole) | cautiously administer therapy concurrently; monitor for enhanced ramelteon pharmacologic/adverse effects | moderate (DrugReax) 2-major (Clinical Pharmacology) |
| ramelteon | fluvoxamine | fluvoxamine inhibition of ramelteon metabolism (CYP1A2) and potential for increased ramelteon serum concentrations and increased clinical/adverse effects | avoid concurrent administration; other selective serotonin reuptake inhibitors (e.g., citalopram, fluoxetine) may be safer alternatives to fluvoxamine | contraindicated (DrugReax) 2 (DIF) 1-severe (Clinical Pharmacology) 1 (Hansten & Horn) |
| ramelteon | strong CYP1A2 inducers (e.g., rifampin, rifabutin) | induction of ramelteon metabolic clearance (CYP1A2) with potential for decreased ramelteon clinical effects | monitor for decreased ramelteon effectiveness | minor (DrugReax) 3-moderate (Clinical Pharmacology) 3 (Hansten & Horn) |
| zolpidem | ketoconazole | potential for increased zolpidem serum concentrations and enhanced pharmacologic/adverse effects (e.g., severe sedation, respiratory depression) as ketoconazole inhibits CYP3A4 | monitor patients for enhanced zolpidem effects; adjust doses as necessary | moderate (DrugReax) 2 (DIF) 3-moderate (Clinical Pharmacology) 3 (Hansten & Horn) |
| zolpidem | rifampin | induction of zolpidem metabolic clearance (CYP3A4) with potential for decreased zolpidem clinical effects | monitor for decreased zolpidem effectiveness | moderate (DrugReax) 3 (DIF) 3-moderate (Clinical Pharmacology) 3 (Hansten & Horn) |
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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.