The Medical Letter publications are protected by US and international copyright laws. Forwarding, copying or any other distribution of this material is strictly prohibited. For further information call: 800-211-2769 Last updated: December 17, 2018 The Medical Letter on s and Therapeutics Expanded Table: Some Hypnotics for Chronic Insomnia Some Hypnotics for Chronic Insomnia Benzodiazepine Receptor Agonists Eszopiclone generic Lunesta (Sunovion) Zaleplon generic Sonata (Pfizer) Zolpidem immediate-release generic Ambien (Sanofi) extended-release generic Ambien CR spray Zolpimist (Atyu Bioscience) Sleep-onset 1, 2, 3 mg <30 min intermediate 1-3 mg elderly: 1-2 mg 5, 10 mg caps <30 min ultra-short 10-20 mg Sleep-onset 5, 10 mg <30 min short men: 5-10 mg 6.25, 12.5 mg ER <30 min intermediate men: 6.25-12.5 mg women: 6.25 mg elderly: 6.25 mg Sleep-onset 5 mg/actuation 20 min short men: 5-10 mg sublingual Edluar (Meda) Sleep-onset 5, 10 mg SL Intermezzo (Purdue) generic Insomnia following middle-of-the-night awakening 1.75, 3.5 mg SL <30 min short men: 5-10 mg 20 min ultra-short men: 3.5 mg women: 1.75 mg elderly: 1.75 mg Headache and dizziness are common possible increased risk of cancer and death Increased risk of adverse cognitive effects and falls in elderly Withdrawal, dependence, and abuse can occur Eszopiclone has an unpleasant aftertaste Decrease sleep latency Zaleplon has been used off-label for following middle-of-the-night awakening Risk factors for complex sleep-related behaviors include use of the drug in high doses, with other sedating drugs, or while still active Observational cohort studies have found an increased risk of cancer and death with use of hypnotics; a causal relationship has not been established eszopiclone and all formulations of zolpidem may be slower if taken with or immediately after a meal Zaleplon should not be taken with or immediately after a high-fat meal Zolpimist and Intermezzo should only be taken if 4 hours remain before waking Classified as schedule IV controlled substances Interactions: Metabolized by CYP3A4 (zaleplon to a lesser extent); concurrent use of CYP3A4 inducers could decrease their effectiveness and is not recommended and concurrent use of CYP3A4 inhibitors could increase their serum concentrations and the risk of adverse effects Preterm birth and low birth weight have been reported Third-trimester use of zolpidem has caused respiratory depression and sedation in neonates Zaleplon and zolpidem have been detected in human breast milk Excess sedation has been reported in breastfed infants of mothers who took zolpidem $19.20 470.40 9.50 322.90 2.40 504.90 22.50 504.90 659.00 4 356.20 372.30 237.10 e209
Some Hypnotics for Chronic Insomnia (continued) Benzodiazepines Estazolam generic Flurazepam generic Lorazepam generic Ativan (Valeant) Quazepam generic Doral (Galt) Temazepam generic Restoril (Mallinckrodt) Triazolam generic Halcion (Pfizer) Not FDA-approved for treatment of Sleep-onset 1, 2 mg 15-60 min intermediate 1-2 mg elderly: 0.5-1 mg 15, 30 mg caps 10-30 min long 15-30 mg elderly: 15 mg 0.5, 1, 2 mg 30-60 min intermediate 0.5-2 mg elderly: 0.5-1 mg 15 mg 30 min long 7.5-15 mg elderly: 7.5 mg 7.5, 15, 22.5, 30 mg caps 0.125, 0.25 mg 0.25 mg 30-60 min intermediate 7.5-30 mg elderly: 7.5-15 mg 15-30 min short 0.125-0.25 mg elderly: 0.125-0.25 mg anterograde amnesia (particularly triazolam), aggressive behavior I ncreased risk of adverse cognitive effects and falls in elderly Dependence, tolerance, abuse, and rebound can occur Withdrawal, which may be life-threatening, can occur with rapid dosage reductions or abrupt discontinuation Decrease sleep latency and prolong the first two stages of sleep Tolerance to their sedative effects develops rapidly; they are not recommended for longterm use Classified as schedule IV controlled substances Interactions: Metabolized to some extent by CYP3A4 (except lorazepam, oxazepam, and temazepam); concurrent use of inducers could decrease their serum concentrations and their effectiveness and concurrent use of inhibitors could increase their serum concentrations and the risk of adverse effects Concurrent use of an opioid and benzodiazepine has been associated with a significant increase in the risk of overdose compared to use of an opioid alone $33.50 14.90 1.80 699.30 281.30 5 705.00 5 121.00 924.10 87.90 83.90 6 Increase the risk of fetal malformations and should not be used during pregnancy American College of Obstetricians and Gynecologists (ACOG) considers benzodiazepines moderately safe for use during breastfeeding e210
Some Hypnotics for Chronic Insomnia (continued) Melatonin Receptor Agonist Ramelteon Rozerem (Takeda) Sleep-onset 8 mg 15-30 min short 8 mg Somnolence, dizziness, fatigue, and nausea are common Hallucinations, agitation, mania, complex sleeprelated increased serum prolactin concentrations, decreased serum testosterone concentrations Efficacy is modest at best Should be taken with or immediately after a high-fat meal Not classified as a controlled substance Interactions: Metabolized by CYP1A2 and to a lesser extent by CYP3A4 and CYP2C isozymes Concurrent use of the strong CYP1A2 inhibitor fluvoxamine increased ramelteon serum concentrations and is contraindicated; other strong CYP1A2 inhibitors may have a similar effect Concurrent use of CYP1A2 or 2C9 inhibitors could increase ramelteon serum concentrations and the risk of adverse effects Concurrent use of rifampin decreased ramelteon serum concentrations by 80% No adequate studies in pregnant women Developmental toxicity and teratogenic effects have occurred in the offspring of pregnant rats given doses higher than the recommended human dose No data on the presence of ramelteon in human breast milk or on its effects on the breastfed infant or milk production Excreted in milk of lactating rats $377.70 e211
Some Hypnotics for Chronic Insomnia (continued) Tricyclic Antidepressant Doxepin Silenor (Pernix) Sleep-maintenance 3, 6 mg 30 min long 3-6 min elderly: 3 mg Residual next-day somnolence reported with 6-mg dose In low doses, it is claimed to have a hypnotic effect without anticholinergic or other typical tricyclic adverse effects Should not be taken within 3 hours of a meal Not classified as a controlled substance Interactions: Coadministration with cimetidine, a CYP2C19, 2D6, and 1A2 inhibitor, can double doxepin serum concentrations; maximum doxepin dose of 3 mg is recommended Contraindicated for use with a monoamine oxidase inhibitor (MAOI) or within two weeks of stopping one No adequate studies of low-dose doxepin in pregnant women Administration of doxepin doses 6 mg/day to pregnant rats resulted in adverse effects on fetal development Excreted in human breast milk Apnea and drowsiness reported in an infant whose mother was taking doxepin in doses used to treat depression Effect on milk production is unknown $428.30 e212
Some Hypnotics for Chronic Insomnia (continued) Orexin Receptor Antagonist Suvorexant Belsomra (Merck) 5, 10, 15, 20 mg 30 min intermediate 10-20 mg Somnolence, fatigue, and abnormal dreams are common cataplexy-like symptoms Has been associated with narcolepsy; contraindicated for use in patients with narcolepsy Should be administered with caution in patients with compromised respiratory function; it appears to be safe for use in mild to moderate COPD Classified as a schedule IV controlled substance Interactions: Metabolized by CYP3A4; should not be administered with strong CYP3A4 inhibitors or inducers Recommended dose is 5 mg when taken concurrently with moderate CYP3A4 inhibitors Suvorexant is a P-glycoprotein inhibitor and can increase digoxin serum concentrations if taken concomitantly No adequate studies in pregnant women Administration of higher-than-recommended doses to pregnant rats resulted in reduced fetal weight in offspring No data on the presence of suvorexant in human breast milk or on its effects on the breastfed infant or milk production Excreted in milk of lactating rats ER = extended-release; SL = sublingual 1. Treatment should be started with the lowest dose, especially in patients who have a low body weight, are debilitated, or are receiving opioids or other CNS or cardiorespiratory depressants. 2. Dosage adjustment may be required for renal or hepatic impairment. 3. Approximate WAC for 30 days treatment at the lowest usual adult hypnotic dosage. WAC = wholesaler acquisition cost or manufacturer s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price. Source: AnalySource Monthly. December 5, 2018. Reprinted with permission by First Databank, Inc. All rights reserved. 2018. www.fdbhealth.com/policies/ drug-pricing-policy. 4. Cost of a 7.7-mL bottle that contains 60 5-mg actuations after 5 initial priming actuations. 5. Cost of 15 15-mg tablets. 6. Cost of 15 0.25-mg tablets. $331.50 e213