Lunesta (Eszopiclone) Food & Supplement Interactions: What to Avoid and Why

What does food do to eszopiclone?

The dosing section of the Lunesta label says: do not take Lunesta with or immediately after a meal [1]. In the label's food-effect data, a 3 mg dose taken after a high-fat meal had an unchanged AUC, a Cmax 21% lower, and a Tmax delayed by about one hour [1]. Slower absorption would be expected to reduce the effect on sleep latency [1].

Eszopiclone reaches peak blood levels at about 1 hour. Its terminal half-life is about 6 hours in adults and about 9 hours in people 65 and older, whose AUC is 41% higher [1].

How the dose is meant to be timed

The label says Lunesta should be taken immediately before bedtime, and warns that taking a sedative-hypnotic while still up and about may result in short-term memory impairment, hallucinations, impaired coordination, dizziness and lightheadedness [1]. It gives a recommended starting dose of 1 mg with at least 7 to 8 hours remaining before the planned time of awakening, raised to 2 mg or 3 mg if clinically indicated, with a maximum of 3 mg once daily [1]. The label says the total dose should not exceed 2 mg in elderly or debilitated patients, in severe hepatic impairment, or when a potent CYP3A4 inhibitor is taken [1]. The 2 mg and 3 mg doses carry a higher risk of next-day driving impairment [1].

Alcohol

The label reports an additive effect on psychomotor performance when eszopiclone and ethanol are taken together [1]. Additive effects also occur with other CNS depressants. The label names benzodiazepines, opioids and tricyclic antidepressants alongside alcohol, including daytime use, and says downward dose adjustment of Lunesta and the other CNS depressant should be considered [1]. Next-day impairment risk is higher with less than 7 to 8 hours of sleep remaining, higher doses, other CNS depressants, and drugs that raise eszopiclone levels [1].

The label's most serious warning is about complex sleep behaviors. The boxed warning states that sleep-walking, sleep-driving and engaging in other activities while not fully awake may follow use of Lunesta, and that some of these events may cause serious injuries including death [1]. The warnings section adds that they may occur with Lunesta alone at recommended doses, with or without alcohol or other CNS depressants [1]. Patients usually do not remember these events [1]. The label says use with other sedative-hypnotics at bedtime or in the middle of the night is not recommended [1].

The FDA added the boxed warning and a contraindication for eszopiclone, zaleplon and zolpidem following a safety announcement posted 2019-04-30 [2][3]. Its analysis of 66 serious cases reported through 2018-02-27 found 20 deaths and 46 serious injuries, and the agency said these drugs should not be prescribed to anyone who has previously had a complex sleep behavior on any of the three [2][3]. A previous complex sleep behavior after Lunesta is a contraindication in the label [1].

Medicines that change eszopiclone levels

Eszopiclone is extensively metabolized by CYP3A4 and CYP2E1, and less than 10% of a dose is excreted unchanged in urine [1]. Ketoconazole, a potent CYP3A4 inhibitor, increased eszopiclone exposure, and the label says dose reduction is needed, with a total dose of no more than 2 mg, when Lunesta is taken with a potent CYP3A4 inhibitor [1]. The label says other strong inhibitors, including itraconazole, clarithromycin, nefazodone, troleandomycin, ritonavir and nelfinavir, would be expected to behave similarly [1].

In the other direction, rifampicin, a potent CYP3A4 inducer, lowered racemic zopiclone exposure by 80%, and the label says a similar effect would be expected with eszopiclone, decreasing its effect [1].

Olanzapine is the other drug named in the interactions section: the combination produced a decrease in DSST scores, a pharmacodynamic interaction with no change in the pharmacokinetics of either drug [1].

Grapefruit juice and sleep supplements

The label's drug interactions section names ethanol, olanzapine, ketoconazole and rifampicin, and says other strong CYP3A4 inhibitors would be expected to behave like ketoconazole [1]. Grapefruit juice, melatonin, valerian, kava, CBD, magnesium and caffeine are not named there [1].

The label's general statements are that CNS depressants have additive CNS-depressant effects in combination, and that using another sedative-hypnotic at bedtime or in the middle of the night is not recommended [1].

Older adults

The label caps the dose at 2 mg for elderly or debilitated patients, notes the roughly 9-hour half-life and 41% higher AUC in people 65 and older, and says drowsiness and a decreased level of consciousness put patients, particularly the elderly, at higher risk of falls [1]. The 2023 AGS Beers Criteria advise avoiding eszopiclone in older adults [4].