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Drug Interactions between eszopiclone and Tolsura

This report displays the potential drug interactions for the following 2 drugs:

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Interactions between your drugs

Major

itraconazole eszopiclone

Applies to: Tolsura (itraconazole) and eszopiclone

ADJUST DOSE: Coadministration with potent inhibitors of CYP450 3A4 may increase the plasma concentrations of both zopiclone and its pharmacologically active S(-) enantiomer, eszopiclone. Zopiclone has been shown in vitro to be metabolized by CYP450 3A4 and CYP450 2C8, while eszopiclone is primarily metabolized by CYP450 3A4 and 2E1 via demethylation and oxidation. In 18 healthy subjects, administration of a single 3 mg dose of eszopiclone with the potent CYP450 3A4 inhibitor ketoconazole (400 mg daily for 5 days) increased eszopiclone half-life, peak plasma concentration (Cmax) and systemic exposure (AUC) by 1.3-, 1.4- and 2.2-fold, respectively. In 10 healthy young subjects, itraconazole 200 mg daily given for 4 days increased the Cmax and AUC of a single 7.5 mg dose of zopiclone by 29% and 73%, respectively, and prolonged its half-life by 40%. The pharmacokinetics of eszopiclone were not reported in this study. A case report describes an 86-year-old woman who experienced morning drowsiness during coadministration of zopiclone and nefazodone, a known potent CYP450 3A4 inhibitor. Zopiclone plasma concentrations were measured both during and after withdrawal of nefazodone therapy. Following discontinuation of nefazodone due to lack of therapeutic effect, the plasma concentration of S(-) zopiclone decreased from 107 to 16.9 ng/mL, and that of R(+) zopiclone decreased from 20.6 to 1.45 ng/mL.

MANAGEMENT: Due to increased risk of next-day psychomotor impairment, the dosages of eszopiclone and zopiclone should be reduced when used with potent CYP450 3A4 inhibitors. The manufacturers recommend that total dose of eszopiclone not exceed 2 mg. An initial dose of 3.75 mg is recommended for zopiclone, which may be increased up to 5 mg if clinically indicated. Patients should be advised to avoid driving or operating hazardous machinery until they know how these medications affect them, preferably at least 12 hours after administration of the hypnotic.

References

  1. Dresser GK, Spence JD, Bailey DG "Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition." Clin Pharmacokinet 38 (2000): 41-57
  2. Becquemont L, Mouajjah S, Escaffre O, Beaune P, Funck-Bretano C, Jaillon P "Cytochrome P-450 3A4 and 2C8 are involved in zopiclone metabolism." Drug Metab Dispos 27 (1999): 1068-73
  3. Alderman CP, Gebauer MG, Gilbert AL, Condon JT "Possible interaction of zopiclone and nefazodone." Ann Pharmacother 35 (2001): 1378-80
  4. "Product Information. Lunesta (eszopiclone)." Sepracor Inc (2004):
  5. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0
  6. Cerner Multum, Inc. "Australian Product Information." O 0
  7. "Product Information. Imovane (zopiclone)." Rhone-Poulenc Rorer Canada Inc (2014):
View all 7 references

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Drug and food interactions

Moderate

itraconazole food

Applies to: Tolsura (itraconazole)

ADJUST DOSING INTERVAL: Food increases the absorption of itraconazole capsules but decreases the absorption of itraconazole oral solution. Cola beverages may increase the bioavailability of itraconazole capsules. Itraconazole capsules require an acidic gastric pH for adequate dissolution and subsequent absorption. Cola beverages help lower gastric pH and improve absorption.

GENERALLY AVOID: Grapefruit juice may impair the absorption of itraconazole capsules, resulting in decreased antifungal effects. In a small, randomized, crossover study, the administration of itraconazole capsules with double-strength grapefruit juice (compared to water) was associated with significantly decreased (43%) plasma concentrations of itraconazole and its pharmacologically active hydroxy metabolite, as well as delayed times to reach peak concentrations of both. The exact mechanism of interaction is unknown but may involve reduced absorption of itraconazole secondary to enhanced activity of intestinal P-glycoprotein drug efflux pumps and delayed gastric emptying induced by certain compounds present in grapefruits. Another study reported no pharmacokinetic changes with single-strength grapefruit juice. Whether or not these observations apply to itraconazole oral solution is unknown.

MANAGEMENT: The manufacturer recommends that the capsules be taken immediately after a full meal and the solution be taken on an empty stomach to ensure maximal absorption. Cola beverages may help increase the bioavailability of itraconazole capsules, particularly in patients with hypochlorhydria or those treated concomitantly with gastric acid suppressants. Until more information is available, it may be advisable to avoid the consumption of grapefruits and grapefruit juice during itraconazole therapy.

References

  1. Van Peer A, Woestenborghs R, Heykants J, et al. "The effects of food and dose on the oral systemic availability of itraconazole in healthy subjects." Eur J Clin Pharmacol 36 (1989): 423-6
  2. Wishart JM "The influence of food on the pharmacokinetics of itraconazole in patients with superficial fungal infection." J Am Acad Dermatol 17 (1987): 220-3
  3. "Product Information. Sporanox (itraconazole)." Janssen Pharmaceuticals PROD (2002):
  4. Barone JA, Koh JG, Bierman RH, Colaizzi JL, Swanson KA, Gaffar MC, Moskovitz BL, Mechlinski W, Van de Velde V "Food interaction and steady-state pharmacokinetics of itraconazole capsules in healthy male volunteers." Antimicrob Agents Chemother 37 (1993): 778-84
  5. Zimmermann T, Yeates RA, Albrecht M, Laufen H, Wildfeuer A "Influence of concomitant food intake on the gastrointestinal absorption of fluconazole and itraconazole in japanese subjects." Int J Clin Pharmacol Res 14 (1994): 87-93
  6. "Product Information. Sporanox (itraconazole)." Janssen Pharmaceuticals (2022):
  7. Kawakami M, Suzuki K, Ishizuka T, Hidaka T, Matsuki Y, Nakamura H "Effect of grapefruit juice on pharmacokinetics of itraconazole in healthy subjects." Int J Clin Pharmacol Ther 36 (1998): 306-8
  8. Barone JA, Moskotitz BL, Guarnieri J, Hassell AE, Colaizzi JL, Bierman RH, Jessen L "Food interaction and steady-state pharmacokinetics of itraconazole oral solution in healthy volunteers." Pharmacotherapy 18 (1998): 295-301
  9. Penzak SR, Gubbins PO, Gurley BJ, Wang PL, Saccente M "Grapefruit juice decreases the systemic availability of itraconazole capsules in healthy volunteers." Ther Drug Monit 21 (1999): 304-9
  10. Katz HI "Drug interactions of the newer oral antifungal agents." Br J Dermatol 141 (1999): 26-32
View all 10 references

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Moderate

eszopiclone food

Applies to: eszopiclone

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of zopiclone and eszopiclone. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

ADJUST DOSING INTERVAL: Administration of eszopiclone (the S-enantiomer of zopiclone) with or immediately after a high-fat/heavy meal may delay the onset of hypnotic effects. In healthy adults, administration of a 3 mg dose of eszopiclone after a high-fat meal decreased the mean peak plasma drug concentration (Cmax) by 21% and delayed the time to reach peak plasma drug concentration (Tmax) by approximately 1 hour. Theoretically, this interaction should also affect racemic zopiclone.

MANAGEMENT: Patients receiving zopiclone or eszopiclone should be advised to avoid consumption of alcohol. For faster sleep onset, eszopiclone and zopiclone should not be administered with or immediately after a high-fat/heavy meal.

References

  1. "Product Information. Lunesta (eszopiclone)." Sepracor Inc (2004):
  2. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0

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Therapeutic duplication warnings

No warnings were found for your selected drugs.

Therapeutic duplication warnings are only returned when drugs within the same group exceed the recommended therapeutic duplication maximum.

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Drug Interaction Classification

These classifications are only a guideline. The relevance of a particular drug interaction to a specific individual is difficult to determine. Always consult your healthcare provider before starting or stopping any medication.
Major Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit.
Moderate Moderately clinically significant. Usually avoid combinations; use it only under special circumstances.
Minor Minimally clinically significant. Minimize risk; assess risk and consider an alternative drug, take steps to circumvent the interaction risk and/or institute a monitoring plan.
Unknown No interaction information available.

Further information

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