Eszopiclone Drug Interactions: What You Need to Know

Eszopiclone (brand name Lunesta) can interact with other medications, supplements, and even certain foods in ways that increase side effects or change how well it works. Understanding these interactions is essential for your safety.

This guide covers the most important drug interactions for Eszopiclone — what to avoid, what to use with caution, and what to tell your doctor before starting treatment.

How Drug Interactions Work with Eszopiclone

Eszopiclone is broken down in your liver by an enzyme called CYP3A4. Many drug interactions happen because other medications either slow down or speed up this enzyme:

• CYP3A4 inhibitors slow down the enzyme, causing Eszopiclone to build up in your body. This increases the risk of side effects like excessive sedation.
• CYP3A4 inducers speed up the enzyme, causing Eszopiclone to be cleared too quickly. This reduces its effectiveness.

Other interactions happen because certain drugs add to Eszopiclone's sedative effects, increasing the risk of dangerous oversedation.

Medications That Interact with Eszopiclone

Major Interactions — Avoid or Use Extreme Caution

These combinations are either contraindicated or require dose adjustments and close monitoring:

Alcohol

• Alcohol is contraindicated with Eszopiclone. Combining them causes additive CNS depression — meaning profound sedation, impaired breathing, loss of coordination, and increased risk of complex sleep behaviors. Do not drink alcohol while taking Eszopiclone.

Opioid Medications

• Opioids like Oxycodone (OxyContin), Hydrocodone (Vicodin), Morphine, Fentanyl, and Tramadol combined with Eszopiclone increase the risk of severe sedation, respiratory depression, coma, and death. If you must take both, your doctor should use the lowest effective doses and monitor you closely.

Strong CYP3A4 Inhibitors

• These drugs slow down Eszopiclone's metabolism, raising its levels in your blood. If you take any of these, your Eszopiclone dose should not exceed 2 mg:
• Ketoconazole (Nizoral) — antifungal
• Itraconazole (Sporanox) — antifungal
• Clarithromycin (Biaxin) — antibiotic
• Ritonavir (Norvir) — HIV protease inhibitor

Other CNS Depressants

• Any medication that causes drowsiness can amplify Eszopiclone's sedative effects. This includes:
• Benzodiazepines: Alprazolam (Xanax), Lorazepam (Ativan), Diazepam (Valium), Clonazepam (Klonopin)
• Sedating antihistamines: Diphenhydramine (Benadryl), Hydroxyzine (Vistaril), Doxylamine (Unisom)
• Antipsychotics: Quetiapine (Seroquel), Olanzapine (Zyprexa)
• Muscle relaxants: Cyclobenzaprine (Flexeril), Tizanidine (Zanaflex)
• Other sleep medications: Zolpidem (Ambien), Suvorexant (Belsomra)

Moderate Interactions — Use with Caution

Moderate CYP3A4 Inhibitors

• These drugs partially slow Eszopiclone metabolism. Your doctor may adjust your dose:
• Erythromycin — antibiotic
• Fluconazole (Diflucan) — antifungal
• Verapamil (Calan) — calcium channel blocker

CYP3A4 Inducers

• These drugs speed up Eszopiclone metabolism, potentially making it less effective:
• Rifampin (Rifadin) — antibiotic for tuberculosis
• Carbamazepine (Tegretol) — seizure medication
• Phenytoin (Dilantin) — seizure medication
• St. John's Wort — herbal supplement

If you take any of these, your doctor may need to increase your Eszopiclone dose or consider an alternative sleep medication.

Supplements and OTC Medications to Watch

Several over-the-counter products can interact with Eszopiclone:

• Diphenhydramine (Benadryl, ZzzQuil, Tylenol PM): Additive sedation. Avoid combining with Eszopiclone.
• Doxylamine (Unisom SleepTabs): Same issue — doubled sedation risk.
• Melatonin: Generally considered safe to take with Eszopiclone, but talk to your doctor first, as both promote sleep and combining them may cause excessive drowsiness.
• Valerian root: May increase sedation. Limited data available — use with caution.
• CBD products: CBD can inhibit CYP3A4, potentially increasing Eszopiclone levels. Discuss with your doctor.
• Kava: May add to CNS depression. Avoid.
• St. John's Wort: A CYP3A4 inducer that can reduce Eszopiclone's effectiveness. Avoid.

Food and Drink Interactions

High-Fat Meals

Taking Eszopiclone with or immediately after a heavy, high-fat meal delays absorption and reduces its effectiveness. Take it on an empty or light stomach for the best results.

Grapefruit and Grapefruit Juice

Grapefruit is a known CYP3A4 inhibitor. Drinking grapefruit juice while taking Eszopiclone may increase drug levels in your blood, raising the risk of side effects. Avoid grapefruit products or discuss them with your doctor.

Caffeine

While not a direct pharmacological interaction, consuming caffeine — especially in the afternoon or evening — can counteract Eszopiclone's effects. If you're taking a sleep medication, limit caffeine after noon.

What to Tell Your Doctor

Before starting Eszopiclone, give your doctor a complete picture of everything you take. This includes:

• All prescription medications — even ones you think are unrelated (heart medications, antibiotics, antifungals, HIV drugs, seizure medications)
• Over-the-counter medications — especially antihistamines, pain relievers containing PM formulas, and cold/flu medications
• Supplements and herbal products — including melatonin, valerian, CBD, St. John's Wort, and kava
• Alcohol use — be honest, as combining alcohol with Eszopiclone is dangerous
• Recreational substances — including marijuana, which can add to sedation

Bring a written list to your appointment. This helps your doctor check for interactions and adjust your treatment plan accordingly. For tips on preparing for your visit, see our guide on finding a doctor who prescribes Eszopiclone.

Final Thoughts

Drug interactions with Eszopiclone are manageable when you and your doctor know what to watch for. The biggest risks come from combining it with alcohol, opioids, or other sedating medications. Keep your provider informed about everything you take, and don't add new medications or supplements without checking first.

If you're ready to fill your Eszopiclone prescription, Medfinder can help you find a pharmacy with it in stock near you.