Key takeaways:
Phenobarbital is an older medication that’s used as a sedative and to treat seizures. But it’s less commonly prescribed today due to its possible side effects and interactions.
Phenobarbital is notorious for having many potential interactions. It can interact with alcohol, blood thinners, and other medications that cause drowsiness. It can also interact with seizure medications and many hormonal forms of birth control.
Be sure to provide a current medication list to your healthcare team before taking phenobarbital. Your pharmacist and prescriber can check for possible interactions and help you avoid or manage them.
Phenobarbital is a barbiturate medication used to treat seizures. It’s also sometimes used as a sedative. It has been around for over a century and is available in tablet, liquid, and injectable (Sezaby) forms. Phenobarbital is notorious for its many interactions, which is one of the reasons why it’s now prescribed less often.
When combined with other medications that affect the brain, phenobarbital can cause excessive drowsiness and other side effects. It also impacts liver enzymes (proteins), which can affect how other medications are broken down in the body.
Phenobarbital interactions summary
Phenobarbital can interact with each of the medications listed below. Though, this isn’t a comprehensive list. Keep your healthcare team updated on your current medications. They can check for possible interactions whenever you have a medication change.
The following medications and substances can interact with phenobarbital:
Alcohol
Benzodiazepines, such as alprazolam (Xanax) and diazepam (Valium)
Buspirone
Diphenhydramine (Benadryl)
Doxycycline (Vibramycin, Doryx, Oracea)
Dronedarone (Multaq)
Eletriptan (Relpax)
Eplerenone (Inspra)
Felodipine
Griseofulvin (Fulvicin, Gris-PEG)
Hormonal birth control
Ivabradine (Corlanor)
Lovastatin (Altoprev)
Monoamine oxidase inhibitors (MAOIs), such as rasagiline (Azilect) and selegiline (Emsam, Zelapar)
Muscle relaxers, such as cyclobenzaprine (Amrix) and tizanidine (Zanaflex)
Opioids, such as fentanyl
Paxlovid (nirmatrelvir / ritonavir)
Seizure medications, such as carbamazepine (Tegretol) and phenytoin (Dilantin)
Sleep medications, such as zolpidem (Ambien) and eszopiclone (Lunesta)
Sildenafil (Viagra, Revatio)
Simvastatin (Zocor, Flolipid)
Steroids, such as prednisone
Ticagrelor (Brilinta)
Tricyclic antidepressants (TCAs), such as amitriptyline
Warfarin (Jantoven)
Here, we’ll cover details about eight phenobarbital interactions.
1. Alcohol
Alcohol and phenobarbital both slow brain activity. Taking them together can cause extreme drowsiness, poor coordination, and impaired thinking. For this reason, it’s best to avoid alcohol while you’re taking phenobarbital. Another reason to steer clear is that alcohol can make seizures more likely if you have a seizure disorder.
It’s best to be open and honest with your prescriber about your alcohol intake. If needed, they can help you stop drinking safely.
2. Benzodiazepines
Similar to phenobarbital, benzodiazepines — such as alprazolam, diazepam, and lorazepam (Ativan) — calm brain activity. Taking them with phenobarbital can compound side effects such as drowsiness, confusion, and slowed breathing. This combination also increases the risk of an overdose.
It’s best to avoid combining benzodiazepines and phenobarbital. But in some rare situations, such as with severe seizures, people may need to take both.
3. Sleep medications
Sleep medications, such as zolpidem, eszopiclone, and even over-the-counter diphenhydramine, can worsen sedation when taken with phenobarbital. While feeling drowsy may help you get to sleep, excessive sleepiness can be dangerous. It can also impair your ability to think clearly and increase the risk of falls.
It’s best to avoid sleep medications with phenobarbital unless this combination is specifically recommended by your healthcare team.
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4. Other medications that cause sleepiness
Apart from sleep aids, there are other medications that cause drowsiness. When these medications are taken with phenobarbital, there’s a higher risk of excessive drowsiness. Examples include:
MAOIs, such as rasagiline and selegiline
TCAs, such as amitriptyline
Muscle relaxers, such as cyclobenzaprine and tizanidine
It’s also important to note that TCAs and some of the other medications in this group can lower the seizure threshold. This means they can increase the likelihood of having a seizure, even though phenobarbital is used to prevent seizures.
It’s generally best not to mix these medications with phenobarbital, unless directed to do so by your healthcare team.
5. Blood thinners
Phenobarbital can lower the effectiveness of certain blood thinners, including warfarin and ticagrelor. This happens because phenobarbital causes your liver to break them down faster. Because blood thinners treat and prevent unwanted blood clots, lower levels can mean a higher risk of clotting.
Be sure your prescriber knows if you’re taking a blood thinner. They may take extra precautions, such as raising your dose or checking your blood work more often.
6. Seizure medications
Although phenobarbital is used to treat seizures, combining it with other seizure medications can be tricky. Phenobarbital may raise or lower the levels of other seizure medications, such as phenytoin, carbamazepine, and divalproex (Depakote). These interactions can increase the risk of side effects or cause unpredictable changes in seizure control.
Phenobarbital may be combined with other seizure medications in some cases, but it isn’t common. Your prescriber will help ensure that you take the most effective and safest regimen possible to treat your seizures.
7. Hormonal birth control
Phenobarbital can speed up the breakdown of hormones in many hormonal forms of birth control, including birth control pills, patches, and vaginal rings. This can make them less effective at preventing pregnancy.
Phenobarbital can also cause harm to a growing fetus if taken during pregnancy. If you’re able to get pregnant, talk to your healthcare team about your contraception options. They can help you find a birth control method that’s best for your situation.
8. Steroids
Corticosteroids (also known as “steroids”) are medications that help lower inflammation and calm the immune system. One common example is prednisone.
Phenobarbital can cause your liver to break down steroids more quickly, reducing their effect. If taken together, you might need a higher steroid dose, or your prescriber may want to monitor you more closely.
The bottom line
Phenobarbital can interact with many medications. Examples include blood thinners, many hormonal forms of birth control, and other seizure medications. It can also interact with alcohol, opioids, and benzodiazepines.
To stay safe, always share your full medication list with your prescriber and pharmacist. They can check for interactions and come up with a plan to manage them if needed.
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References
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e5 Pharma. (2024). Phenobarbital - phenobarbital tablet [package insert].
Jain, P., et al. (2022). Treatment of benzodiazepine-resistant status epilepticus: Systematic review and network meta-analyses. Seizure: European Journal of Epilepsy.
Reddy, D. S. (2010). Clinical pharmacokinetic interactions between antiepileptic drugs and hormonal contraceptives. Expert Review of Clinical Pharmacology.
Schachter, S. C. (n.d.). Alcohol as a seizure trigger. Epilepsy Foundation.
U.S. Food and Drug Administration. (2025). For healthcare professionals | FDA’s examples of drugs that interact with CYP enzymes and transporter systems.
Yasiry, Z., et al. (2012). How phenobarbital revolutionized epilepsy therapy: The story of phenobarbital therapy in epilepsy in the last 100 years. Epilepsia.
