11 Phenytoin Interactions You Should Know About

Phenytoin (Dilantin, Phenytek) is a medication that treats certain types of seizures. It works by stopping your nerves from sending abnormal messages in the brain.

If you take phenytoin, it’s important to know that it has many likely drug interactions. Some interactions can increase your risk of phenytoin side effects. In other cases, it can make phenytoin less effective. Phenytoin can also affect how well many other medications work.

Here, we’ll discuss 11 phenytoin interactions to be aware of. But this isn’t a complete list. So, talk to your prescriber or pharmacist before starting phenytoin. Give them a list of all the medications you take, including over-the-counter (OTC) products. This will help them check for phenytoin interactions.

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1. Azole antifungals like fluconazole and ketoconazole

Azoles are a group of medications that treat different types of fungal infections. Fluconazole (Diflucan), ketoconazole, and voriconazole (Vfend) are a few examples of azoles. Azoles can increase phenytoin levels. But phenytoin can also lower azole levels.

This may sound confusing, so let’s break it down.

Many azoles block one or more of the enzymes (proteins) that metabolize (break down) phenytoin. When phenytoin isn’t broken down, you experience higher levels of phenytoin in the body. This raises the risk of side effects like drowsiness, coordination problems, and abnormal eye movements.

On the other hand, phenytoin can speed up the metabolism of azoles in the body. This may decrease levels of azoles and make them less effective, leaving your fungal infection under-treated.

If you’re taking an azole, your prescriber may keep an eye on your phenytoin levels more closely. They may also suggest adjusting your phenytoin dose. Or they may recommend taking an antifungal that isn't known to interact with phenytoin.

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2. Some antibiotics like Bactrim and doxycycline

Sulfamethoxazole / trimethoprim (Bactrim), rifampin (Rifadin), and doxycycline (Vibramycin, Doryx, Oracea) are antibiotics that can interact with phenytoin. Isoniazid, an antibiotic that treats tuberculosis, can also interact with phenytoin. Antibiotics are medications that treat different types of bacterial infections.

Bactrim and isoniazid may block metabolism of phenytoin. This can increase levels of phenytoin and raise your risk of side effects. On the other hand, rifampin causes phenytoin to leave the body more quickly. This may lead to lower levels of phenytoin, which raises your risk of having a seizure. What’s more, phenytoin can also make rifampin less effective. It can also have this effect on doxycycline. Combining these medications with phenytoin could leave your infection under-treated.

If you take Bactrim or rifampin, your prescriber may check your phenytoin levels more frequently. Watch out for any new or worsening side effects, seizures, or signs that your bacterial infection hasn’t improved.

Good to know: Phenytoin doesn’t interact with all antibiotics. So there’s a good chance your prescriber can recommend antibiotic options that don’t interact with phenytoin.

3. Other seizure medications like phenobarbital and Depakote

Phenytoin may interact with other seizure medications in several ways.

For example, phenytoin may lower blood levels of some seizure medications. This raises your risk of having a seizure. Examples of these interacting seizure medications include:

• Felbamate (Felbatol)

• Oxcarbazepine (Trileptal)

• Carbamazepine (Tegretol)

• Lacosamide (Vimpat)

• Lamotrigine (Lamictal)

• Topiramate (Topamax)

Some seizure medications can also affect how well phenytoin works in the body. This includes some of the same medications listed above. Interacting seizure medications may affect phenytoin in several ways:

• Lowering phenytoin levels: Carbamazepine and vigabatrin (Sabril) can decrease phenytoin levels. This makes phenytoin less effective and increases your risk of seizures.

• Increasing phenytoin levels: Felbamate, oxcarbazepine, and ethosuximide (Zarontin) can increase phenytoin levels. This raises the risk of phenytoin side effects.

• Having unpredictable effects on phenytoin: Phenobarbital, valproic acid, and divalproex (Depakote) may have varying effects on phenytoin. They may increase or decrease levels of phenytoin.

Before starting phenytoin, tell your prescriber if you take other seizure medications. They may need to watch you more closely for side effects or for seizure recurrence. In some cases, they may recommend adjusting the doses of your seizure medications. But don’t do this without talking to them first.

4. HIV medications like ritonavir

Many medications that treat HIV are known to have several drug interactions, including with phenytoin. For example, ritonavir (Norvir), nelfinavir (Viracept), and fosamprenavir (Lexiva) may decrease phenytoin levels in the body. This can make phenytoin less effective and increase your risk of having a seizure.

But phenytoin can also decrease the levels of these exact same HIV medications and others, including efavirenz (Sustiva) and saquinavir (Invirase). This is a possibly dangerous interaction, because it could make these HIV medications less effective.

If you need phenytoin and an HIV medication, your prescriber may want to adjust your medication regimen.

5. Heartburn medications like omeprazole and Tums

Some stomach acid-lowering medications can interact with phenytoin. These medications treat heartburn, gastroesophageal reflux disease (GERD), and other digestive conditions. For example, omeprazole (Prilosec), a proton pump inhibitor (PPI), can increase phenytoin levels. So can cimetidine (Tagamet HB), a histamine-2 antagonist (H2 blocker).

But other acid-lowering medications called antacids can decrease levels of phenytoin. This could make phenytoin less effective. These medications typically contain calcium carbonate, aluminum hydroxide, or magnesium hydroxide (or a combination of these ingredients). This includes common brand names like Tums, Rolaids, and Mylanta Maximum Strength.

Several PPIs, H2 blockers, and antacids are available OTC. Still, let your prescriber know if you take one before starting phenytoin. If you take an antacid, you shouldn’t take it at the same time of day as phenytoin. You’ll need to space out your doses so antacids don’t block phenytoin from being absorbed. Talk to your prescriber or pharmacist about how to space your doses.

6. Antidepressants like sertraline and fluoxetine

Medications that treat depression and other mental health conditions can interact with phenytoin. This includes a group of antidepressants called selective serotonin reuptake inhibitors (SSRIs). SSRIs like fluoxetine (Prozac), sertraline (Zoloft), and fluvoxamine (Luvox) can boost phenytoin levels. This makes phenytoin side effects more likely.

On the other hand, phenytoin can lower levels of many antidepressants. Examples include paroxetine (Paxil) and sertraline. This can make your antidepressant less effective.

If you take an antidepressant, check with your prescriber and pharmacist to see if it interacts with phenytoin. Even if it does, it may be possible to take both medications together. Your prescriber may just recommend watching for phenytoin side effects or signs of worsening depression.

7. Anticoagulants like warfarin and apixaban

Phenytoin can have unpredictable effects on warfarin (Jantoven), a type of anticoagulant that can prevent and treat blood clots. Anticoagulants are also sometimes called “blood thinners.” 

Warfarin may not work as well when taken with phenytoin. This can increase your risk of blood clots. Or, phenytoin can increase warfarin levels, and raise your risk of bleeding.

If you take both warfarin and phenytoin, make sure the prescriber of each medication knows. They may monitor a blood test called the international normalized ratio (INR) more often. The INR test checks how well your blood is able to clot while taking warfarin.

Another group of anticoagulants can also interact with phenytoin. They're called direct oral anticoagulants (DOACs). Examples include apixaban (Eliquis), dabigatran (Pradaxa), and rivaroxaban (Xarelto).

DOACs may not work as well when they’re taken with phenytoin, making blood clots more likely. If you take a DOAC and phenytoin, talk to your prescriber about whether you should adjust your doses. In some cases, they may recommend another seizure medication that doesn’t interact.

8. Alcohol

Drinking alcohol while taking phenytoin can have unpredictable effects on phenytoin levels. When you drink alcohol sporadically, it can raise phenytoin levels and increase your risk of side effects. Alcohol and phenytoin can also have additive side effects, like drowsiness or dizziness.

On the other hand, drinking large amounts of alcohol over time can decrease phenytoin levels. This raises the risk of seizures. So if you drink alcohol regularly, phenytoin may not be the best option for you. Talk to your prescriber about whether you drink alcohol before taking phenytoin.

If you or someone you know struggles with substance use, help is available. Call SAMHSA’s National Helpline at 1-800-662-4357 to learn about resources in your area.

9. Hormonal birth control

Many anti-seizure medications are well-known for making hormonal birth control less effective. Hormonal birth control products contain lab-made versions of sex hormones (estrogen and progestin). Examples include birth control pills, most intrauterine devices, and vaginal rings.

Phenytoin may lower the effectiveness of hormonal birth control. This can cause side effects like breakthrough bleeding. And more importantly, this can lead to unplanned pregnancies.

If you’re taking phenytoin and hormonal birth control, you should assume that your birth control isn’t as effective. Use backup contraception, like condoms, to prevent an unplanned pregnancy. Or, consider switching to a non-hormonal birth control option. One example is the copper intrauterine device (Paragard).

It’s also important to note that taking phenytoin while pregnant may cause risks to your unborn baby. This includes cleft lip/palate, heart problems, and growth problems. So it’s important to use backup contraception to prevent an unplanned pregnancy while taking phenytoin. If you’re interested in becoming pregnant, or you become pregnant while taking phenytoin, let your prescriber know immediately.

10. Immunosuppressants like cyclosporine, tacrolimus, and prednisone

Cyclosporine (Sandimmune, Gengraf, Neoral) and Tacrolimus (Prograf, Astagraf XL, Envarsus XR) are immunosuppressant medications. They help prevent and treat organ transplant rejection, among other uses. But phenytoin can decrease cyclosporine and tacrolimus levels in the body. This could reduce the effectiveness of these medications, increasing your risk of organ rejection.

Additionally, phenytoin can decrease prednisone (Rayos) levels. Prednisone is also commonly used after an organ transplant and for several other conditions. It's part of a group of medications called corticosteroids.

If you’ve been prescribed phenytoin, make sure all your prescribers know if you take an immunosuppressant (including prednisone). They can let you know if you need to make any changes to your medication regimen.

11. Chemotherapy medications like methotrexate

Several chemotherapy medications can affect phenytoin levels. This can happen in many ways. For example, capecitabine (Xeloda) and fluorouracil (Carac, Efudex, Tolak) can increase phenytoin levels. Other medications may decrease phenytoin levels, including:

• Bleomycin

• Carboplatin (Paraplatin)

• Cisplatin

• Doxorubicin (Doxil)

• Methotrexate (Trexall, Otrexup, others)

Additionally, phenytoin may decrease levels of some chemotherapy medications. This includes irinotecan (Camptosar, Onivyde) and paclitaxel (Abraxane). This can decrease how effective your chemotherapy is.

If you’re receiving chemotherapy, make sure your oncologist knows if you’re also taking phenytoin. They can determine whether you need to make any changes to your medication regimen.

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Written by:

Makaela Premont, PharmD

Makaela Premont, PharmD, is a pharmacist and the founder of uniquelymickie.com, a website dedicated to helping pharmacy students and pharmacists create a life that they enjoy. She received her Doctorate of Pharmacy from the University of South Carolina and is a licensed pharmacist in North Carolina.

Edited by:

Amy B. Gragnolati, PharmD, BCPS

Amy Gragnolati, PharmD, BCPS, is a pharmacy editor for GoodRx. Amy currently holds her pharmacist license in Georgia and California.

Reviewed by:

Austin Ulrich, PharmD, BCACP

Austin Ulrich, PharmD, BCACP, is a board-certified ambulatory care clinical pharmacist. In his early career, he provided direct patient care in a variety of settings, including hospital and community pharmacies, and in a primary care clinic as a clinical pharmacist.

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