Phenytoin XR Has More Drug Interactions Than Most Medications

Phenytoin XR is one of the most effective seizure medications available — but it also has one of the longest lists of drug interactions in modern medicine. If you're taking Phenytoin XR, knowing what can interact with it is essential for your safety.

This isn't meant to scare you. Many of these interactions are manageable with proper monitoring. But you need to know what to watch for and what to tell your doctor.

How Drug Interactions Work with Phenytoin XR

Phenytoin XR is processed by your liver using a group of enzymes called the cytochrome P450 system (mainly CYP2C9 and CYP2C19). Here's why that matters:

• Phenytoin XR is a potent enzyme inducer — It speeds up the liver's processing of many other drugs, making them less effective. This is why it can reduce the effectiveness of birth control pills, blood thinners, and other medications.
• Other drugs can affect Phenytoin XR levels — Some medications slow down or speed up how your liver processes Phenytoin XR, raising or lowering your blood levels. Because Phenytoin XR has a narrow therapeutic index, even small changes in blood levels can mean the difference between seizure protection and toxicity.
• Protein binding displacement — Phenytoin XR is highly bound to proteins in your blood. Some drugs can displace it, temporarily increasing the active (free) drug level.

Medications That Interact with Phenytoin XR

This is not a complete list, but these are the most clinically significant interactions:

Drugs That INCREASE Phenytoin XR Levels (Risk of Toxicity)

• Amiodarone — A heart rhythm medication. Can significantly raise Phenytoin XR levels.
• Fluconazole — An antifungal. Inhibits the enzymes that process Phenytoin XR.
• Cimetidine — An older heartburn medication (Tagamet).
• Omeprazole — A proton pump inhibitor (Prilosec). Can raise phenytoin levels.
• Disulfiram — Used for alcohol dependence (Antabuse).
• Valproic acid — Another seizure medication. Displaces Phenytoin XR from protein binding and inhibits metabolism, causing complex level changes.

Drugs That DECREASE Phenytoin XR Levels (Risk of Seizures)

• Rifampin — A tuberculosis antibiotic. Potent enzyme inducer that can dramatically lower Phenytoin XR levels.
• Chronic alcohol use — Stimulates enzymes that process Phenytoin XR faster.
• Theophylline — A breathing medication. Can lower phenytoin levels while phenytoin lowers theophylline levels.

Drugs Made LESS Effective by Phenytoin XR

• Oral contraceptives (birth control pills) — Phenytoin XR can make hormonal birth control unreliable. Talk to your doctor about alternative contraception methods.
• Warfarin — Phenytoin XR can alter how warfarin works. Your doctor will need to monitor your INR closely.
• Corticosteroids — Prednisone and similar drugs may be less effective.
• Cyclosporine — An immunosuppressant. Phenytoin XR can dangerously reduce cyclosporine levels.
• Doxycycline — This antibiotic may not reach effective levels while taking Phenytoin XR.
• Digoxin — A heart medication. Levels may drop below the therapeutic range.
• Methotrexate — A chemotherapy/autoimmune drug. Interaction can increase methotrexate toxicity.

Contraindicated Combinations

• Delavirdine — An HIV medication. Taking it with Phenytoin XR is contraindicated because Phenytoin XR can cause loss of virologic response and potential HIV resistance.

Supplements and Over-the-Counter Interactions

Don't overlook OTC products and supplements:

• Folic acid — Supplementation may lower Phenytoin XR levels. Your doctor may still recommend it (especially if you're of childbearing age), but your phenytoin levels should be monitored.
• Calcium supplements — Taking calcium at the same time as Phenytoin XR may reduce absorption. Separate them by at least 2 hours.
• Antacids — Calcium- and magnesium-containing antacids can reduce Phenytoin XR absorption. Take them at different times.
• St. John's Wort — An herbal supplement that can speed up Phenytoin XR metabolism, potentially lowering levels.

Food and Drink Interactions

• Alcohol — The interaction depends on the pattern. Acute (one-time heavy) drinking can increase Phenytoin XR levels and toxicity risk. Chronic heavy drinking does the opposite — it speeds up metabolism and lowers levels, increasing seizure risk.
• Enteral tube feeding — Tube feeding formulas can reduce Phenytoin XR absorption significantly. If you receive tube feeds, hold them for 2 hours before and 2 hours after each Phenytoin XR dose.
• Calcium-rich foods — Dairy products and other high-calcium foods may slightly reduce absorption if consumed at the same time. This is usually not a major concern with normal dietary intake, but avoid taking Phenytoin XR with a large glass of milk.

What to Tell Your Doctor

Before starting Phenytoin XR — and at every visit — tell your doctor about:

• All prescription medications — Even ones prescribed by other doctors.
• All over-the-counter drugs — Including pain relievers, heartburn medications, cold medicines, and sleep aids.
• All supplements and herbs — Including vitamins, minerals, and herbal products.
• Alcohol use — Be honest about how much and how often you drink.
• Any planned surgeries or dental procedures — Phenytoin XR can interact with anesthesia and other surgical medications.
• Pregnancy plans — Phenytoin XR affects birth control effectiveness and is dangerous during pregnancy.

If any doctor, dentist, or pharmacist adds or changes a medication while you're on Phenytoin XR, make sure your prescribing neurologist knows. Even a common antibiotic or antifungal can shift your levels.

Final Thoughts

Phenytoin XR's long list of drug interactions is one of its biggest drawbacks, but it's manageable with good communication between you and your healthcare team. The key is to never start or stop any medication without telling your doctor that you take Phenytoin XR.

If you're looking for a medication with fewer interactions, talk to your doctor about alternatives to Phenytoin XR. And if you need help finding your medication, Medfinder can help you locate Phenytoin XR in stock near you.