Phenytoin and Generics: What You Need to Know About Therapeutic Drug Monitoring

Switching from brand-name Dilantin to a generic version of phenytoin might seem like a simple cost-saving move. But for patients taking this drug, it can be anything but simple. Phenytoin isn’t like most medications. Even small changes in how much of the drug gets into your bloodstream can lead to seizures-or worse, toxicity. That’s why therapeutic drug monitoring isn’t optional when you switch generics. It’s essential.

Why Phenytoin Is Different

Phenytoin has been used since the 1930s to control seizures. It’s cheap, effective, and still widely prescribed. But its behavior in the body is unpredictable. The therapeutic range is narrow: 10 to 20 mcg/mL. Go below 10, and seizures may return. Go above 20, and you risk dizziness, loss of coordination, confusion, or even coma. At levels over 50 mcg/mL, death can occur.

What makes phenytoin especially tricky is its non-linear pharmacokinetics. That means if you increase the dose by just 25-50 mg, the drug concentration in your blood might jump way more than expected. Your body’s ability to clear it gets overwhelmed. This isn’t like taking a painkiller, where doubling the dose roughly doubles the effect. With phenytoin, it’s like turning a dimmer switch into an on/off button.

Add to that: phenytoin is 90-95% bound to proteins in your blood. Only the small unbound fraction (about 10%) actually works to prevent seizures. If your protein levels drop-because you’re sick, malnourished, or have liver disease-more of the drug becomes unbound. Even if your total blood level looks normal, you could be getting too much active drug. That’s why a "normal" level doesn’t always mean safe.

Generic Switches Aren’t Always Safe

The FDA says generic drugs must be bioequivalent to the brand. That means their absorption must fall within 80-125% of the original. Sounds fair, right? But for phenytoin, that 20% variation is dangerous.

Imagine you’ve been stable on brand-name Dilantin for years. Your level is 15 mcg/mL. You switch to a generic that’s on the high end of bioequivalence-125% absorption. Your new level might jump to nearly 19 mcg/mL. Still in range? Maybe. But now you’re close to the top. A slight change in diet, a new antibiotic, or even dehydration could push you over 20. Suddenly, you’re at risk.

Or worse: you switch to a generic that absorbs only 80% as well. Your level drops from 15 to 12. You feel fine. But then you miss a dose. Now you’re at 9.6. Your seizure control slips. No warning. No symptoms until it’s too late.

This isn’t theoretical. Clinicians have documented cases where patients had breakthrough seizures after switching to a different generic-sometimes even between two generics made by different companies. The FDA’s standards were designed for drugs with wide safety margins. Phenytoin doesn’t have one.

When to Monitor Levels

You don’t need to check phenytoin levels every month. But you absolutely must check them at key moments:

• Before switching formulations-Get a baseline level right before you switch from brand to generic, or from one generic to another.
• 5 to 10 days after switching-That’s when steady-state levels are reached. A level taken too early won’t tell you anything.
• After any dose change-Even if you’re staying on the same brand, changing your dose requires a follow-up level.
• If you start or stop another medication-Many drugs interact with phenytoin. Antibiotics like trimethoprim-sulfamethoxazole, antifungals like fluconazole, and even alcohol can spike or drop your levels.
• If you develop symptoms-Tremors, slurred speech, dizziness, or nausea? Don’t wait. Get a level checked.

The NHS Tayside guidelines say it plainly: "Therapeutic monitoring may be required when switching formulations." That’s not a suggestion. It’s a safety rule.

What the Level Doesn’t Tell You

A total phenytoin level is just part of the picture. If you’re low on albumin-common in older adults, people with liver disease, or those who are malnourished-you need a free phenytoin level. That measures only the active, unbound drug.

There’s a formula to estimate free levels from total levels and albumin: Corrected phenytoin = Total level / ((0.9 × Albumin / 42) + 0.1). But here’s the catch: it’s only a rough estimate. The best practice? If your albumin is below 3.5 g/dL, ask for a free phenytoin test. Don’t rely on the math.

Also, don’t assume your level is stable just because you haven’t changed your dose. Your liver metabolism can shift over time. Your kidney function can decline. You might start eating differently. All of these affect how phenytoin moves through your body.

Other Things to Watch For

Phenytoin doesn’t just affect your brain. Long-term use can cause:

• Gingival hyperplasia (swollen, overgrown gums)
• Hirsutism (excessive hair growth)
• Vitamin D deficiency and bone loss
• Folic acid deficiency
• Peripheral neuropathy

That’s why regular blood tests aren’t just about drug levels. You need:

• Full blood count (to check for low white cells)
• Liver function tests
• Electrolytes and kidney function
• Vitamin D and calcium levels
• Albumin levels

These should be checked at least once a year, more often if you’re older or have other health issues.

What Patients Should Do

If you’re on phenytoin:

• Know your current level. Ask your doctor for a copy.
• Ask if your pharmacy is switching your prescription to a different generic. If they are, insist on a follow-up level.
• Don’t accept a new generic without checking with your neurologist or pharmacist.
• Keep a list of all your medications-including over-the-counter drugs and supplements. Many interact with phenytoin.
• Report any new symptoms, no matter how small. Dizziness, clumsiness, or odd eye movements could be early signs of toxicity.

What Doctors Should Do

Clinicians need to stop treating phenytoin like any other drug. Routine monitoring isn’t needed for everyone-but switching formulations? That’s a red flag.

The American Academy of Family Physicians says monitoring during formulation changes is "clinically useful"-even if evidence is limited. That’s the best we’ve got. And in practice, it’s the only way to prevent harm.

When switching phenytoin:

• Document the exact product being switched from and to.
• Check a level before and 5-10 days after the switch.
• For patients with low albumin, order a free phenytoin level.
• Warn patients about signs of toxicity and when to seek help.
• Don’t assume bioequivalence means interchangeability.

Bottom Line

Generic phenytoin is not the same as brand-name Dilantin-not in clinical practice. The FDA’s bioequivalence standards were never meant for drugs with phenytoin’s narrow window and non-linear behavior. For patients, the stakes are high: seizures, toxicity, even death.

Therapeutic drug monitoring isn’t a luxury. It’s a lifeline. If you’re on phenytoin, don’t let a pharmacy change your medication without checking your level. If you’re prescribing it, don’t assume a switch is safe. Track your numbers. Watch your patients. And never treat phenytoin like an ordinary pill.