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

Switching from brand-name phenytoin to a generic version might seem like a simple cost-saving move - but for patients taking this drug, it can be risky. Phenytoin isn’t like most medications. Even small changes in blood levels can lead to seizures or serious toxicity. That’s why therapeutic drug monitoring isn’t optional when switching between phenytoin formulations - it’s essential.

Why Phenytoin Is Different

Phenytoin has been used since the 1930s to control seizures, and it still works. But it’s tricky. It has a very narrow therapeutic window: 10 to 20 mcg/mL. Go below 10, and seizures might return. Go above 20, and you risk confusion, loss of coordination, or even coma. At levels over 50 mcg/mL, death becomes possible.

What makes it worse is how the body handles the drug. At low doses, phenytoin is cleared predictably. But as levels rise, the enzymes that break it down get overwhelmed. That’s called zero-order kinetics. A tiny increase in dose - say, 25 to 50 mg - can cause a huge spike in blood levels. There’s no safety buffer.

Add to that: phenytoin is 90-95% bound to proteins in the blood. Only the small unbound portion actually works. So if a patient has low albumin (common in elderly people, those with liver disease, or malnutrition), their total phenytoin level might look normal - but the active, unbound part could be dangerously high.

Generic Substitutions: The Hidden Risk

Generic drugs must meet FDA standards for bioequivalence. That means the amount of drug absorbed should be within 80-125% of the brand-name version. Sounds fine, right?

Not for phenytoin.

That 45% range - from 80% to 125% - is huge when your therapeutic window is only 10 mcg/mL wide. A patient stable at 15 mcg/mL on one generic could drop to 12 mcg/mL or jump to 18 mcg/mL after switching to another. Both changes can be dangerous. One might trigger a seizure. The other could cause toxicity.

Studies and guidelines from NHS Tayside, the American Academy of Family Physicians, and others agree: when switching phenytoin formulations - whether from brand to generic, or between two generics - you must monitor blood levels.

When to Check Levels

Timing matters. Phenytoin takes time to reach steady state. Don’t test too early.

• Check a level 2-3 days after starting or changing dose - just to make sure metabolism isn’t abnormal.
• Check again at 5-7 days - this is when steady state is usually reached.
• After switching formulations, check a trough level (just before the next dose) at 5-10 days.
• If given intravenously, wait 2-4 hours after a loading dose before testing.
• For oral doses, wait 12-24 hours.

The NHS Tayside guideline says it clearly: don’t assume the new version works the same. Test before and after the switch.

Special Cases: Who Needs Extra Care

Not everyone needs frequent monitoring. But some patients are at higher risk:

• Older adults - often have lower albumin, slower metabolism.
• People with liver disease - phenytoin is metabolized in the liver.
• Those with kidney failure - affects protein binding and clearance.
• Pregnant women - metabolism changes during pregnancy.
• Patients on multiple medications - many drugs interfere with phenytoin.

Drugs like amiodarone, fluconazole, and valproate can raise phenytoin levels. Alcohol, rifampin, and carbamazepine can lower them. If a patient starts or stops another med while on phenytoin, check levels again.

Correcting Levels for Low Albumin

If a patient has low albumin, the total phenytoin level can be misleading. A “normal” level of 14 mcg/mL might actually mean a toxic unbound level.

The formula used to estimate the corrected level is:

Corrected phenytoin = Measured level / [(0.9 × Albumin g/L) / 42 + 0.1]

But here’s the catch: this formula is just a rough estimate. It’s based on population averages. In real patients, especially those who are critically ill or malnourished, it can be off.

The best approach? If albumin is below 30 g/L, check the free phenytoin level instead. That tells you exactly how much active drug is in the blood. Many hospitals now offer this test - and it’s worth requesting if the patient seems off despite a “normal” total level.

Long-Term Monitoring Beyond Blood Levels

Phenytoin doesn’t just affect your brain. Long-term use causes other problems:

• Gingival hyperplasia (swollen gums)
• Hirsutism (excess hair growth)
• Thickened facial features
• Vitamin D deficiency
• Folic acid deficiency
• Osteomalacia (soft bones)
• Peripheral neuropathy

That’s why monitoring isn’t just about blood levels. Patients on long-term phenytoin should get:

• Baseline: CBC, liver function, electrolytes, vitamin D, calcium, phosphate
• Every 2-5 years: repeat bone health tests and CBC
• For Asian patients (Han Chinese or Thai): test for HLA-B*1502 gene before starting - this variant increases risk of severe skin reactions

These checks are just as important as tracking the drug level. You can’t control seizures if the patient breaks a bone or develops an infection from gum disease.

What to Do When Switching Formulations

Here’s a simple, practical plan:

1. Before switching, get a trough level.
2. Record how the patient is feeling - seizure frequency, dizziness, tremors, gum swelling.
3. Switch to the new formulation.
4. Check another trough level at 5-10 days.
5. If the level is outside 10-20 mcg/mL, adjust dose and recheck in 5-7 days.
6. If the patient feels worse - even if levels look fine - check free phenytoin and review all other medications.

Don’t rely on the pharmacy’s label saying “bioequivalent.” That label doesn’t guarantee safety for phenytoin.

Bottom Line

Generic phenytoin is cheaper. But cost savings shouldn’t come at the cost of safety. For this drug, therapeutic drug monitoring isn’t a nice-to-have. It’s a must.

Patients on phenytoin need consistent formulations. If a switch happens, monitor closely. Test levels. Watch for side effects. Check albumin. Consider free phenytoin. Track bone and vitamin health.

This isn’t about being overly cautious. It’s about understanding how phenytoin works - and why even small changes can have big consequences. For people who depend on this drug to prevent seizures, there’s no room for guesswork.