Fosphenytoin and Levothyroxine: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Fosphenytoin
Levothyroxine
How we grade severity & evidence
Severity levels
- Contraindicated: These should generally not be used together.
- Major: Potentially serious — often needs a change or close monitoring.
- Moderate: Can be significant — usually manageable with monitoring.
- Minor: Usually limited clinical impact.
Evidence grades
- Established: Well documented — supported by controlled studies or strong clinical data.
- Probable: Good supporting evidence, though not definitively proven.
- Suspected: Some evidence suggests this interaction, but it is not well established.
- Possible: Limited or conflicting evidence; the interaction may occur.
- Theoretical: Predicted from the drugs' pharmacology; not yet confirmed in people.
Ratings come from the documented interaction literature and are reviewed by a pharmacist. They describe the documented risk of the combination, not what will necessarily happen to you — your dose, timing, and health picture all matter.
What happens
Reduced efficacy of levothyroxine
Interaction Deep Dive
Concomitant use of levothyroxine and phenytoin or fosphenytoin (prodrug of phenytoin) may reduce the efficacy of levothyroxine4. Case reports, matched-controlled studies, and pharmacokinetic studies with healthy volunteers describe interactions between levothyroxine and hydantoins 876. Phenytoin reduces serum protein binding of levothyroxine, and total and free-T4 may be reduced by 20% to 40%, however most patients have normal serum TSH levels and are clinically euthyroid. Closely monitor thyroid hormone parameters with concomitant use of levothyroxine and phenytoin or fosphenytoin 31. Additionally, consider increasing levothyroxine dose in patients with a history of thyroidectomy 2.
Why it happens (mechanism)
Increased metabolism of levothyroxine by hydantoin stimulation of hepatic drug-metabolizing enzyme activity; reduced serum protein binding of levothyroxine
Literature reports
5 reports — tap to read
a) Concomitant use levothyroxine and hydantoins may reduce the efficacy of levothyroxine. The mechanisms of this drug interaction are increased metabolism of levothyroxine by hydantoin stimulation of hepatic drug-metabolizing enzyme activity, reduced serum binding of levothyroxine, and possible displacement of the levothyroxine protein-binding site. An increase in levothyroxine degradation causes an increase in levothyroxine requirements. Displacement of the levothyroxine protein-binding site causes an initial and transient increase in free total thyroxine (T4). Continued administration causes a decrease in serum T4, and normal free T4 and TSH concentrations, resulting in clinical euthyroid status 4.
b) Concomitant phenytoin and levothyroxine therapy has been reported to result in displacement of levothyroxine from plasma protein binding sites by phenytoin. This originally was reported to be a problem when phenytoin was administered parenterally 5. However, a case following oral administration has also been reported 6.
c) Combined levothyroxine 0.15 mg and oral phenytoin 300 mg daily was reported to result in clinical hypothyroidism in a 32-year-old woman with primary hypothyroidism. It is postulated that phenytoin can accelerate levothyroxine clearance and increase T4 and triiodothyronine (T3) catabolism with failure of the thyroid gland to respond to augmented pituitary TSH secretion. The hypothesis that phenytoin can increase the catabolism of T4 and T3 is supported by previous data indicating that phenytoin decreased T4 and T3 levels in hyperthyroid patients which paralleled clinical improvement. Initiation of phenytoin therapy may increase levothyroxine replacement requirements in primary hypothyroidism and possibly precipitate de novo hypothyroidism in patients with diminished thyroid reserve 6.
d) Five normal volunteers received IV injections of radiothyroxine and subsequent phenytoin therapy. During oral administration of phenytoin (300 mg to 400 mg daily), the plasma T4 concentration decreased approximately 20% and the plasma radiothyroxine disappearance rate increased a maximum of 20% over control estimates. A minimum plasma T4 was evident after phenytoin administration for 10 to 12 days. The low plasma free T4 level did not imply hypothyroidism in these patients 7.
e) Twenty-three patients on long-term phenytoin therapy, these same patients 1 month after discontinuing phenytoin, and 23 matched controls who had received phenytoin were studied. All patients were clinically euthyroid, and the phenytoin group had plasma phenytoin levels within the therapeutic range. Results showed that total T4 concentrations and free thyroxine index (FTI) were significantly decreased in patients receiving phenytoin. The T3 and TSH levels were not significantly altered. The authors concluded that the depression of total T4 levels was not solely due to diminished protein binding, but may be the result of enhanced T4 degradation following phenytoin therapy 8.
Common questions
Can I take Fosphenytoin and Levothyroxine together?
Reduced efficacy of levothyroxine Always confirm with your pharmacist or prescriber before making any change.
How serious is the Fosphenytoin and Levothyroxine interaction?
It is rated moderate. Can be significant — usually manageable with monitoring.
How quickly could this interaction happen?
The documented onset is "delayed". Effects tend to build up gradually over days to weeks.
How strong is the evidence for this interaction?
The evidence is graded "probable". Good supporting evidence, though not definitively proven.
From our Q&A
Real reader questions about these medications, each personally answered by our pharmacist:
Questions for your pharmacist
- Does my dose of Fosphenytoin or Levothyroxine need adjusting while I take them together?
- What symptoms should prompt me to call you or my prescriber right away?
- Does the timing of my doses matter for this combination?
- Is there anything you'd monitor while I'm on both?
References (8)
- Product Information: LEVO-T® oral tablets, levothyroxine sodium oral tablets. Neolpharma Inc, Caguas, PR, 2026. DailyMed
- Centanni M, Duntas L, Feldt-Rasmussen U, et al: ETA guidelines for the use of levothyroxine sodium preparations in monotherapy to optimize the treatment of hypothyroidism. Eur Thyroid J 2025; 14(4):e250123. PubMed
- Product Information: TIROSINT(R)-SOL oral solution, levothyroxine sodium oral solution. IBSA Pharma Inc. (per FDA), Parsippany, NJ, 2023. DailyMed
- Product Information: SYNTHROID(R) oral tablets, levothyroxine sodium oral tablets. Abbott Laboratories (per DailyMed), North Chicago, IL, 2011. DailyMed
- Avery GS: Check-list of potential clinically important interactions. Drugs 1973; 5:187-211.
- Blackshear JL, Schultz AL, Napier JS, et al: Thyroxine replacement requirements in hypothyroid patients receiving phenytoin. Ann Intern Med 1983; 99:341-342. PubMed
- Larsen PR, Atkinson AJ Jr. Wellman HN, et al: The effect of diphenylhydantoin on thyroxine metabolism in man. J Clin Invest 1970; 49:1266-1279. DOI
- Heyma P, Larkins RG, Perry-Keene D, et al: Thyroid hormone levels and protein binding in patients on long-term diphenylhydantoin treatment. Clin Endocrinol 1977; 6:369-376. DOI
Keep reading about Fosphenytoin
Keep reading about Levothyroxine
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