Levothyroxine with Phenytoin Interaction Details

Brand Names Associated with Levothyroxine

Brand Names Associated with Phenytoin

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Nov 05, 2023

Interaction Effect

Decreased levothyroxine effectiveness

Interaction Summary

Concomitant use of levothyroxine and hydantoins may reduce the efficacy of levothyroxine. Case reports, matched-controlled studies, and pharmacokinetic studies with healthy volunteers describe interactions between levothyroxine and hydantoins . The mechanisms of this interaction are increased metabolism of levothyroxine by hydantoin stimulation of hepatic drug-metabolizing enzyme activity, reduced serum protein binding of levothyroxine, and possible displacement of the levothyroxine protein-binding site; however, the clinical significance of this interaction is uncertain because most patients have normal serum levels of TSH and are clinically euthyroid . If concomitant use of levothyroxine and a hydantoin is required, consider periodic assessment of patient stability and adequate clinical response.

Severity

Moderate

Onset

Delayed

Evidence

Probable

How To Manage Interaction

Concomitant use of levothyroxine and hydantoins, such as phenytoin and fosphenytoin, may reduce the efficacy of levothyroxine. The clinical significance of this interaction is uncertain because most patients have normal serum levels of TSH and are clinically euthyroid. If concomitant use of levothyroxine and a hydantoin is required, consider periodic assessment of patient stability and adequate clinical response.

Mechanism Of Interaction

Increased metabolism of levothyroxine by hydantoin stimulation of hepatic drug-metabolizing enzyme activity; reduced serum protein binding of levothyroxine

Literature Reports

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 T4. Continued administration causes a decrease in serum T4, and normal free T4 and TSH concentrations, resulting in clinical euthyroid status .

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 . However, a case following oral administration has also been reported .

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 T(4) and T(3) catabolism with failure of the thyroid gland to respond to augmented pituitary TSH secretion. The hypothesis that phenytoin can increase the catabolism of T(4) and T(3) is supported by previous data indicating that phenytoin decreased T(4) and T(3) 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 .

D) Five normal volunteers received intravenous injections of radiothyroxine and subsequent phenytoin therapy. During oral administration of phenytoin (300 mg to 400 mg daily), the plasma thyroxine concentration decreased approximately 20% and the plasma radiothyroxine disappearance rate increased a maximum of 20% over control estimates. A minimum plasma thyroxine was evident after phenytoin administration for 10 to 12 days. The low plasma free thyroxine level did not imply hypothyroidism in these patients .

E) Twenty-three patients on long-term phenytoin therapy, these same patients one 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 thyroxine (T4) concentrations and free thyroxine index (FTI) were significantly decreased in patients receiving phenytoin. The triiodothyronine (T3) and thyrotrophin (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 .

Levothyroxine Overview

• Levothyroxine is used to treat hypothyroidism (condition where the thyroid gland does not produce enough thyroid hormone). It is also used with surgery and radioactive iodine therapy to treat thyroid cancer. Levothyroxine is in a class of medications called hormones. It works by replacing thyroid hormone that is normally produced by the body.

• Without thyroid hormone, your body cannot function properly, which may result in poor growth, slow speech, lack of energy, excessive tiredness, constipation, weight gain, hair loss, dry, thick skin, increased sensitivity to cold, joint and muscle pain, heavy or irregular menstrual periods, and depression. When taken correctly, levothyroxine reverses these symptoms.

Phenytoin Overview

• Phenytoin is used to control certain type of seizures, and to treat and prevent seizures that may begin during or after surgery to the brain or nervous system. Phenytoin is in a class of medications called anticonvulsants. It works by decreasing abnormal electrical activity in the brain.

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Definitions

Severity Categories

Contraindicated

These drugs, generally, should not be used together simultaneously due to the high risk of severe adverse effects. Combining these medications can lead to dangerous health outcomes and should be strictly avoided unless otherwise instructed by your provider.

Major

This interaction could result in very serious and potentially life-threatening consequences. If you are taking this drug combination, it is very important to be under close medical supervision to minimize severe side effects and ensure your safety. It may be necessary to change a medication or dosage to prevent harm.

Moderate

This interaction has the potential to worsen your medical condition or alter the effectiveness of your treatment. It's important that you are monitored closely and you potentially may need to make adjustments in your treatment plan or drug dosage to maintain optimal health.

Minor

While this interaction is unlikely to cause significant problems, it could intensify side effects or reduce the effectiveness of one or both medications. Monitoring for changes in symptoms and your condition is recommended, and adjustments may be made if needed to manage any increased or more pronounced side effects.

Onset

Rapid: Onset of drug interaction typically occurs within 24 hours of co-administration.

Delayed: Onset of drug interaction typically occurs more than 24 hours after co-administration.

Evidence

Level of documentation of the interaction.

Established: The interaction is documented and substantiated in peer-reviewed medical literature.

Theoretical: This interaction is not fully supported by current medical evidence or well-documented sources, but it is based on known drug mechanisms, drug effects, and other relevant information.

How To Manage The Interaction

Provides a detailed discussion on how patients and clinicians can approach the identified drug interaction as well as offers guidance on what to expect and strategies to potentially mitigate the effects of the interaction. This may include recommendations on adjusting medication dosages, altering the timing of drug administration, or closely monitoring for specific symptoms.

It's important to note that all medical situations are unique, and management approaches should be tailored to individual circumstances. Patients should always consult their healthcare provider for personalized advice and guidance on managing drug interactions effectively.

Mechanism Of Interaction

The theorized or clinically determined reason (i.e., mechanism) why the drug-drug interaction occurs.

Disclaimer: The information provided on this page is for informational purposes only and should not be considered medical advice. Always consult with a qualified healthcare professional regarding your specific circumstances and medical conditions.

Where Does Our Information Come From?

Information for our drug interactions is compiled from several drug compendia, including:

• Gold Standard Drug Database
• Micromedex
• Lexicomp
• DrugBank

The prescribing information for each drug, as published on DailyMED, is also used. 

Individual drug-drug interaction detail pages contain references specific to that interaction. You can click on the reference number within brackets '[]' to see what reference was utilized.

The information posted is fact-checked by HelloPharmacist clinicians and reviewed quarterly.