Understanding When Phenytoin Should Be Avoided: A Comprehensive Guide

October 13, 2025 •

4 min read

Phenytoin is an effective anticonvulsant, but its use comes with significant risks that necessitate caution; in fact, phenytoin can cause severe, sometimes fatal, skin reactions and other serious adverse effects, making it critical to understand when should phenytoin be avoided. Its narrow therapeutic index means factors like genetics and other medications can turn it from a treatment into a toxicity risk.

Quick Summary

Phenytoin must be avoided in cases of severe hypersensitivity, previous liver injury, and while taking certain medications. Genetic factors, pregnancy, and heart conditions require careful evaluation.

Key Points

Hypersensitivity and Liver Injury: Phenytoin is contraindicated if you have a history of an allergic reaction to it or other hydantoins, or previous acute liver damage from the drug.
Genetic Risk Factors: Individuals of Asian descent may carry the HLA-B15:02* allele, which increases the risk of severe, sometimes fatal, skin reactions like Stevens-Johnson syndrome (SJS).
Pregnancy and Fetal Harm: Phenytoin is a teratogen and can cause birth defects; women of childbearing potential should use effective non-hormonal contraception and discuss risks with a doctor.
Dangerous Drug Interactions: Avoid taking phenytoin with delavirdine, and be cautious with anticoagulants, certain antibiotics, and alcohol, as they can alter phenytoin levels.
Avoid Abrupt Withdrawal: Never stop taking phenytoin suddenly, as this can trigger a dangerous increase in seizures, including status epilepticus; dose adjustments must be made gradually under medical supervision.
Liver and Cardiac Monitoring: Use with caution in patients with liver or heart disease, and monitor serum levels closely to avoid toxicity, especially with IV administration.
Recognize Serious Side Effects: Report any rash, fever, swollen lymph nodes, or facial swelling immediately, as these could signal a life-threatening reaction.

Absolute Contraindications

There are several situations where phenytoin is absolutely contraindicated and should never be used. The most critical of these include a known hypersensitivity to phenytoin, its ingredients, or other hydantoin-class drugs. An allergic reaction can be severe and potentially fatal, often presenting as a rash, fever, or swelling. Patients who have previously experienced acute liver toxicity attributable to phenytoin should also never be readministered the drug.

Additionally, concomitant use of phenytoin with the antiretroviral drug delavirdine is contraindicated. Phenytoin can substantially reduce the concentration of delavirdine in the blood, leading to a loss of virologic response and potential resistance to this and other non-nucleoside reverse transcriptase inhibitors.

Serious Warnings and Genetic Risk Factors

Even without an absolute contraindication, several serious warnings and risk factors must be considered before prescribing phenytoin. A crucial consideration is the patient's genetic makeup, particularly in individuals of Asian ancestry.

Genetic Risks and Severe Skin Reactions

Carriers of the HLA-B15:02 allele, which is most prevalent in Southeast Asian populations, have a significantly higher risk of developing severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), when treated with phenytoin. These conditions can be fatal and typically develop within the first 28 days of treatment. Genotyping for this allele can help identify at-risk individuals before starting therapy. Similarly, variations in the CYP2C9 gene, specifically the CYP2C93 variant, can decrease phenytoin clearance, increasing the risk of toxicity and SCARs.

Pregnancy Risks

Phenytoin is a known teratogen, meaning it can cause harm to an unborn baby. Prenatal exposure is associated with an increased risk of congenital malformations, including orofacial clefts, cardiac defects, and features of fetal hydantoin syndrome (e.g., abnormal facial features, nail and digit hypoplasia). A potentially life-threatening bleeding disorder in newborns can also occur due to decreased levels of vitamin K-dependent clotting factors. Effective contraception should be used by women of childbearing potential, and alternative treatments should be considered for pregnant women.

Liver and Heart Conditions

Phenytoin is primarily metabolized by the liver, so patients with impaired liver function or low serum albumin levels are at a higher risk of drug toxicity due to increased unbound phenytoin in the blood. Acute hepatotoxicity, while rare, can be fatal and requires immediate discontinuation. For the intravenous form, rapid administration can cause severe hypotension and cardiac arrhythmias, including bradycardia and cardiac arrest, especially in patients with pre-existing heart disease.

Drug and Substance Interactions

Phenytoin has numerous drug-drug interactions that can alter its serum concentration or the effectiveness of other medications. The following are some of the most notable interactions:

Other Antiepileptic Drugs: Co-administration with drugs like valproate or phenobarbital can have unpredictable effects on phenytoin levels, necessitating close monitoring.
Anticoagulants: The combination of phenytoin and warfarin can lead to an increased risk of bleeding or blood clots, and careful monitoring of INR is required.
Alcohol: Acute alcohol intake can increase phenytoin levels, while chronic use can decrease them. Both can lead to serious problems and should be avoided.
Antifungals and Antibiotics: Many azole antifungals (e.g., fluconazole, ketoconazole) and certain antibiotics (e.g., isoniazid, cimetidine) can inhibit phenytoin's metabolism and increase its concentration.
Hormonal Contraceptives: Phenytoin can decrease the effectiveness of hormonal birth control, increasing the risk of unplanned pregnancy.
Herbal Supplements: St. John's wort can decrease phenytoin levels, reducing its effectiveness.

Comparison of Contraindications vs. Precautions


Condition	Contraindication	Precaution	Management
Hypersensitivity	Yes (to phenytoin or hydantoins)	N/A	Do not use. Consider alternatives from a different drug class.
Acute Liver Injury	Yes (prior injury from phenytoin)	N/A	Do not re-administer. Discontinue immediately if acute hepatotoxicity occurs.
Delavirdine Use	Yes (co-administration)	N/A	Do not use. Seek alternative medication.
Genetic Predisposition	No (for HLA-B15:02*)	Yes (Asian ancestry, HLA-B15:02* allele)	Consider alternative therapy. Screen for the allele and monitor closely.
Chronic Liver Disease	No	Yes	Use with caution. Monitor phenytoin serum levels, especially unbound fraction.
Pregnancy	No (not absolute)	Yes	Advise against use. Discuss risks, use contraception, and consider alternative AEDs.
Heart Conditions	No	Yes (especially with rapid IV infusion)	Use with caution. Closely monitor cardiac function during and after IV infusion.
Porphyria	No	Yes (exacerbation risk)	Use with caution. Monitor for worsening symptoms.

Gradual Withdrawal and Patient Counseling

Abruptly stopping phenytoin can be very dangerous and may trigger an increase in seizure frequency, including a life-threatening condition called status epilepticus. Any dose reduction or discontinuation must be done gradually under a doctor's supervision. In cases of allergic reactions, a more rapid, but still medically guided, substitution with another anticonvulsant from a different chemical class may be necessary.

Patients and their families should be fully informed about the signs of serious side effects, such as rash, fever, or swelling, and instructed to seek immediate medical attention if they occur. Due to the drug's narrow therapeutic window and numerous interactions, patients should inform their healthcare providers of all other medications, supplements, and alcohol use.

Conclusion

Phenytoin is a powerful tool for controlling seizures but carries significant risks. Understanding when phenytoin should be avoided is crucial for patient safety. Absolute contraindications, such as hypersensitivity and prior acute hepatotoxicity, prohibit its use entirely. Furthermore, serious warnings related to genetic predisposition, pregnancy, liver function, and cardiac health require careful consideration and monitoring. Comprehensive patient counseling and controlled, gradual dose adjustments or withdrawals are essential to mitigate risks associated with this medication. Given the complexity, patients should always work closely with their healthcare team to weigh the benefits against the risks of phenytoin therapy.

For more information on phenytoin's use and safety, consult the official package insert or a reliable medical source like MedlinePlus.

Frequently Asked Questions

Abrupt withdrawal of phenytoin can precipitate status epilepticus, a life-threatening condition involving prolonged or repeated seizures. Dosage should always be reduced gradually under a doctor's guidance.

If you have impaired liver function, phenytoin should be used with caution and careful monitoring. The liver metabolizes phenytoin, so impaired function can lead to increased serum levels and a higher risk of toxicity.

For individuals of Asian ancestry, genetic testing for the HLA-B15:02* allele may be considered. Carriers of this allele have a higher risk of developing severe skin reactions like SJS/TEN and should consider alternative medications.

Phenytoin can cause birth defects and decrease the effectiveness of hormonal contraception. Women should use reliable, non-hormonal birth control and discuss their plans for pregnancy with their doctor, as alternatives may be necessary.

Phenytoin should not be taken with delavirdine. It also has significant interactions with anticoagulants like warfarin, certain antibiotics, and herbal supplements like St. John's wort, requiring careful management.

Serious allergic reactions, including DRESS and SJS/TEN, can present with a skin rash, fever, swollen lymph glands, or facial swelling. These symptoms should be reported to a doctor immediately.

Yes, alcohol can interfere with phenytoin levels. Acute alcohol intake can increase phenytoin levels and side effects, while chronic use can decrease them, increasing seizure risk. Alcohol should be avoided.