Phenytoin is an antiepileptic drug that is commonly used for epilepsy treatment. It is indicated for the control of generalized tonic-clonic, complex partial seizures, and prophylaxis of seizures after neurosurgery.1 Phenytoin has a narrow therapeutic index and requires monitoring of drug levels to decrease the risk of toxicity. Drug interactions with phenytoin are important to note for three reasons: phenytoin is extensively bound to plasma proteins and is prone to displacement, it is metabolized by two cytochrome P450 (CYP) enzymes, CYP2C9 and CYP2C19, and it is subject to saturable metabolism.
The addition of a highly protein-bound drug, inhibition of metabolism, or a change in dose can cause a significant increase in phenytoin concentration, which can lead to phenytoin toxicity.1 Phenytoin impacts multiple substrates of the CYP450 system because it is metabolized extensively by CYP2C9 and CYP2C19 and minimally by CYP3A4. Phenytoin also strongly induces the CYP3A4 enzyme in addition to weakly inducing CYP1A2 and CYP2B6.2
Doxepin is a tricyclic antidepressant that was introduced in 1969 for the treatment of depression and anxiety, although, due to its adverse reaction profile, it is primarily used in modern medicine for the treatment of insomnia.3 Doxepin is metabolized hepatically via CYP2C19 and CYP2D6 and has an active metabolite, N-desmethyldoxepin. Although drug interactions between the tricyclic antidepressant class and phenytoin have been identified previously in the literature, there are limited data describing the addition of doxepin to a stable phenytoin regimen resulting in phenytoin toxicity. The following case report discusses the clinical impact of a drug-drug interaction between phenytoin and doxepin, highlighting the consequences of a supratherapeutic phenytoin level.
Ms. D, a 70-year-old White female, presented to the ED with a chief complaint of dizziness. Emergency medical services (EMS) personnel reported that she had multiple recent falls but denied any loss of consciousness. EMS also noted that prior to her arrival, the patient was combative and uncooperative, although these behaviors had subsided upon admission.
Her vitals were as follows: temperature 99.2° F (37. 3° C), heart rate 73 beats/minute, a respiratory rate of 18, initial BP 156/91 mm Hg, and her pulse oximeter oxygen saturation level of 98% on room air. At the time of the evaluation, she was alert and oriented but was tremulous and unable to recall history of events in the past 24 hours.
Ms. D's general physical exam was significant for horizontal nystagmus bilaterally. The provider was unable to elicit any reflexes because of Ms. D's position in the bed. Her coordination was intact with no gross deficits, but the patient did have diffuse tremulousness on exam. There were bilateral abrasions on the lower aspect of her anterior tibia as well as erythema in the same general area on her right lower extremity. The rest of her physical exam was unremarkable.
The patient's medical history included coronary artery disease status post-coronary artery bypass surgery, chronic obstructive pulmonary disease, prior stroke, seizure disorder, hypothyroidism, and hypertension. Her home medications included aspirin, doxepin, gabapentin, levetiracetam, levothyroxine, lorazepam, metoprolol, phenytoin, potassium chloride, simvastatin, tizanidine, and acetaminophen. According to the patient and her family, the patient had been adherent to her medication regimen, and her last reported seizure was over 8 years ago. The family also stated that Ms. D had not had any recent changes in her medication regimen and that she has been stable on her current regimen for the past few years.
Initial lab studies revealed sodium 141 mEq/L, potassium 3.8 mEq/L, chloride 106 mEq/L, bicarbonate 27 mEq/L, blood urea nitrogen 10 mg/dL, and a serum creatinine of 0.7 mg/dL, albumin of 3.5 g/dL, and prealbumin of 12.6 mg/dL, and most important, a phenytoin level of 39.3 mcg/mL. A complete blood cell count showed a white blood cell count, 7,570 cells/mm3; hemoglobin, 13.4 g/dL; hematocrit, 42%; and platelet count, 143,000/mm3. Urinalysis was negative for protein, glucose, nitrites, or leukocyte esterase, and showed trace amounts of ketones.
Because of the patient's clinical presentation, she was admitted for treatment of encephalopathy secondary to phenytoin toxicity, and a neurologist was consulted to assist with management. For treatment of acute encephalopathy secondary to phenytoin toxicity, the patient was given supportive care, phenytoin was withheld, and serial phenytoin measurements were taken until serum levels decreased to normal range, 10 to 20 mcg/mL total phenytoin (see Phenytoin levels).
The patient's clinical presentation, lab values, and analysis for drug-drug interactions led the medical team to determine that this patient's phenytoin toxicity was caused by an interaction between doxepin and phenytoin in addition to her poor protein levels. After holding the phenytoin dose for a total of 4 days and stopping doxepin, the patient's phenytoin levels showed a consistent downward trend and ultimately returned to normal, nystagmus and tremulousness improved, and her mentation returned to baseline. The decision was made to discontinue phenytoin and doxepin to ensure toxicity did not occur again. Since phenytoin was discontinued, levetiracetam was increased to optimize seizure prevention. Lorazepam was also tapered down given the patient's fall risk and age.
Phenytoin is an antiepileptic medication that is approved to treat and prevent seizures in patients with epilepsy. Along with being metabolized by CYP2C9, CYP2C19, and minimally by CYP3A4, phenytoin also induces CYP3A4, CYP1A2, and CYP2B6. Because the drug is highly protein bound and given its unique pharmacokinetics and impact on the CYP450 system, phenytoin has the potential for serious drug-drug interactions that can cause harm.1,2 Doxepin is a tricyclic antidepressant that is approved to treat depression, anxiety, and insomnia. Similar to phenytoin, doxepin is metabolized via the CYP2C19 enzyme as well as the CYP2D6 enzyme and is also highly protein bound.2,3
There are multiple CYP enzymes that make up the CYP450 system, and many medications are metabolized by a single or multiple CYP enzymes. CYP enzymes play a key role in drug metabolism and therefore can be a factor in drug-drug interactions. Depending on whether a drug is a substrate inhibitor or substrate inducer can lead to clinically different results. Substrates are drugs that use the CYP enzyme for metabolism to either an inactive or an active form of the drug. Inhibitors slow down the metabolism rate of the enzyme, resulting in increased blood levels and potential toxicity. Inducers speed up the metabolism rate of the enzyme, resulting in decreased blood levels and potential treatment failure.4,5
In addition to interactions via the CYP enzymes, phenytoin and doxepin are highly protein bound, which is also an important consideration.2,6 Displacement of phenytoin that is bound to protein can increase concentrations in the blood. Factors that can alter drug metabolism and protein binding include the patient's age, diet, concomitant medications, and dose changes.7 These factors need to be assessed and monitored, specifically with phenytoin because of its narrow therapeutic index and propensity to cause toxicity.
Because phenytoin and doxepin are metabolized via CYP2C19, there is a potential for competition for the enzyme in the liver subsequently leading to increased levels of phenytoin or doxepin. Phenytoin having a narrow therapeutic index would be more likely to result in clinically significant toxicity. In addition to the drug-drug interaction, both drugs being highly protein bound can increase the risk of displacement of phenytoin and can lead to an increased risk of toxicity.7
Coadministration of these two medications can place patients at risk for phenytoin toxicity based on the factors previously described. Competitive metabolism and protein binding should be considered and careful monitoring for signs of phenytoin toxicity should be performed to ensure this combination is used safely and effectively.
The literature describing the clinical implications of an interaction between phenytoin and doxepin is scarce. Besag and colleagues provided pharmacokinetic evidence that phenytoin and tricyclic antidepressants interact, specifically clomipramine and imipramine.5 The authors concluded that there are no published clinical data on interactions but that the interactions are based on induction and inhibition of the CYP450 enzymes as well as protein binding.5 In addition, Mula and colleagues state that tricyclic antidepressants have a greater potential for drug-drug interactions.7
Case study revisited
Upon review of her medications, it was determined that doxepin was the only medication that significantly interacted with her phenytoin and could have contributed to Ms. D's phenytoin toxicity. Ms. D was adherent to all her medications at home, she reported no changes or extra doses, and no additional over-the-counter or herbal medications that could have impacted her phenytoin levels. Although the interaction has not been noted to have a clinical impact, the authors believe based on this patient's specific factors the interaction could have led to her presentation.
Despite there being no recent changes in the patient's medication, the patient reported some weight loss and decreased appetite over the past few months. Even with the decrease in her weight, Ms. D remained on the same dosage of phenytoin and doxepin and had not had her phenytoin levels monitored by her primary care provider during this time. The patient was found to have a low-normal albumin of 3.5 g/dL, which could be explained by poor oral intake over the past few months and weight loss. Additionally, because of age-related muscle mass loss, older adult patients have less protein, which could also have an effect on highly protein-bound drugs.8
Ms. D had three potential causes that could have led to phenytoin toxicity: first, she had a reduction in body weight; second, a decline in nutrition intake; and last, a drug that was competing for metabolism. The authors believe that it is prudent to monitor a patient's weight and nutrition status, especially if the patient is on a medication that is highly protein bound and taking other medications that could impact the metabolism of phenytoin.
Prior reports have hypothesized the risk of drug-drug interactions and protein displacement leading to phenytoin toxicity.6,7,9,10 The Adverse Drug Reaction Probability Scale, developed by Naranjo and colleagues, helped determine the probability that a drug caused an adverse drug reaction, which possibly caused the patient's presentation.11
This case offers evidence of the importance of being vigilant in monitoring changes in patient's body weight, nutrition status, as well as drug-drug interactions when a patient is taking phenytoin. This case serves as a reminder to all NPs that there are numerous drug interactions with phenytoin that, if missed, can lead to toxicity.
Phenytoin toxicity can occur because of a change in plasma protein levels, inhibition of metabolism, and a change in dose. Because of the risk of toxicity, NPs should be cognizant of monitoring levels in patients who may experience a decline in their oral intake, have a decrease in body mass, or who are taking drugs that interact with phenytoin. NPs should be particularly proactive in monitoring levels in patients who have multiple risk factors that predispose patients to phenytoin toxicity as presented in the case above. Awareness of these issues, particularly of the interaction between doxepin and phenytoin, should prompt NPs to assess all medications that can interact with phenytoin to ensure the risk of toxicity with phenytoin is minimized.