Phenytoin and fosphenytoin

General adverse effects and adverse reactions

Phenytoin can cause vestibulocerebellar, oculomotor, and cognitive dysfunction. It can also cause gingival hyperplasia, hirsutism, and acromegaly-like facial features. Movement disorders, symptoms of peripheral neuropathy, and endocrine changes are uncommon. Interstitial nephritis, interstitial pneumonia, and hepatotoxicity are rare. High intravenous doses are cardiotoxic. Hypersusceptibility reactions range from relatively common mild rashes to life-threatening Stevens–Johnson syndrome and toxic epidermal necrolysis. Hepatic, cardiac, muscular, pulmonary, hematological, reticuloendothelial, and renal reactions and systemic lupus erythematosus are uncommon. Pseudolymphoma and a condition resembling malignant lymphoma are very rare.

Observational studies

The effects of phenytoin have been studied in 39 patients with acute mania [ ]. One patient dropped out because of tachycardia and one required a dosage reduction because of nystagmus.

Comparative studies

Intravenous phenytoin and intravenous fosphenytoin have been compared in an open, randomized study in 256 emergency department patients who were given 279 doses [ ]. The mean phenytoin-equivalent dose was similar in the two groups. Adverse events occurred with similar frequencies, but slightly more often with fosphenytoin (phenytoin 9.1%, fosphenytoin 16%). The most common events were pruritus, pain on infusion, and paresthesia. Only one patient developed hypotension, with fosphenytoin. Thus, this study has not demonstrated obvious advantages of fosphenytoin.

Phenytoin and valproate have been compared in 68 patients with convulsive status epilepticus in a randomized controlled trial [ ]. The adverse effects in the two groups did not differ. Phenytoin caused hypotension and respiratory depression in two patients each and a cardiac dysrhythmia in one.

In a randomized open comparison of intravenous phenytoin (n = 50) and intravenous valproate (n = 50) in patients with benzodiazepine-refractory status epilepticus the adverse effects attributed to phenytoin were hypotension in six cases and respiratory depression in two [ ].

Cardiovascular

Intravenous phenytoin can cause cardiac dysrhythmias, hypotension, and potentially fatal cardiovascular collapse, especially if the highest recommended infusion rate (50 mg/minute or 1 mg/kg/minute in children) is exceeded. One case of hypersensitivity myocarditis was probably initiated by phenytoin, although carbamazepine may have contributed [ ].

After intravenous use, the most common vascular complication is the so-called purple-glove or purple-limb syndrome, defined as the progressive development of edema, discoloration, and pain in the limb; sequelae include soft-tissue necrosis and limb ischemia. Retrospective analysis of data from 152 patients treated with intravenous phenytoin identified nine (6%) who developed this syndrome: they had received a greater mean initial dose of phenytoin (500 versus 300 mg) and a larger dose over 24 hours (800 versus 500 mg), and they tended to be older (72 versus 49 years) than those without the complication [ ]. In one case surgical therapy was required; the others resolved conservatively within 1 month. Extravasation of intravenously injected phenytoin has caused tissue necrosis requiring amputation [ ]. Purple glove syndrome has generally been reported after intravenous phenytoin.

• In a 49-year-old otherwise healthy woman undergoing craniotomy for aneurysm clipping, inadvertent overdose with phenytoin (1500 mg) by rapid infusion caused intraoperative sinus arrest, which was managed successfully with standard resuscitative measures [ ].

This report highlights the cardiovascular risk of intravenous phenytoin, particularly when high infusion rates are used.

However, the purple-glove syndrome can also occasionally occur after oral administration.

• A 10-year-old boy took phenytoin 100 mg/day and his seizures were well controlled [ ]. However, a pharmacist gave him about 1000 mg of phenytoin instead of the prescribed dose, and several hours later he became drowsy and his hands and feet turned dark purple with marked swelling. Phenytoin was withdrawn after 4 days and the swelling and discoloration of his hands and feet improved gradually and disappeared 11 days later.

The incidence of purple-glove syndrome associated with intravenous phenytoin has been assessed in a prospective review of 179 consecutive exposures [ ]. There were only three mild cases (1.7%).

However, the purple-limb syndrome was recorded in 20 of 67 patients who received intravenous phenytoin over a 5-month period [ ]. Affected cases tended to be older (median age 70 years versus 57 years in non-affected cases), and all resolved spontaneously within 3 weeks. These data suggest that the incidence of the syndrome may have been underestimated in the past, possibly owing to its delayed onset, frequent occurrence in patients with impaired communication abilities, and its usually mild self-limiting course.

In 775 patients who received intravenous phenytoin, valproate, or placebo, intravenous site reactions occurred in 25% of patients who received phenytoin [ ]. Most of the events (70%) occurred in the first intravenous site, and all occurred in peripheral administration sites. When patients who received the drug by central line were excluded, the estimated incidence was 30%. There were fewer adverse events when phenytoin was given alone than when it was given together with valproate.

Fosphenytoin-induced QT interval prolongation has been reported [ ].

• A 23-year-old man was given intravenous fosphenytoin (equivalent to phenytoin 1500 mg or 20.5 mg/kg) over 85 minutes. He was normocalcemic before the infusion. During the infusion he had prolongation of the QT interval and reductions in the concentrations of total and ionized serum calcium. Plasma phenytoin concentrations were within the target range during the electrocardiographic changes, and the blood pressure was stable.

Fosphenytoin is metabolized by phosphatases to yield phenytoin plus inorganic phosphate. Binding of calcium by phosphate could have lowered the serum concentration of ionized calcium.

Phenytoin in supratherapeutic concentrations can unmask an electrocardiographic Brugada pattern, which is a susceptibility factor for sudden death [ ].

• An 81-year-old Caucasian man with dementia and seizures taking phenytoin developed new right bundle branch block with coved ST segment elevation in leads V1–3, consistent with a type 1 Brugada pattern. The serum phenytoin concentration was 22 mg/l (usual target range 10–20). Phenytoin was withdrawn and the electrocardiogram returned to baseline after 24 hours. The patient remained free of cardiac events for 3 years afterwards.

Respiratory

Interstitial pneumonitis is extremely rare with phenytoin [ ]. The clinical features are fever, dyspnea, hypoxemia, and bilateral radiographic infiltrates. It responds to withdrawal and corticosteroids. Bronchiolitis obliterans organizing pneumonia in the context of a severe hypersensitivity syndrome also improved rapidly with high-dose steroids [ ].

Nervous system

Ataxia, dysarthria, fatigue, dizziness, tremor, and nystagmus are relatively common in patients with phenytoin intoxication. Sedation occurs only at high serum drug concentrations; however, toxic effects at relatively low serum concentrations can occur when drug binding to plasma proteins is impaired [ ]. Uncommon effects include seizure exacerbation [ ], reversible monoplegia or hemiplegia [ ], reversible spastic rigidity, hyper-reflexia and clonus, hyperkinetic disorders, choreoathetosis [ ], hemiballismus [ ], hemichoreiform movements, local dystonia in the foot, myoclonus [ ], and reversible parkinsonism [ ].

Three patients with severe myoclonic epilepsy in infancy developed choreoathetosis after an increase in phenytoin dosage; it resolved when the phenytoin dosage was reduced [ ]. In one, an ictal SPECT showed reduced perfusion in the basal ganglia contralateral to the unilateral choreoathetosis. Polypharmacy, including carbamazepine and zonisamide, may have facilitated the onset of choreoathetosis.

Phenytoin can aggravate symptoms and worsen outcome in patients with Baltic myoclonic epilepsy [ ] and susceptibility to neurological complications can be increased in patients with organic brain disorders.

Long-term phenytoin can cause cerebellar degeneration, but this is probably rare [ , ]; irreversible cerebellar atrophy after acute intoxication is extremely rare [ ].

• Distal lower extremity paresthesia in stocking distribution and motor weakness with loss of the Achilles tendon reflex, associated with reduced sensory conduction velocity, occurred in an 18-year-old girl a few hours after the administration of phenytoin (7.5 mg/kg) [ ]. The condition regressed after phenytoin withdrawal.

Peripheral neuropathy is a known adverse effect of phenytoin, but this is the first report of an acute neuropathy within less than 1 week of treatment.

Cerebellar atrophy has been reported in association with phenytoin intoxication [ ].

Cerebellar atrophy and skull thickening has been described as a result of chronic phenytoin intoxication [ ] (see also Skin ).

Cerebellar symptoms due to phenytoin intoxication have been described [ , ].

Pre-existing myasthenia gravis can be aggravated by phenytoin [ ].

Sensory systems

Psychological, psychiatric

Phenytoin has been implicated in psychiatric adverse reactions with or without other signs of toxicity, and at serum concentrations above or below the upper limit of the target range, but the actual incidence of these reactions is unknown [ ].

• A 9-year-old boy with seizures developed intermittent complex visual hallucinations during therapy with fosphenytoin and, on a separate occasion, carbamazepine [ ].

Five patients with Down’s syndrome and dementia, aged 44–67 years, taking phenytoin had progressive cognitive decline [ ]. This resolved once the drug was withdrawn. Cognitive decline was not related to high serum concentrations. Older patients with Down’s syndrome might be especially sensitive to the effects of phenytoin.

Endocrine

Phenytoin can cause a rise in growth hormone concentration [ ].

Phenytoin can cause acromegaly-like facial features, possibly related to its osteogenic actions [ ].

Hematologic

Megaloblastic anemia and pancytopenia have been rarely attributed to phenytoin [ , ], whereas aplastic anemia has been observed with mephenytoin [ ].

Single cases of a hemophilia-like disorder [ ], hemolytic anemia associated with renal insufficiency [ ], and pure red cell aplasia [ ], have been reported.

Mouth and teeth

Gingival hyperplasia is a well-known adverse effect of phenytoin. It occurs in at least one-third of patients, although it can be prevented by careful dental hygiene [ ], and does not occur in edentulous mouths. In one case generalized palatal hyperplasia occurred in a patient in whom retained roots and teeth were suspected of having perpetuated a pre-extraction lesion; a subsequently placed complete denture initiated a midpalatal hyperplasia [ ].

In 114 patients, of whom 20% took phenytoin, 5 taking phenytoin had gingival hyperplasia [ ], which can on occasion be extensive.

• A 17-year-old boy took phenytoin 300 mg/day unsupervised for 2 years and developed coarsening of the facial features, extensive gingival hyperplasia, and cerebellar ataxia [ ]. The gingival hyperplasia resolved within 3 months of withdrawal but the ataxia persisted.

Salivary glands

Phenytoin was implicated in a case of reversible hypertrophy of the submandibular salivary gland, but cause and effect were speculative [ ].

Liver

Chronic hepatitis is rarely caused by phenytoin [ ]. When it occurs, the signs of hepatotoxicity usually appear after 1–8 weeks in acute cases, and after 4 months to several years in chronic cases [ ]. Among 16 acute cases, there was fever in 75%, rash in 63%, jaundice in 44%, hepatomegaly in 13%, and lymphadenopathy and splenomegaly in 60% [ ]. Less common symptoms included sore throat, malaise, chills, myalgia, and pruritus. The condition can be fatal.

A 51-year-old woman developed hepatitis while taking phenytoin 300 mg/day [ ]. However, the authors did not discuss the possible role of paracetamol, which was co-administered in a dosage of 4 g/day (see Paracetamol section under Drug–Drug Interactions in this monograph).