Dilantin (Page 3 of 7)

6 ADVERSE REACTIONS

The following serious adverse reactions are described elsewhere in the labeling:

The following adverse reactions associated with the use of DILANTIN were identified in clinical studies or postmarketing reports. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole: Allergic reactions in the form of rash and rarely more serious forms and DRESS have been observed, as has angioedema [see Warnings and Precautions (5.3, 5.4, 5.7)]. Anaphylaxis has also been reported.

There have also been reports of coarsening of facial features, systemic lupus erythematosus, periarteritis nodosa, and immunoglobulin abnormalities.

Digestive System: Acute hepatic failure, toxic hepatitis, liver damage, nausea, vomiting, constipation, enlargement of the lips, and gingival hyperplasia.

Hematologic and Lymphatic System: Hematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression. While macrocytosis and megaloblastic anemia have occurred, these conditions usually respond to folic acid therapy. Lymphadenopathy including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin’s disease have been reported [see Warnings and Precautions (5.9)].

Laboratory Test Abnormality: Phenytoin may decrease serum concentrations of thyroid hormone (T4 and T3), sometimes with an accompanying increase in thyroid-stimulating hormone (TSH), but usually in the absence of clinical hypothyroidism. Phenytoin may also produce lower than normal values for dexamethasone or metyrapone tests. Phenytoin may cause increased serum levels of glucose [see Warnings and Precautions (5.14)] , alkaline phosphatase, and gamma glutamyl transpeptidase (GGT).

Nervous System: The most common adverse reactions encountered with phenytoin therapy are nervous system reactions and are usually dose-related. Reactions include nystagmus, ataxia, slurred speech, decreased coordination, somnolence, and mental confusion. Dizziness, vertigo, insomnia, transient nervousness, motor twitchings, paresthesias, and headaches have also been observed. There have also been rare reports of phenytoin-induced dyskinesias, including chorea, dystonia, tremor and asterixis, similar to those induced by phenothiazine and other neuroleptic drugs. Cerebellar atrophy has been reported, and appears more likely in settings of elevated phenytoin levels and/or long-term phenytoin use [see Warnings and Precautions (5.15)].

A predominantly sensory peripheral polyneuropathy has been observed in patients receiving long-term phenytoin therapy.

Skin and Appendages: Dermatological manifestations sometimes accompanied by fever have included scarlatiniform or morbilliform rashes. A morbilliform rash (measles-like) is the most common; other types of dermatitis are seen more rarely. Other more serious forms which may be fatal have included bullous, exfoliative or purpuric dermatitis, acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, and toxic epidermal necrolysis [see Warnings and Precautions (5.3)]. There have also been reports of hypertrichosis and urticaria.

Special Senses: Altered taste sensation including metallic taste.

Urogenital: Peyronie’s disease

7 DRUG INTERACTIONS

Phenytoin is extensively bound to plasma proteins and is prone to competitive displacement. Phenytoin is primarily metabolized by the hepatic cytochrome P450 enzyme CYP2C9 and to a lesser extent by CYP2C19, and is particularly susceptible to inhibitory drug interactions because it is subject to saturable metabolism. Inhibition of metabolism may produce significant increases in circulating phenytoin concentrations and enhance the risk of drug toxicity. Monitoring of phenytoin serum levels is recommended when a drug interaction is suspected.

Phenytoin is a potent inducer of hepatic drug-metabolizing enzymes.

7.1 Drugs that Affect Phenytoin Concentrations

Table 2 includes commonly occurring drug interactions that affect phenytoin concentrations. However, this list is not intended to be inclusive or comprehensive. Individual prescribing information from relevant drugs should be consulted.

The addition or withdrawal of these agents in patients on phenytoin therapy may require an adjustment of the phenytoin dose to achieve optimal clinical outcome.

Table 2: Drugs That Affect Phenytoin Concentrations
Interacting Agent Examples
*
Antacids may affect absorption of phenytoin.
The induction potency of St. John’s wort may vary widely based on preparation.
Drugs that may increase phenytoin serum levels
Antiepileptic drugs Ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate
Azoles Fluconazole, ketoconazole, itraconazole, miconazole, voriconazole
Antineoplastic agents Capecitabine, fluorouracil
Antidepressants Fluoxetine, fluvoxamine, sertraline
Gastric acid reducing agents H2 antagonists (cimetidine), omeprazole
Sulfonamides Sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole-trimethoprim
Other Acute alcohol intake, amiodarone, chloramphenicol, chlordiazepoxide, disulfiram, estrogen, fluvastatin, isoniazid, methylphenidate, phenothiazines, salicylates, ticlopidine, tolbutamide, trazodone, warfarin
Drugs that may decrease phenytoin serum levels
Antacids * Calcium carbonate, aluminum hydroxide, magnesium hydroxide Prevention or Management: Phenytoin and antacids should not be taken at the same time of day
Antineoplastic agents usually in combination Bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate
Antiviral agents Fosamprenavir, nelfinavir, ritonavir
Antiepileptic drugs Carbamazepine, vigabatrin
Other Chronic alcohol abuse, diazepam, diazoxide, folic acid, reserpine, rifampin, St. John’s wort , sucralfate, theophylline
Drugs that may either increase or decrease phenytoin serum levels
Antiepileptic drugs Phenobarbital, valproate sodium, valproic acid

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