Dilantin Stevens-Johnson Syndrome. Dilantin & Stevens-Johnson Syndrome a life-threatening skin disease. With Stevens-Johnson Syndrome the sufferer can first experience Dilantin side effects

As early as 1939, there have been scientific publications that have reported cases of SJS and TEN caused by Dilantin. These articles include Dilantin-related reports of TEN in both adult and pediatric populations. Starting in the 1980’s, there was overwhelming epidemiological and clinical evidence of the causal relationship and increased risks between Dilantin and SJS/TEN.

Beginning in 1984, there are references in dermatology textbooks that specifically mention that “Dilantin often causes morbilliform eruptions, erythema multiforme and toxic epidermal necrolysis.” In 1987, scientists again reported that “Dilantin is also a well-recognized cause of toxic epidermal necrolysis.” Bigby, et. al. reported in 1989 that Dilantin was one of the most commonly implicated drugs in causing toxic epidermal necrolysis.

Other researchers evaluated case report literature between 1966 and 1987 using the MEDLINE database, and reported that one of the most frequently reported drugs to cause SJS and TEN was Dilantin, and based on the two largest series that had been conducted reported an additional 17 confirmed cases of TEN caused by Dilantin reported from series in Seattle, Washington and France. These authors noted that only a small fraction of cases of TEN are reported in the literature.

In 1990, a couple of epidemiological papers reported that there had beenadditional case reports of Dilantin-induced TEN, and that anticonvulsants had accounted for 14.5% of all TEN cases reported in France between 1981-1985. In Germany, there were an additional ten cases of TEN caused by Dilantin during 1981-1985, which was two times greater than other anticonvulsants. Other experts in dermatology stated in a review on TEN that “Phenytoin [Dilantin] probably carries the highest risk [of TEN amongst anticonvulsants],” and that “anticonvulsants are the main cause of drug-induced TEN in children.”

By 1994, it was reported that Dilantin was a “classic culprit” for causing TEN. In this same review article, a reported frequency of hypersensitivity syndrome, which includes SJS and TEN was reported to be “an estimated one reaction per 5000 patients.”

In 1995, the largest epidemiological study on SJS and TEN, partially funded by drug companies was published in the New England Journal of Medicine by the Severe Cutaneous Adverse Reaction Study Group (SCAR), which was an international case-control study to evaluate the relative risks of drugs associated with SJS and TEN. In that study, the authors reported that Dilantin had a relative risk of 53, which represented a significant increase in risk of SJS and TEN associated with Dilantin therapy.

In a study using Saskatchewan Health data published in 1997, phenytoin was reported to have a incidence of severe rashes, including SJS/TEN in about 1.4/1000 in children less than 16 years of age, and 0.9/1000 for adults. In 1999, the reported incidence of aromatic hypersensitivity syndrome associated with Dilantin and other aromatic anticonvulsants was about 1 in 3000 new users of Dilantin would develop this reaction, making it one of the most frequent severe adverse cutaneous reactions to drugs. The authors reports that TEN was included in this morphology of hypersensitivity syndrome associated with Dilantin. (Id.) Subsequent literature references support that Dilantin is the leading cause of SJS and TEN in children, 18 and several papers have cited Dilantin as having the highest risk among anticonvulsants for SJS and TEN. Rzany, et. al. reporting on a more detailed and updated description of the SCAR data reported a univariate relative risk of SJS/TEN for Dilantin as 91(95% CI, 26-∞). Sixteen percent (16%) of all cases of SJS/TEN are caused by anticonvulsants.

From 1998 to the present, there were a significant number of reports of children reported to have SJS and TEN caused by anticonvulsants, including Dilantin. Sharma, et. al. reported that 30% of hospitalized patients developed SJS and TEN associated with antiepileptics,mostly from Dilantin. In another study published in 2002, a multi-center review of TEN cases from 15 burn centers across the U.S. reported that over 20% of all TEN patients were caused by Dilantin from 1995 to 2000.

Estimates of risk of SJS and TEN associated with anticonvulsants were recently published in 2005, by another Pfizer-retained expert, Dr. Mockenhaupt revealing that the incidence of SJS and TEN associated with new users of this drug was reported to be 8.3/10,000 users, and was reported to be higher than some of the other available anticonvulsants.

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In 1984, Chadwick, et. al. reported results from two prospective studies in which high initial serum concentrations were associated with increased incidence of rash with phenytoin at 6%. (Chadwick, 1984) This is also consistent with the dosing relationship seen in Lamictal and cutaneous reactions, which ultimately led to increased warnings with a Black Box warning for SJS and TEN in children in 1997, and contraindications for the use of Lamictal in children under the age of 16.

Scientists reported that “Phenytoin [Dilantin] probably carries the highest risk [of TEN amongst anticonvulsants]” and that “anticonvulsants are the main cause of drug-induced TEN in children.” The abnormal metabolism of Dilantin by children results in reduced clearance of phenytoin and this increases the risks of serious skin reactions, including SJS and TEN. This risk factor for children is not warned about in the prescribing information for Dilantin and that represents an indifference to the safety and health of children taking Dilantin.

Anticonvulsant Hypersensitivity syndrome or Dilantin hypersensivity syndrome are rare, but potentially life-threatening reactions that occur after an exposure to an anticonvulsant, most commonly the aromatic anticonvulsants, including phenytoin. A triad of fever, skin eruption and internal organ involvement is the defining presentation of the syndrome; however, there are variable presentations encompassing a spectrum of clinical features that often result in a delay of diagnosis. There have been a large number of cases of hypersensitivity syndrome just reported as hepatotoxicity reactions to phenytoin. Yet a closer investigation reveals that many of those cases reveals a rash or serious cutaneous reactions that are also present with the hepatotoxicities caused mostly by phenytoin.

AHS can cause both cutaneous and extracutaneous manifestations as part of the syndrome. Internal organ involvement mainly involves the liver, but can also involve the kidneys, CNS, heart, and lungs. Severe liver involvement can increase the mortality from AHS to 12%-50% and the degree of hepatitis is related to the interval of onset of the syndrome and the discontinuation of the phenytoin. This emphasizes the importance of prompt recognition and discontinuation of the anticonvulsant.

The incidence and epidemiology of AHS has been reported in a record linkage study within 60 days of the first or second prescription in new users of phenytoin that was estimated to be 2.3 to 4.5 per 10,000.

Clinical evidence to support that the black population has a higher risk of hypersensitivity syndromes, includes numerous reports that black-skinned subjects (Africans, Caribbeans, Afro-Americans) seem to have an increased risk of hepatotoxicity, and SJS and TEN from phenytoin.

Other scientists have reported that there is a higher incidence of hypersensitivity syndrome among black men caused by phenytoin, and that the overall incidence of AHS from phenytoin is higher in the black population.

Stanley reported as early as 1978 that a large majority of patients of reported cases of hypersensitivity syndrome associated with phenytoin have been blacks. Citing data from Dhar, et. al. he reported that 12 of 16 patients were black; and of the eight reported cases by

Robinson, all were blacks; and Stanley’s two patients were black. In a review article by Roujeau and Stern, they reported a frequency of hypersensitivity syndrome, which includes SJS and TEN to be “an estimated one reaction per 5000 patients, and perhaps a higher rate among black patients.”

Although anticonvulsant drugs have been considered as the primary factor in the etiology of SJS; the drugs responsible for SJS have not been clearly identified yet. However, combined use of these drugs have been reported to cause an increase in the blood levels of each other by competing with glucuronidaiton metabolsim and lead to severe skin reactions. This report presents a SJS case triggered by combined use of anticonvulsant drugs.