Stevens-Johnson syndrome carbamazepine

Dermatologic Severe dermatologic reactions, including toxic epidermal necrolysis (Lyell syndrome) and Stevens-Johnson syndrome, have been reported with carbamazepine. These reactions have been extremely rare however, a few fatalities have been reported. 

Carbamazepine stimulates antidiuretic hormone activity and has been used for the treatment of neurohypophyseal diabetes insipidus. Carbamazepine induces microsomal enzymes and its metabolism is subject to auto-induction. Frequently occurring adverse effects are sedation, dry mouth, dizziness and gastrointestinal disturbances. Photosensitivity reactions, urticaria and Stevens-Johnson syndrome have been described. The elderly are more prone to mental confusion, cardiac abnormalities and problems due to inappropriate ADH secretion. 

Rash risk in 5%-10% Rarely, life-threatening rash (including Stevens-Johnson syndrome) Risk minimized by low starting dose and slow titration Metabolism inhibited by valproate Metabolism induced by carbamazepine... 

An exanthematous rash is one of the more common side effects of carbamazepine, occurring in 3%-17% of patients. This reaction typically begins within 2-20 weeks after the start of treatment. Car-bamazepine is generally discontinued if a rash develops because of the risk of progression to an exfoliative dermatitis or Stevens-Johnson syndrome, a severe bullous form of erythema multiforme. 

Oxcarbazepine is typically started at a dosage of 150 mg twice a day and titrated by 300 mg/day at weekly intervals. Therapeutic dosages are in the range of 450 mg twice a day to 1,200 mg twice a day. The conversion from carbamazepine to oxcarbazepine is approximately 1 to 1.5. Oxcarbazepine has a higher risk of hyponatremia than does carbamazepine. Serum sodium should be monitored in patients at risk for hyponatremia, such as the elderly or patients who are also taking diuretics. Stevens-Johnson syndrome and toxic epidermal necrolysis may occur between 3 and 10 times more frequently in oxcarbazepine-treated patients than in the general population. Median time from starting treatment to the development of these serious reactions is 19 days. 

Carbamazepine Dose-related double vision, vertigo, gastrointestinal disturbance Idiosyncratic agranulocytosis, Stevens-Johnson syndrome, aplastic anemia... 

A skin rash occurs in 5-20% of patients started on carbamazepine, and is a common cause of early drug withdrawal. The rash is usually erythematous or maculopapular and may accompany systemic manifestations of hypersensitivity. Exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis are relatively rare (SED-13, 148) (55,56). 

A 17-year-old girl developed Stevens-Johnson syndrome after using carbamazepine 400 mg/day for 2 weeks (63). She was treated with intravenous immunoglobulin and intravenous methylprednisolone and recovered completely. 

Straussberg R, Harel L, Ben-Amitai D, Cohen D, Amir J. Carbamazepine-induced Stevens-Johnson syndrome... 

In a 26-year-old woman who had severe Stevens-Johnson syndrome induced by phenytoin and later by carbamazepine, gabapentin resulted in an erythematous pruriginous skin eruption limited to the legs without mucosal involvement (35). 

The following drugs have been most often associated with erythema multiforme and Stevens-Johnson syndrome allopurinol, lamotrigine phenytoin, barbiturates, carbamazepine, estrogens/progestins, gold, NSAIDs, penicillamine, sulfonamides, tetracycline, and tolbutamide. 

Rashes are the most frequent hypersensitivity response. An incidence of approximately 10% has been reported. These usually are mildly eczematous but may progress to Stevens-Johnson syndrome. Other rare side effects reported with carbamazepine include hepatitis, osteomalacia, cardiac conduction defects, and lupus-like reactions. 

Carbamazepine has a moderate anticholinergic action that may cause symptoms of dry mouth and constipation. CNS effects include somnolence, ataxia, diplopia, loss of accommodation, dizziness, and headache, which are most prominent with overdosage. Erythroderma, photosensitivity, and skin rashes may also be seen, and, rarely, Stevens-Johnson syndrome or systemic lupus-like syndrome also occur. The drug also has other serious adverse effects, such as suppression of ventricular automaticity, and, rarely, blood dyscrasias (e.g.. agranulocytosis, leukopenia, thrombocytopenia, and aplastic anemia). Due to hepatic metabolism, hepatocellular and cholestatic jaundice may also be seen. 

Carbamazepine (CBZ) is a widely used anticonvulsant that can cause rashes in up to 10% of patients, and in occasional cases this may be the precursor to the development of a hypersensitivity syndrome characterized by systemic manifestations such as fever and eosinophilia (Feeder 1998 Vittorio and Muglia 1995). Rarely, CBZ can induce blistering skin reactions such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis, two conditions associated with a high fatality rate (Rzany et al. 1999). There is now increasing laboratory evidence to show that... 

Locharemkul C, Loplumlert J, Limotai C, Korkij W, Desudchit T, Tongkobpetch S, Kangwanshiratada O, Hirankam N, Suphapeetipom K, Shotelersuk V (2008) Carbamazepine and phenytoin induced Stevens-Johnson syndrome is associated with HLA-B 1502 allele in Thai population. Epilepsia 49 2087-2091... 

Three patients treated with various antipsychotics (fluphenazine, ha-loperidol, trifluoperazine, chlorpromazine) developed Stevens-Johnson syndrome within 8 to 14 days of starting to take carbamazepine. All 3 had erythema multiforme skin lesions and at least two mucous membranes were affected. After treatment, all 3 were restarted on all their previous drugs, except carbamazepine, without problems. Another case of Stevens-Johnson syndrome has been reported in a patient taking carbamazepine, lithium carbonate, haloperidol and trihexyphenidyl. The reasons are not understood. Stevens-Johnson syndrome with carbamazepine alone is rare, and the risk appears to be mostly confined to the first 8 weeks of treatment. It may be more common in patients being treated for conditions other than epilepsy. It is not possible to say whether the concurrent use of antipsychotics increases the risk of its development, but until more is known it would be prudent to monitor the outcome, particularly during the first 2 weeks of combined use. 

Dhar S, Todi SK. Are carbamazepine-induced Stevens-Johnson syndrome and toxic epider-malnecrolysismore common innonepileptic patients D mia/t)/t) (1999) 199, 194. 

Another noteworthy adverse drug reaction (ADR) with a higher incidence in Asian patients on the anticonvulsant drugs carbamazepine and phenytoin is the Stevens-Johnson syndrome (SJS) (Locharernkul et al., 2008). SJS is a serious and potentially life-threatening skin condition. There is a conjecture that this higher risk in SJS is associated with a higher presence of the HLA-B 1502 allele in the Asian population. Phillips et al. (2011) argued that carriers of this allele could also avoid other structurally similar anticonvulsants. 

Genetic factors associated with severe adverse skin reactions induced by antiepileptic drugs in different ethnic populations have been discussed [80 , 81" ]. Several studies have shown that Han Chinese patients carrying the HLA-B 1502 are at high risk of Stevens-Johnson syndrome or toxic epidermal necrolysis when exposed to carbamazepine. 

HLA-B 1301, Cw 0801, and DRB1 1602 also showed an association with phenytoin. The authors concluded that HLA-B 1502 is a susceptibility factor for Stevens-Johnson syndrome/toxic epidermal necrolysis in patients taking these aromatic antiepileptic drugs, as has previously been shown with carbamazepine. 

Skin Several further cases of Stevens— Johnson syndrome/toxic epidermal necrolysis associated with carbamazepine have been described [120, 121 ], sometimes evolving to septic shock and multiple organ failure followed by death [122 ]. 

HLA class I has been examined in 15 Japanese patients who fulfilled the diagnostic criteria for carbamazepine-induced cutaneous adverse reactions (mild in 10 and Stevens-Johnson syndrome in 5) [124 ]. HLA-B 1518, HLA-B 5901, and HLA-C 0704 alleles were associated with higher relative risks of severe cutaneous adverse reactions. The haplotype HLA-A 2402-B 5901-C 0102 carried a high relative risk of severe adverse reactions. In patients with severe cutaneous adverse reactions, the frequencies of HLA-A 1101, HLA-A 3303, HLA-B 1501, HLA-B 4403, HLA-B 5101, HLA-B 5201, HLA-C 0702, and HLA-C 1202 alleles were relatively lower than in the general population of Japanese people. The authors suggested that HLA-B 5901 may be a marker of carbamazepine-induced Stevens-Johnson syndrome in Japanese people. 

In a case-control study to determine whether HLA-B 1502 is a valid pharmaco-genetic test for carbamazepine-induced Stevens-Johnson syndrome/toxic epidermal necrolysis in Thai patients, 79 with these serious complications carried... 

The application of genomics promises to better explain and ultimately reduce some ADRs. Results so far have demonstrated the association in Han Chinese of carbamazepine-indnced Stevens-Johnson syndrome with the HLA-B 15 02 allele and the association of abacavir hypersensitivity in AHS with HLA-B 57 01. 

Wei C-Y, Chung W-H, Huang H-W, et al. Direct interaction between HLA-B and carbamazepine activates T cells in patients with Stevens-Johnson syndrome. J Allergy Chn Immunol. 2012 129 1562-9. 

Serious, sometimes fatal dermatological reactions have been reported, including Stevens-Johnson syndrome and toxic epidermal necrolysis. The risk is 10 times greater in some Asian countries due to a strong association with the HLA-B 1502 allele, which is found almost exclusively in Asian patients. Genetically at-risk patients should be screened prior to receiving carbamazepine, and carbamazepine should not be given to patients who test positive for the allele. 

Drug overdose Of 16 796 toxic exposures to antiepileptic drugs (phenytoin, valproic acid, and carbamazepine) in the USA in 2006, 12 resulted in death, as reported by the US Toxic Surveillance System [67 ]. Some specific problems determined by overdose of some old and new antiepileptic drugs have been briefly reviewed. For example, topiramate can cause a significant metabolic acidosis, lamotrigine Stevens-Johnson syndrome, oxcarbazepine hyponatremia, and levetiracetam psychosis. Possible adoption of guidelines for critical care management of overdose are discussed. 

HLA allele B 1502 is a marker for an increased risk of carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in Han Chinese. The FDA has therefore changed the carbamazepine label, recommending genotyping in all Asians [90 ]. 

The possible association between HLA-B 1502 and carbamazepine- or phenytoin-induced Stevens-Johnson syndrome or maculopapular eruptions has been explored in 31 Thai subjects who had these antiepileptic drug-induced complications between 1994 and 2007 and in 50 antiepileptic drug-tolerant controls [92. There was a strong association between HLA-B 1502 and phenytoin- and carbamazepine-induced Stevens-Johnson syndrome. However, some patients with HLA-B 1502 had had carbamazepine-induced Stevens-Johnson syndrome and were tolerant of phenytoin and vice versa, which suggests that other factors contribute to this adverse reaction. 

The association between HLA-B 1502 and carbamazepine-induced Stevens- Johnson syndrome and toxic epidermal necrolysis has been investigated in eight Indian patients, of whom six had the HLA-B 1502 allele, confirming the association in Indian patients [93 ]. 

The risk of erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis in 72 patients with bipolar disorder taking carbamazepine, valproate, or other medications has been analysed using a large... 

Skin Oxcarbazepine is considered to be much less likely than carbamazepine to cause skin reactions, owing to its different metabolic pathway. Oxcctrbazepine-associated Stevens-Johnson syndrome has been described in two Chinese patients with epilepsy, one of whom was positive for HLA-B 1502 [223, 224 ]. 

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