Carbamazepine is an anticonvulsant primarily used to treat epilepsy but also neuropathic pain and psychiatric disorders. It has a hypersensitivity risk of up to 10% presenting as a skin rash, but sometimes causing more severe reactions like hypersensitivity syndrome (HSS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). HSS is a severe adverse drug reaction affecting multiple organs with considerable morbidity and mortality. Genetic factors like the HLA-B*15:02 and HLA-A*31:01 alleles may predispose patients to carbamazepine hypersensitivity reactions.

1. CARBAMAZEPINE
HYPERSENSITIVITY
Ade Wijaya, MD
January 2019

2. Type of Hypersensitivity
(Demoly, et al. 2014)

3. Carbamazepine
 A tricyclic anticonvulsant that is primarily used for the treatment of focal epilepsy
 Now also prescribed for the treatment of neuropathic pain and psychiatric disorders
 Mechanism of action: sodium channel blocker
(Marson et al. 2007, Ambrosio et al. 2002, Bialer 2012)

4. Carbamazepine Pharmacokinetics
 Absorbed slowly from the GI tract with a bioavailability of approximately 75%
 Peak plasma concentrations are typically reached between 4 and 8 h after oral
administration and plateau for 10-30 h before declining
 Plasma protein binding 70-80 %
 Carbamazepine 10,11-epoxide (CBZE) is the major metabolite of CBZ metabolism 
plasma protein binding 50-60 %
 Hepatic metabolism
(Tolbert et al. 2015, Rawlins et al. 1975, Spina 2002)

5. Hypersensitivity Syndrome
 A severe ADR with considerable morbidity and mortality that affects multiple organs
including the kidney, liver, lung, gastrointestinal tract, central nervous and lymphoid
systems
 ~ Drug induced hypersensitivity syndrome, drug reaction with eosinophilia and
systemic symptoms (DRESS) and drug-induced delayed multiorgan hypersensitivity
syndrome (Pirmohamed et al. 2011)
 Skin rash is the most commonly reported feature along with fever, hypereosinophilia,
liver involvement and lymphadenopathy (Cacoub et al. 2011).
 Anticonvulsants are the most common trigger for HSS accounting for about one
third of cases followed by allopurinol and antibiotics (Kardaun et al. 2013)

6. Hypersensitivity Syndrome
 Several viral infections including Human Immunodeficiency Virus (HIV), Human
Herpes Virus (HHV), Cytomegalovirus (CMV) and Epstein Barr Virus (EBV) have been
identified as risk factors for development of HSS (Dodiuk-Gad et al. 2014).
 The incidence of HSS secondary to phenytoin or CBZ has been estimated to be
between 1.0-4.5 per 10,000 prescriptions (Tennis and Stern 1997)
 The mortality associated with 36 HSS has been estimated to range between 1.7%
and 5.0%, although death rates of up to 10% have been reported when
anticonvulsants are the culprit drugs (DodiukGad et al. 2014)

7. Carbamazepine Hypersensitivity Reaction
 Up to 10% of patients starting treatment experience a hypersensitivity reaction
(Marson et al. 2007)
 The majority of these patients present with a skin rash which typically presents after
a few days and can resolve spontaneously without further intervention. (Yip et al.
2012).
 However, some patients present with more severe reactions that include HSS, SJS
and TEN (Yip et al. 2012).
 The current clinical guidance is that patients should stop CBZ therapy if a rash
appears (Garcia-Doval et al. 2000)
 The incidence of CBZ-induced HSS has an estimated frequency of 1.0-4.1 per 10,000
exposures (Tennis and Stern 1997)
 The estimated incidence of CBZ-induced SJS/TEN is greater in Asian populations
(Chen et al. 2011) than European populations (McCormack et al. 2011), 25 cases
per 10,000 compared with 1 to 6 cases per 10,000, respectively

8. Carbamazepine Hypersensitivity Reaction
 Predisposition to CBZ hypersensitivity reactions is thought to have a genetic
component because of cases reported in families and monozygotic twins
 HLA-B*15:02 allele & e HLAA*31:01 allele
(Edwards et al. 1999, Chung et al. 2004, McCormack et al. 2011; Ozeki et al. 2011)

9. Criado, et al. 2012

10. Summary
 Anticonvulsants: Hypersensitivity type 4
 Carbamazepine
 Rash  hypersensitivity syndrome  SJS/TEN
 HLA-B*15:02 allele & e HLAA*31:01 allele

11. THANK YOU