Idiosyncratic drug reactions are unexpected and unpredictable adverse reactions, fundamentally different from the dose-related side effects of drugs. A variety of idiosyncratic reactions may occur, such as aplastic anemia, acute liver failure, and rash. Genetic factors may be important in many of these events (Pirmohamed & Park, 2001).
Drug-induced rashes are the most common type of idiosyncratic reaction due to the use of antiepileptic drugs (AEDs). The most common presentation is a maculopapular (Figure 26.1) or erythematous pruritic rash appearing within 4 weeks of initiating therapy with a new AED. Systemic symptoms are usually absent, although fever may occur. The rash usually disappears within several days of discontinuing the drug. Other therapeutic measures are rarely needed, although diphenhydramine may help suppress itching, and a brief course of steroids may be helpful for severe rash, particularly when fever is present. Occasionally, the rash can be severe and present as erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis (Lyell syndrome) (Asconapé, 2002; Alvestad et al., 2007).
The AED hypersensitivity syndrome (AHS), also known as drug reaction with eosinophilia and systemic symptoms (DRESS), is not common but is important and potentially life threatening. A triad of fever, skin rash, and internal organ involvement characterizes AHS. It usually starts within the first 2−8 weeks after initiation of therapy. The initial symptoms include a low-grade fever followed by rash, lymphadenopathy, and pharyngitis. This is followed by internal organ involvement (e.g., eosinophilia, hepatitis, and less commonly, nephritis, carditis, pneumonitis, myositis, or blood dyscrasias). Facial edema is a striking feature of AHS, particularly in the periorbital area (Figure 26.2). The reported rate of liver involvement ranges from 34% to 94%, and fulminant hepatic necrosis can be seen. The presence of hepatitis worsens prognosis. Prompt recognition is the mainstay of treatment of AHS. To establish whether a drug is the cause of an immune-mediated reaction such as AHS, alternative causes, latency of a reaction after drug intake, and improvement after drug cessation should be considered. The causative drug should be immediately discontinued. The patient should never be rechallenged with the offending agent, as the relapse rate is extremely high. Sometimes, even after discontinuation of the offending agent, the disease activity can persist for 2–16 weeks. Cross-reactivity among the aromatic AEDs may explain these prolonged symptoms after switching to another aromatic AED. The most controversial issue in the management of AHS is the use of systemic corticosteroids. Although the role of corticosteroids is controversial, we advise prescribing prednisone, starting at a dosage of 1−2 mg/kg/day if symptoms are severe (e.g., hepatic involvement). Because stopping the offending AED increases the risk of having seizures, a new AED must be started immediately. In choosing a new drug, it is important to consider potential cross-reactivity and to try and avoid this problem. Valproate should be avoided if significant hepatic involvement has developed. Lacosamide, levetiracetam, gabapentin, pregabalin, and topiramate are reasonably safe options and can be immediately begun at therapeutic doses. Use of intermittent benzodiazepine therapy can help manage breakthrough seizure clusters during the transition. However, the structure of benzodiazepines contains aromatic rings, and part of their metabolism involves cytochrome P-450 isoforms. Therefore, there is still potential for cross-reactivity (Knowles et al., 1999; Asconapé, 2002; Kwong et al., 2006; Alvestad et al., 2007).
Stevens-Johnson and other severe syndromes have been reported in patients taking many AEDs. It is possible that lamotrigine is associated with a higher risk of developing a severe skin eruption than other drugs. Unfortunately, there is no reliable way to determine early in the clinical course of a rash if it will remain as a benign maculopapular rash or evolve into a severe skin reaction. Therefore, the offending drug should usually be discontinued as soon as possible. Signs and symptoms that may indicate the presence of a more severe reaction include a painful rash, mucosal involvement (Figure 26.3), fever, and other systemic symptoms (Asconapé, 2002). There are occasions, however, when it may be undesirable to stop a particular AED that has just caused a rash. In these circumstances, provided there are no signs of a more severe problem, one can continue that AED while observing the patient closely and treating symptoms such as itching with an antihistamine. Provided more severe symptoms do not appear, the rash will prove to be transient and disappear in many cases. This course of action should be carried out only when there are compelling reasons to continue an AED, or there is a strong presumption that the next drug will likely provoke a similar initial rash.
The aromatic (Figure 26.4) AEDs—phenytoin, carbamazepine, oxcarbazepine, eslicarbazepine acetate, phenobarbital, primidone, zonisamide, and lamotrigine—are more frequently associated with cutaneous eruptions and other signs or symptoms of drug hypersensitivity. There is a high degree of cross-reactivity (40%–80%) in patients with hypersensitivity or allergic reactions to phenytoin, phenobarbital, primidone, and carbamazepine. These drugs are all metabolized to hydroxylated aromatic compounds via the cytochrome P-450 hepatic enzymes. Arene oxide intermediates are formed during metabolism and are thought to be responsible for cross-sensitivity among these AEDs in susceptible individuals. Some individuals may have a reduced ability to detoxify intermediate toxic metabolites (e.g., arene oxides) of these AEDs, which may be genetically mediated. However, there is no way to predict with certainty which patients will exhibit cross-sensitivity (Knowles et al., 1999; Asconapé, 2002; Levy et al., 2002; Kwong et al., 2006; Alvestad et al., 2007; Drug Facts and Comparisons, 2007). Whether drugs such as lamotrigine and zonisamide will also show a similar risk of cross-reactivity has not been properly evaluated, but it is likely due to the aromatic structure of these drugs. Nonaromatic AEDs (e.g., levetiracetam, topiramate, valproate) are safe alternatives for patients with aromatic AED-induced severe cutaneous adverse drug reactions.
According to a recent study, the rate of an AED rash is greater in patients with another AED rash (8.8%) versus in those without (1.7%) (odds ratio 3:1) (Arif et al., 2007). Therefore, patients with a history of an AED-induced rash should be treated with drugs with a lower risk for allergic reactions (e.g., valproate, benzodiazepines, gabapentin, topiramate, levetiracetam, or tiagabine). The rate of dose titration is also an important issue. The risk of allergic reaction is decreased when a drug is begun at a low dose and gradually increased; slow titration may allow desensitization to occur. A relation between starting dose and titration rate and the incidence of skin reactions is particularly evident for lamotrigine, carbamazepine, and phenytoin (Zaccara et al., 2007). Females may also be associated with a higher risk of AED-induced rash (Alvestad et al., 2007).
Skin testing, in particular the patch test, may be a useful screening method to discover the specific cause of an exanthematous cutaneous reaction if several drugs are possible offenders (Lammintausta & Kortekangas-Savolainen, 2005). In the unusual patient considered to be at high risk for a hypersensitivity reaction, skin tests to predict individual reactivity may be helpful (Zaccara et al., 2007).
Recent studies have shown that different ethnic populations may have dissimilar risks regarding the development of AED-severe cutaneous adverse drug reactions due to various genetic backgrounds. Genetic markers such as the human leukocyte antigen (HLA) are useful in predicting an individual’s predisposition to AED hypersensitivity reactions. Ever since it was first linked with carbamazepine-SJS in Han Chinese, HLA allele B*1502 (HLA-B*1502) has become the strongest HLA correlation among human diseases. This association holds true for certain ethnic groups only, in particular Han Chinese, Thai, Malay, and to a lesser degree, Indians. Regardless of ethnicity, hypersensitivity reactions predisposition can be predicted by the in vitro lymphocyte toxicity assay (LTA) as well. LTA is a good predictor tool for possible hypersensitivity reactions in patients with epilepsy (Neuman et al., 2012).
Another potential adverse effect of AEDs is photosensitivity, which describes either a phototoxic response or a less frequent photoallergic reaction. A phototoxic reaction is immediate and resembles exaggerated sunburn. In comparison, a photoallergic reaction has an immunological basis and requires previous exposure to the photo-sensitizing agent. Patients who experience photoallergic responses typically present 1−14 days after exposure to sunlight with a papulovesicular eruption, pruritus, and eczematous dermatitis (Dubakiene & Kupriene, 2006). Photosensitivity reactions are not predictable and can occur at any age. Many medications, including antiepileptic drugs (AEDs), are associated with photosensitivity reactions (Moore, 2002; Dubakiene & Kupriene, 2006; Drug Facts and Comparisons, 2007). Protection from sunlight often prevents photosensitivity reactions. Avoidance of direct sunlight and sun-tanning facilities, using protective clothing and eyewear, application of an appropriate sunscreen with high UV protection rating, and evening dosing of the drug are measures that can minimize the risk of photosensitivity effects of most drugs (Moore, 2002; Dubakiene & Kupriene, 2006). Treatment is necessary when severe burning reaction occurs. In the case of a phototoxic reaction, the treatment is the same as used for sunburn. Avoidance of the offending photosensitizing agent or sunlight exposure is required, but sometimes an offending AED may not be avoidable. Therefore, preventive measures are of great significance. Antihistamines and corticosteroids may be required to treat the inflammation arising from photoallergic reactions (Moore, 2002). Should preventative measures be impractical or ineffective, then a new drug should be chosen. Photosensitivity has been reported with lamotrigine treatment in 2% of patients. Other AEDs associated with photosensitivity include carbamazepine, felbamate, gabapentin, oxcarbazepine, phenobarbital, phenytoin, tiagabine, topiramate, and valproic acid. The incidence of photosensitivity in patients taking these AEDs is less than 1%. Insufficient data are available for accurate estimates of incidence in most AEDs.
Note: Avoid lamotrigine and acetazolamide in patients with known photosensitivity to multiple drugs.
Acetazolamide is a sulfonamide. Acetazolamide has been associated with Stevens-Johnson syndrome, toxic epidermal necrolysis, and acute generalized exanthematous pustulosis. The nonfollicular, pustular, erythematous rash starts 2–3 weeks after starting the drug and is associated with fever. Reexposure may cause a second episode within 2 days. Acetazolamide is contraindicated in any patient with sulfonamide sensitivity (Levy et al., 2002; Drug Facts and Comparisons, 2007).
Like other sulfonamide derivatives, photosensitivity may occur with carbonic anhydrase inhibitors including acetazolamide. Some patients may be more sensitive to sunlight (UV) exposure while receiving acetazolamide.
Drug-induced rashes and allergic reactions are not frequent with benzodiazepines (Levy et al., 2002; Drug Facts and Comparisons, 2007). Approximately 2% of patients taking clobazam develop a skin rash (Arif et al., 2007).
Some dermatological effects of carbamazepine include photosensitivity, alopecia, urticaria, alterations in skin pigmentation, exfoliative dermatitis, erythema multiforme, and erythema nodosum. Approximately 4%–11% of patients develop a skin rash (Alvestad et al., 2007; Arif et al., 2007). Rashes associated with carbamazepine do not have specific identifying characteristics. The rash usually develops during the first 2–8 weeks of therapy. Serious dermatologic reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis, and angioedema have been reported. Carbamazepine has also been associated with acute generalized exanthematous pustulosis. Multiorgan hypersensitivity reactions (AHS) occurring days to weeks or months after initiating treatment are rare (Levy et al., 2002; Drug Facts and Comparisons, 2007).
Serious dermatologic reactions including Stevens-Johnson syndrome (SJS) and also AHS have been reported in association with eslicarbazepine acetate. Rare cases of anaphylaxis and angioedema have been reported in patients taking this drug. Risk factors for development of these serious reactions have not been identified. This drug is chemically similar to carbamazepine and oxcarbazepine. Patients with a prior dermatologic reaction, AHS, or other serious reactions with either oxcarbazepine or eslicarbazepine acetate should not be treated with this drug.
Dermatological side effects during ethosuximide therapy include erythematous skin rash, pruritus, and urticaria. More serious reactions, which may be accompanied by fever, lymphadenopathy, pharyngitis, and muscle pain, are uncommon but can develop, including erythema multiforme and Stevens-Johnson syndrome. Ethosuximide should not be used in patients with a history of succinimide hypersensitivity (Levy et al., 2002; Drug Facts and Comparisons, 2007).
Ezogabine can cause skin discoloration (blue, gray-blue, or brown). It is predominantly on or around the lips or in the nail beds of the fingers or toes, but more widespread involvement has also been reported. Approximately, 10% of patients in long-term clinical trials developed skin discoloration, generally after 2 or more years of treatment and at higher doses (900 mg or greater). Pathophysiology of skin discoloration with ezogabine remains unclear. The possibility of more extensive systemic involvement has not been excluded. If a patient develops skin discoloration, serious consideration should be given to changing to an alternate medication.
Acne, rash, and pruritus have occurred with felbamate therapy. Approximately 1%–2% of patients develop a skin rash (Arif et al., 2007). Toxic epidermal necrolysis due to felbamate has been reported. Felbamate is contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients (Levy et al., 2002; Drug Facts and Comparisons, 2007).
Less than 1% of patients develop a skin rash (Arif et al., 2007). Gabapentin is contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients (Levy et al., 2002; Drug Facts and Comparisons, 2007).
Mild (e.g., pruritus) and severe (e.g., AHS) reactions have been reported in patients taking lacosamide very rarely.
Rash is the most common cause for discontinuation of lamotrigine therapy. Approximately 10% of patients develop erythema and a maculopapular rash, although the incidence is lower when slow titration schedules are used (Arif et al., 2007). Rashes associated with lamotrigine do not have specific identifying characteristics. The rash usually develops during the first 2–8 weeks of therapy. Serious dermatological reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis, and angioedema have been reported. Serious reactions are observed more often in children (8–10 in 1000) than adults (0.8–3 in 1000). Rash also appears to be more common in patients receiving valproic acid concomitantly or when the recommended dose escalation schedule is exceeded. The increased rate of rash observed in patients taking valproate when lamotrigine is initiated probably reflects reduced metabolism and therefore higher serum levels of lamotrigine (due to enzyme inhibition by valproate). Initiating therapy at the lowest possible dosage and escalating slowly appear to minimize the occurrence of skin rash. Bullous rash or vesicular rash should result in prompt discontinuation of lamotrigine therapy and appropriate evaluation. Hypersensitivity reactions, some fatal or life threatening, have also occurred with lamotrigine. Early manifestations of hypersensitivity (e.g., fever and lymphadenopathy) may be present even though a rash is not evident (Levy et al., 2002; Karande et al., 2006; Drug Facts and Comparisons, 2007).
Lamotrigine is contraindicated for use in any patient who has exhibited or is suspected of having hypersensitivity to lamotrigine or to any components of its formulation. Factors to predict a serious rash are not available; however, children appear to be at greater risk (Levy et al., 2002; Drug Facts and Comparisons, 2007), as are patients receiving valproate. In addition, a history of another AED-related rash is a major risk factor for developing rash to lamotrigine (Hirsch et al., 2006), and this drug should not be an early therapeutic choice for patients with a history of hypersensitivity to other AEDs.
Cutaneous eruptions rarely occur in patients treated with this drug (Arif et al., 2007). Levetiracetam is contraindicated in patients with a known hypersensitivity to the drug or any of the active ingredients in the formulations (Levy et al., 2002; Drug Facts and Comparisons, 2007).
Allergic skin reactions such as rash, pruritus, or urticaria may occur with oxcarbazepine. Approximately 2.5% of patients develop a skin rash (Arif et al., 2007). Rashes associated with oxcarbazepine do not have specific identifying characteristics. Other skin conditions reported include erythema multiforme and oral ulceration. Other serious dermatological reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported in both children and adults in association with oxcarbazepine. AHS rarely occurs. Cross-sensitivity between carbamazepine and oxcarbazepine is approximately 25%–30% and is likely due to the structural similarity of the two drugs (Misra et al., 2003).
No information is available with regard to potential dermatologic or allergic reactions with perampanel use.
Hypersensitivity reactions to phenobarbital may present as various organ system problems, including blood, liver, renal, and skin disorders. Discontinuation of the drug may not be sufficient to reverse progression of any serious hypersensitivity reaction because of the slow metabolism and excretion of phenobarbital.
Cutaneous reactions occur in 1%–2% of patients and include scarlatiniform or morbilliform maculopapular rash. Angioedema, bullous rash, exfoliative dermatitis, lupuslike symptoms, photosensitivity, purpura, serum sickness, Stevens-Johnson syndrome, and toxic epidermal necrolysis are rare but serious adverse effects of phenobarbital. Although uncommon, AHS has been reported with phenobarbital.
Avoid the use of phenobarbital in patients with a history of barbiturate hypersensitivity. Injectable solutions may also contain propylene glycol and should be avoided in patients with a hypersensitivity to propylene glycol. A history of hypersensitivity reactions should be obtained for a patient and the immediate family members. If hypersensitivity histories are positive, caution should be used in prescribing phenobarbital. Hypersensitivity reactions have been reported in patients who previously experienced phenytoin or carbamazepine hypersensitivity (Levy et al., 2002; Drug Facts and Comparisons, 2007). Patients who have experienced reactions due to phenobarbital therapy should not be further exposed to the drug.
Adverse dermatological reactions to phenytoin occur in 5%–10% of patients and usually present as a maculopapular rash. More serious responses such as bullous rash, exfoliative dermatitis, purpura, erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis can occur but are rare. Minor reactions, such as rash, more often develop in the first few weeks of therapy in contrast to more serious reactions, which more often develop later. Skin hyperpigmentation has been reported and is more common in women than in men. Phenytoin can produce hypertrichosis or hirsutism. Coarsening of the facial features and enlargement of the lips are among the side effects.
Hypersensitivity reactions have been reported in patients who previously experienced other hydantoin hypersensitivity (e.g., fosphenytoin), barbiturate hypersensitivity (e.g., hypersensitivity to phenobarbital), or carbamazepine hypersensitivity (Levy et al., 2002; Drug Facts and Comparisons, 2007). Many patients who react to carbamazepine also react to phenytoin, and vice versa.
The incidence of rash is low with this drug. Pregabalin is contraindicated in patients who have a demonstrated or suspected hypersensitivity to the drug or the inactive ingredients. It is not known if cross-hypersensitivity exists between gabapentin and pregabalin, but the drugs are chemically and structurally similar. Use pregabalin with caution in patients with a known hypersensitivity to gabapentin (Levy et al., 2002; Drug Facts and Comparisons, 2007).
Rash, pruritus, Stevens-Johnson syndrome and AHS have rarely been reported in association with rufinamide therapy. All patients who develop a rash while taking rufinamide must be closely supervised. If any severe reaction (e.g., AHS) is suspected, rufinamide should be discontinued and alternative treatment started.
Approximately 2.5% of patients develop a skin rash (Arif et al., 2007). Maculopapular rash, vesicular rash, and (in rare cases) Stevens-Johnson syndrome have been reported due to tiagabine (Levy et al., 2002; Drug Facts and Comparisons, 2007).
Approximately 1% of patients develop a rash (Arif et al., 2007). Topiramate is contraindicated in any patient hypersensitive to the drug or any of the product components. Rarely, serious and potentially fatal exfoliative dermatologic reactions have been reported (Levy et al., 2002; Drug Facts and Comparisons, 2007).
Dermatological reactions have been seen in patients receiving valproic acid. These reactions include transient alopecia, skin rash, pruritus, photosensitivity, erythema multiforme, and Stevens-Johnson syndrome (Levy et al., 2002; Drug Facts and Comparisons, 2007). Approximately 1% of patients develop a rash (Arif et al., 2007). Multiorgan hypersensitivity reactions (AHS) have been rarely reported with valproate. Cross-sensitivity with other drugs that produce this syndrome is unclear but may be possible (Levy et al., 2002; Drug Facts and Comparisons, 2007). As noted, patients taking valproate are more likely to develop a rash when lamotrigine is begun.
Angioedema, maculo-papular rash, pruritus, Stevens-Johnson syndrome, and toxic epidermal necrolysis (TEN) have been reported by patients taking vigabatrin.
Approximately 4.5% of patients develop a rash (Arif et al., 2007). Zonisamide is a sulfonamide and can, in rare cases, produce severe, possibly fatal reactions such as toxic epidermal necrolysis, Stevens-Johnson syndrome, fulminant hepatic necrosis, and blood dyscrasias. Once sensitization to sulfonamides has occurred, a recurrence can be precipitated by administration of sulfonamides by any route. Zonisamide should be discontinued if there is any sign of a hypersensitivity reaction. Rash usually develops early (2–16 weeks) in the course of treatment with zonisamide.
Zonisamide is more likely to cause rash in patients with a history of sulfonamide hypersensitivity. Additionally, zonisamide should be avoided if possible in patients with carbonic anhydrase inhibitor hypersensitivity (Levy et al., 2002; Drug Facts and Comparisons, 2007).
Recommended Antiepileptic Drugs in Patients With History of Drug-Induced Skin Rash
1. Generalized epilepsies: Levetiracetam, topiramate, valproate
2. Focal epilepsies: Gabapentin, lacosamide, levetiracetam, perampanel, pregabalin, topiramate.
Note: The risk for cutaneous adverse effects (e.g., Stevens-Johnson syndrome and toxic epidermal necrolysis) with phenytoin, phenobarbital, and carbamazepine is increased during radiotherapy. When treatment is indicated, a drug with a lower potential for allergic cutaneous reactions (e.g., gabapentin, levetiracetam, pregabalin, or topiramate) is preferred (Michelucci, 2006).
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