Antiepileptic Drugs, 5th Edition

Lamotrigine

39

Adverse Effects

Francesco Pisani MD*

Alan Richens MD, PhD**

* Associate Professor of Neurology, Department of Neurosciences, Psychiatric and Anaesthesiological Sciences, University of Messina, Messina, Italy

** Emeritus Professor of Pharmacology and Therapeutics, Department of Pharmacology and Therapeutics, University of Wales College of Medicine, Cardiff, United Kingdom

Lamotrigine was introduced to its first market in the Republic of Ireland in 1991 and, at the time of writing, 10 years of postmarketing experience has been gained. It is estimated that at May 1, 2000, approximately 11,000 adults and 2,000 children (<12 years of age) in clinical trials and more than 1,000,000 patients worldwide have received lamotrigine, with >583,000 patient-years of experience accumulated (1). Lamotrigine was developed as a member of a series of phenyltriazine compounds with dihydrofolate reductase-inhibiting activity, although in the case of lamotrigine, the latter property is weak and does not appear to create adverse effects in humans. Toxicity studies in rodents, marmosets, and cynomolgus monkeys have shown that the dose of lamotrigine required to produce an anticonvulsant effect is well below that needed to cause toxic effects, such as decreased locomotor activity, ataxia, and reflex impairment (2). Carcinogenicity, reproductive toxicity, and mutagenicity tests have demonstrated no toxic effects.

In general, lamotrigine is well tolerated and the general safety assessment measures usually evaluated in most clinical trials, including the routine measurement of vital signs, clinical chemistry, and hematologic parameters, as well as urinalysis and electrocardiography, were not modified by the use of lamotrigine. Unlike other conventional antiepileptic drugs, such as phenytoin and carbamazepine, long-term use of lamotrigine does not seem to affect peripheral nerve function (3).

MOST COMMONLY OBSERVED ADVERSE EFFECTS

During the phase I clinical development of lamotrigine, a battery of psychomotor, autonomic, sensory, and subjective tests was used in healthy volunteers, with an emphasis on saccadic eye movements, to compare the central nervous system (CNS) effects of lamotrigine with some established drugs, namely, phenytoin and diazepam (4), and carbamazepine (5). Phenytoin and diazepam were found to impair smooth-pursuit eye movements, reduce peak saccade velocity (diazepam only), impair adaptive tracking, and cause drowsiness, but lamotrigine had none of these effects. Carbamazepine impaired smooth pursuit, reduced peak saccade velocity, impaired adaptive tracking, and increased body sway in single doses of 400 and 600 mg, whereas lamotrigine again had none of these effects in doses of 150 and 300 mg. It was predicted from these studies that lamotrigine would be well tolerated in patients at the doses used. These doses subsequently were shown to suppress interictal spikes (6) and photosensitivity (7), and therefore the findings in volunteers were thought to be relevant to subsequent clinical trials.

Central Nervous System Side Effects

Dose Dependency, Incidence, and Prevalence

The first definitive efficacy trials of lamotrigine in patients were conducted in four centers and included a total of 92 patients (8, 9, 10, 11). The trials were of a crossover design, and either lamotrigine or placebo was added to existing therapy in a randomized order for 8 to 12 weeks in patients with refractory epilepsy. The dose of lamotrigine ranged from 50 to 400 mg/day and was adjusted according to the background therapy to allow for the inducing effect of some of the conventional antiepileptic drugs and the inhibitory effect of valproate on the metabolism of lamotrigine (Chapter 37). The most commonly recorded adverse events are given in Table 39.1. Although they were seen more frequently when patients were on lamotrigine rather than placebo, in no case was the difference statistically significant (12). However, with ataxia, the confidence intervals (CIs) intercepted zero, indicating a difference of borderline significance.

A similar spectrum of adverse reactions was seen in an Australian double-blind, crossover study in which doses of

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up to 300 mg of lamotrigine daily or placebo were added to the background therapy in 41 patients with partial seizures (13). Dizziness was significantly more common with lamotrigine treatment (11%) than with placebo (0%). A further double-blind, crossover, add-on study (14) in 81 patients showed a significantly higher incidence of ataxia, diplopia, nausea and vomiting, blurred vision, and insomnia with lamotrigine in doses of up to 400 mg/day.

TABLE 39.1. INCIDENCE OF ADVERSE EVENTS IN PATIENTS TREATED WITH LAMOTRIGINE OR PLACEBO, AND THE 95% CONFIDENCE INTERVAL OF THE DIFFERENCE BETWEEN THE INCIDENCE RATES, BASED ON A METAANALYSIS OF FOUR DOUBLE-BLIND, PLACEBO-CONTROLLED, CROSSOVER, ADD-ON STUDIES INVOLVING A TOTAL OF 92 PATIENTS

 

Incidence (%)

Adverse Experience

Lamotrigine

Placebo

95% Confidence Interval for Difference

Asthenia

17

13

-12; 4

Diplopia

15

12

-13; 6

Headache

13

7

-14; 1

Somnolence

13

12

-9; 7

Ataxia

12

4

-15; 0

Dizziness

9

8

-9; 7

Nausea

4

3

-7; 5

Nervousness

4

2

-7; 3

Modified from Betts T, Goodwin O, Withers RM, et al. Human safety of lamotrigine. Epilepsy Res 1991;32[Suppl 2]:S17-S21, with permission.

Experience in the United States is similar to that in Europe. In a large multicenter study, lamotrigine or placebo was added to the existing therapy in outpatients with partial epilepsy (15). Patients were randomized in a 3-to-1 ratio to receive lamotrigine in doses of up to 500 mg/day or placebo, respectively. Patients receiving valproate were excluded. Follow-up lasted for 24 weeks. The adverse event profiles in 334 patients treated with lamotrigine and 112 treated with placebo are given in Table 39.2. The high incidence of adverse events on adding placebo should be noted, highlighting the need for a placebo control in assessing the adverse reaction profile of a new antiepileptic drug. Headache, for example, occurred in just over one-third of lamotrigine-treated patients, but the incidence with placebo was virtually identical. Significant differences were seen, however, for dizziness, diplopia, ataxia, blurred vision, and somnolence. There was evidence in this trial that the incidence of some CNS adverse effects was dose related.

Systematic reviews (16, 17, 18), including subsequent studies and a larger number of patients, have confirmed the foregoing CNS toxicity profile of lamotrigine and have indicated that the most frequently occurring side effects (i.e. >5% of patients) during lamotrigine therapy at doses of up to 500 mg/day are dizziness, diplopia, ataxia, blurred vision, headache, and nausea or vomiting. It is not known whether the latter two effects are due to a central or peripheral action of the drug.

The CNS adverse effects with lamotrigine often are mild, do not require drug withdrawal, and lessen over time. Consequently, the proportion of patients in whom withdrawal of lamotrigine is necessary for a particular event is much smaller than the overall incidence of the event (Table 39.3). In the analysis of Betts (19), less than 1% of patients had to discontinue lamotrigine for any one CNS adverse event, and in the U.S. trial (15), the proportion of patients withdrawn from the study because of adverse events was identical in both the lamotrigine- and the placebo-treated groups (i.e., 8%). In a recent meta-analysis (16), the overall odds ratio (ratio of incidence with the drug to incidence with placebo) for discontinuation

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for any reason was 1.19 (95% CI, 0.79 to 1.79). This value, slightly above unity, indicates that the difference between lamotrigine and placebo is very small. Lower values, as reported in open observational studies, probably are due to the fact that in these studies the dose of lamotrigine could be modified and rapidly adjusted to the clinical situation without any adherence to the specific rigid protocols that are typical of controlled studies.

TABLE 39.2. ADVERSE EVENTS OCCURRING IN U.S. PLACEBO-CONTROLLED EVALUATION OF THE SAFETY OF LAMOTRIGINE (EVENTS REPORTED IN 10% OR MORE PATIENTS)

 

Number (%) of Patients

Adverse Events

Lamotrigine (n = 334)

Placebo (n = 112)

Dizziness

168 (50)a

20 (18)

Headache

125 (37)

40 (36)

Diplopia

109 (33)a

12 (11)

Ataxia

80 (24)a

5 (5)

Blurred vision

77 (23)a

10 (9)

Nausea

73 (22)

17(15)

Rhinitis

58 (17)

21(19)

Somnolence

46 (14)a

8 (7)

Pharyngitis

42 (13)

13 (12)

Coordination abnormality

39 (12)

7 (6)

Flu syndrome

38 (11)

10(9)

Cough

35 (10)

9 (8)

Rash

34 (10)

6 (5)

Dyspepsia

32 (10)

6 (5)

Vomiting

32 (10)

10 (9)

a Statistically significantly greater than with placebo.
Modified from Schachter SC, Leppik IE, Matsuo F, et al. A multicentre, placebo-controlled evaluation of the safety of lamotrigine (Lamictal) as add-on therapy in outpatients with partial seizures. Epilepsy Res 1992;33[Suppl 3]:1-19, with permission.

TABLE 39.3. ADVERSE EVENTS LEADING TO WITHDRAWAL OF LAMOTRIGINE IN 1,920 PATIENTS INCLUDED IN OPEN-LABEL AND DOUBLE-BLIND STUDIES.

Adverse Event

Number (%) of Patients

Rash

54 (2.8)

Headache

15 (0.8)

Ataxia

12 (0.6)

Diplopia

11 (0.6)

Nausea

11 (0.6)

Blurred vision

10 (0.5)

Dizziness

9 (0.5)

Asthenia

9 (0.5)

Vomiting

9 (0.5)

Somnolence

6 (0.3)

Insomnia

6 (0.3)

Depression

5 (0.3)

Psychosis

4 (0.2)

Increased seizures

4 (0.2)

Total number of patients withdrawn

150 (7.8)

Modified from Betts T. Safety of lamotrigine. In: Richens A, ed. Clinical update on lamotrigine: a novel antiepileptic agent. Tunbridge Wells, UK: Wells Medical 1992:61-68, with permission.

Few published data are available regarding the correlation between lamotrigine dose or plasma concentration and CNS adverse effects. Based on current knowledge, this correlation seems to be poor for most of the aforementioned effects (13,20,21).

Experience with lamotrigine monotherapy is increasing since a number of monotherapy comparative studies have been completed (22, 23, 24, 25). Fifteen countries have approved lamotrigine in monotherapy in adults and six in childhood (i.e., <12 years of age). In two double-blinded, randomized, placebo-controlled, parallel-group studies, lamotrigine was better tolerated than carbamazepine (22) or phenytoin (25). In fact, the withdrawal rate due to adverse events (including rash) was 14% to 15% with 100 to 400 mg/day lamotrigine (plasma concentrations within the target range of 2 to 4 mg/L), this value being lower than that of carbamazepine (27%, daily dose 300 to 1,400 mg, median plasma concentration 8.3 mg/L, target range 4 to 10 mg/L) and phenytoin (19%, modal and maximal daily doses 300 and 600 mg, mean plasma level 13.4 mg/L, target range 10 to 20 mg/L).

Time Dependency

Usually, add-on therapy with lamotrigine is well tolerated. In most clinical trials, as great as 30% to 40% of treatment-emergent adverse events, typically the most frequent on CNS, was judged by the investigators to be reasonably attributable to lamotrigine (17). These effects develop during the first 4 to 6 weeks of treatment and tend to lessen or resolve over time or after dosage adjustment.

Risk Factors

It is general experience that some CNS side effects occur more frequently when lamotrigine is added to carbamazepine (dizziness and diplopia) (15,26,27) or to valproate (hand tremor) (28,29). Adding a new drug to existing therapy can cause adverse reactions by pharmacokinetic or pharmacodynamic interaction with the baseline drugs. Lamotrigine causes little in the way of pharmacokinetic interactions with other drugs, although enzyme inducers and valproate influence its own metabolism (Chapter 37). Available data suggest that lamotrigine does not cause substantial changes in plasma levels of carbamazepine and its active metabolite, carbamazepine 10,11-epoxide, and therefore the dizziness and diplopia associated with a combination of the two drugs is thought to be a pharmacodynamic phenomenon. Hand tremor occurring when lamotrigine and valproate are taken in combination has been observed to be unrelated to plasma drug concentrations (29), and also may be the result of a pharmacodynamic interaction.

Use in Children

Messenheimer and colleagues (30) analyzed the safety data of lamotrigine in 1,096 children who took part in controlled clinical trials. CNS adverse effects were quantitatively and qualitatively similar to those described for adults. Similar results were obtained in a large, placebo-controlled, add-on study in the United States (31). Childhood, therefore, does not seem to be a particular risk factor for lamotrigine-induced CNS adverse effects.

Use in Elderly

Lamotrigine is largely metabolized in the liver to a glucuronide conjugate. This pathway has a large capacity and therefore is little affected by the processes involved in aging. The plasma elimination half-life was found to be no different in a group of elderly subjects compared with young adults (32). On the other hand, changes that occur in the brain as a result of aging may make the elderly more susceptible to the adverse effects of antiepileptic drugs. In a multicenter, double-blind, monotherapy study comparing 75 to 500 mg/day lamotrigine versus 200 to 2,000 mg/day carbamazepine treatment in newly diagnosed patients, the rate of dropout due to adverse events was twofold higher for carbamazepine—42%, versus 18% for lamotrigine (33). This was in part the consequence of lower rash and somnolence rates with lamotrigine (rash: lamotrigine 3%, carbamazepine 19%, 95% CI 7% to 25%; somnolence: lamotrigine 12%, carbamazepine 29%, 95% CI 4% to 30%).

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Advice Concerning Precautions and Management

As stated previously, most of the CNS adverse effects of lamotrigine lessen or resolve over time and therefore do not require any particular treatment. Adherence to the recommended starting doses and to the indicated dose escalation (Table 39.4), especially in patients receiving carbamazepine or valproate (see previous discussion), is a good precaution to avoid increases both in the incidence and in the intensity of these side effects.

Lamotrigine may have beneficial side effects on CNS function. A number of investigators have observed that a small proportion of patients, particularly those with a learning disability, seem much brighter and more responsive when taking lamotrigine. Smith et al. (14) included a health-related quality-of-life measure in their placebo-controlled, crossover study in 81 patients with partial epilepsy. Although only 11 patients experienced at least a 50% reduction in seizure frequency, no fewer than 41 elected to continue with lamotrigine at the end of the trial, indicating that factors other than seizure control influenced their decision. A significant improvement was seen in the subscales for happiness and mastery, suggesting that effects on mood and attitude might be an additional benefit with lamotrigine. Overall, lamotrigine has proven to exhibit a favorable profile on health-related quality-control measures (14,34).

Rash

The most common hypersensitivity reaction to lamotrigine is a simple morbilliform skin rash, typically maculopapular, most frequently with no evidence of systemic involvement. Other reported rash types include angioedema, erythema, petechiae, purpura, pustular and vesicular rashes, and urticaria. Rash also is the most frequent side effect leading to lamotrigine discontinuation and, although rarely serious, it represents an annoying adverse effect of lamotrigine. Rash is not a new concern of antiepileptic therapy because some of the most commonly used conventional antiepileptic drugs, like carbamazepine and phenytoin, exhibit this adverse effect. In recent reviews (17,35), in fact, the incidence of rash in monotherapy showed similar values for lamotrigine (~14%, discontinuation rate ~6%), carbamazepine (~15%, discontinuation rate ~9%), and phenytoin (~12%, discontinuation rate ~5%).

Dose Dependency, Incidence, and Prevalence

The incidence of skin rashes has been evaluated in different systematic reviews of double-blind, placebo-controlled trials (17,18,35,36). The proportion of adult patients experiencing skin rash after addition of placebo in most of the studies analyzed was approximately one-half of that associated with addition of lamotrigine, and ultimately the real incidence of lamotrigine rashes, as indicated by the difference between the drug and placebo, was ~5% (18,36). Table 39.5 shows the results obtained by one of the earlier reviews (36) in which the proportion of patients withdrawn from a trial because of the occurrence of a skin rash was 1.7%. There was, however, a wide range of variation, up to >20-fold, because they are greatly influenced by a number of factors. Overall, it is possible that up to ~3% of patients were withdrawn when data from open-label and controlled trials were combined (19) (Table 39.3). Among those factors influencing the incidence of rash, it has become clear with further experience that the size of the initial dose of lamotrigine and the rate of escalation in dose are two of the most important.

Yuen (36) found a rash rate of 2.1% in patients whose plasma lamotrigine concentration was greater than 1.4 mg/L when measured 2 weeks after initiation of therapy, whereas the rate was only 0.6% when plasma concentrations were below this level. Data from monotherapy studies (17) showed that the withdrawal rates due to rash progressively increased in line with the lamotrigine dose in the first week of treatment, from ~2% at 25 mg/day up to ~40% at 200 mg/day. Similarly, discontinuation rates due to rash ranged from ~2% at a mean daily lamotrigine dose of <100 mg achieved during the first 5 weeks of treatment up to ~13% at a mean dose of ~400 mg/day. This relationship is not unique with antiepileptic drugs, because both phenytoin and carbamazepine are more likely to cause rashes when the starting dose is high (37).

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TABLE 39.4. STARTING AND MAINTENANCE DOSE OF LAMOTRIGINE IN ADULTS AND CHILDREN

   

Daily Dose

Concomitant Therapy

Weeks 1-2

Weeks 3-4

Maintenance Dose

Adults and children >12 yr

     
 

Valproic acid

25 mg on alternate days

25 mg

100-200 mg

 

Nil

25 mg

50 mg

100-200 mg

 

Inducing antiepileptic drugs

50 mg

100 mg

200-400 mg

Children 2-12 yr

     
 

Valproic acid

0.2 mg/kg

0.5 mg/kg

1-5 mg/kg

 

Nil

0.5 mg/kg

1 mg/kg

2-8 mg/kg

 

Inducing antiepileptic drugs

2.0 mg/kg

5 mg/kg

5-15 mg/kg

TABLE 39.5. INCIDENCE OF SKIN RASH IN DOUBLE-BLIND-PLACEBO-CONTROLLED STUDIES.

 

Lamotrigine

Placebo

Difference

Number of patients

890

559

Incidence of rash (%)

10.5

5.2

5.3

Withdrawn due to rash (%)

1.9

0.2

1.7

Modified from Yuen AWC. Safety issues. In: Richens A, ed. Clinical update on lamotrigine: a novel antiepileptic agent. Tunbridge Wells, UK: Wells Medical 1992:69-75, with permission.

Time Dependency

Skin rash with lamotrigine typically occurs within the first 4 to 8 weeks of treatment, occasionally up to 12 weeks, and only rarely after that. Usually, in the absence of systemic involvement, it resolves on discontinuing the drug without any further therapeutic intervention. The fact that it is an immediate immune-mediated hypersensitivity reaction was demonstrated by substantial increases in the percentage of activated T-helper and activated T-suppressor lymphocytes, a slight increase in the percentage of B lymphocytes, and a greater increase in the serum concentration of immunoglobulin E (IgE) in two children immediately after the first manifestation of a rash (38). In one of these children, reevaluation of immunity 20 days after the rash appeared and lamotrigine had been discontinued showed normal proportions of lymphocytes with a parallel decrease in the serum IgE concentration. In another case, a severe hypersensitivity reaction to lamotrigine developed in a man on combination lamotrigine and valproate therapy; skin tests were found to be negative, whereas lymphocyte stimulation tests in vitro were positive on two occasions with lamotrigine (39). Obviously, one of the goals of future immunologic studies is identification of susceptible patients.

Risk Factors

Several risk factors for the development of skin rash with lamotrigine have been identified, including high starting dose and rapid dose escalation (see previous discussion), the presence of valproate in the baseline therapy, pediatric age range, and, possibly, a previous history of allergic reactions. Most rashes recorded in clinical trials with lamotrigine were mild and judged to be nonserious by the investigators, although distinguishing the degree of severity of a given eruption and establishing causality with confidence may not be easy in clinical practice (40).

The incidence of skin rash when lamotrigine was added on to the therapy of patients receiving valproate alone was seen to be in the order of ~13% to 20%; up to ~5% to 14% of patients discontinued the drug, and ~1% to 4 % were hospitalized (17). The lowest incidence usually was associated with the lowest lamotrigine dose. It is unclear whether the occurrence of skin rash in patients comedicated with lamotrigine and valproate is mediated through inhibition of lamotrigine metabolism by valproate (Chapter 37) or through other pathogenetic mechanisms. However, in a recent, large postmarketing survey (41), skin rash occurred in ~14% of patients, with approximately one-half requiring drug discontinuation, but no difference was detected attributable to the presence or absence of valproate in the baseline therapy and, according to the authors, this might have been a consequence of very low initial doses of lamotrigine. Severe rash requiring hospitalization has been reported to occur in <1% of patients in the absence of valproate, and in 1% to 4% when lamotrigine is associated to this drug (17,35). By contrast, when lamotrigine was added on to enzyme-inducing drugs, the incidence of rash was lower than when the drug was used in monotherapy, as was the number of patients who discontinued lamotrigine because of skin rash (17). This protective effect is explained by induction of lamotrigine metabolism, resulting in lower plasma levels of the drug.

Pediatric trials with lamotrigine usually have shown greater incidence of skin rash compared with adult trials, ~12% to 13% with a discontinuation rate of ~5% (17,35,42). Similarly, the proportion of children requiring hospitalization was threefold higher than in adults (0.9% versus 0.3%) (17,35). Two recent trials, however, a randomized, placebo-controlled study (31) and a retrospective investigation (43), have reported a lower incidence (~2%) of rash leading to lamotrigine discontinuation, and this is similar to the incidence observed in adult populations (17,35,36).

Advice Concerning Precautions and Management

If a rash occurs after starting lamotrigine, the drug should be immediately withdrawn because there is evidence that progression to a more serious rash may occur if therapy is continued (35). When a more severe rash occurs and it is accompanied by other manifestations of hypersensitivity, namely, lymphadenopathy, general malaise, fever, and eosinophilia, the need for admission to hospital with prospective administration of intravenous fluids and steroid therapy should be considered. Clearly, because the initial dose and the dose titration play a crucial role in triggering skin rash, it is good practice to prescribe a low starting dose. After 2 weeks, the dose can be doubled; after a further 2 weeks, it can be titrated to an effective maintenance dose. Details of the manufacturer's recommendations for adults and children, in the presence or absence of valproate, are given in Table 39.4. Patients who experienced a previous rash may be considered for rechallenge with lamotrigine if the therapeutic response to the drug was satisfactory (44).

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LESS COMMON, BUT CLINICALLY RELEVANT ADVERSE EFFECTS

Less common effects reported with lamotrigine include diarrhea, dyspepsia, rhinitis, tremor, depression, psychosis, increased seizures, and, especially in children, infection, fever, pharyngitis, abdominal pain, influenza-like symptoms, bronchitis, and cough (17,18,30,36). Usually, the incidence of these effects is <10%, the intensity is mild, and discontinuation of lamotrigine is needed in <1% of the patients. For most of these effects, the causative relation to the drug treatment is not clearly proven and, in any case, they resolve over time or with dosage adjustment. In only a minority of patients is it necessary to discontinue the drug. Insomnia, for example, has been reported to occur in 7 of 109 patients exposed to lamotrigine, to be a dose-dependent effect, and to require drug discontinuation in 5 patients (45).

A paradoxical increase in seizures, an effect that almost always needs drug discontinuation, has been reported to occur in 1.5% of patients in lamotrigine add-on studies and in 2.2% in monotherapy studies (17). The incidence has been seen to be much higher (i.e., up to 30% to 40%) in children with severe myoclonic epilepsy (46). Drug-induced exacerbation of seizures is not a new problem with antiepileptic drug therapy. Carbamazepine, phenytoin, some benzodiazepines, and, among the more recent drugs, vigabatrin and gabapentin have been reported to precipitate seizures (47). Analysis of literature reports showed that the phenomenon is mediated by at least two distinct mechanisms: (a) a nonspecific drug intoxication, possibly consequent to an excessive dose or to complex drug combinations; and (b) a specific primary action of the drug in certain types of seizures or particular syndromes (47).

A mild hand tremor occurs in a minority of patients on lamotrigine therapy, and is more common when lamotrigine is combined with sodium valproate (28,29).

Isolated cases of encephalopathy (48), tic disorder (49), pseudolymphoma (50), hepatic involvement (51,52) or adverse hematologic effects such as leukopenia (53), anemia (54), or agranulocytosis (55) have been described in the literature. All the patients involved recovered completely after discontinuation of lamotrigine.

POTENTIALLY LIFE-THREATENING ADVERSE EFFECTS

When systemic manifestations of hypersensitivity, such as general malaise, fever, and eosinophilia, occur and are associated with a rapidly developing, blistering rash and involvement of mucous membranes or even signs of involvement of internal organs, urgent admission to hospital is essential. Two potentially life-threatening disorders have been reported in a small number of patients started on lamotrigine, the Stevens-Johnson syndrome (SJS) and Lyell's syndrome, or toxic epidermal necrolysis (TEN). These are known to be a rare complication of other antiepileptic drug therapy, including phenytoin, carbamazepine, and valproate (56) and, in some cases, they represent the cutaneous manifestation of a condition that has been labeled the antiepileptic drug hypersensitivity syndrome. This syndrome is characterized by the hallmark features of fever, internal organ involvement with lymphadenopathy, and cutaneous reactions.

With lamotrigine, severe rashes, including SJS and TEN, have been reported in approximately 1 in 1,000 to 10,000 adult patients after short-term (within 4 to 8 weeks) exposure to lamotrigine (35,57, 58, 59). These values are lower that those with carbamazepine, phenytoin, and phenobarbital, and are similar to those found with valproate (59). Analysis of the literature data suggests that the risk factors for these rare and life-threatening adverse effects are the same as those influencing skin rash (see page 412, Risk Factors).

During the phase III trials program, three patients were reported to have died of disseminated intravascular coagulation and multiorgan failure, but an evaluation of case records of these patients suggested that their condition was the result of seizures rather than treatment with lamotrigine (60). Multiorgan failure is a recognized complication of status epilepticus, and lamotrigine was shown not to affect the coagulation pathways in humans or in a rat model (36). Although a few further cases suggesting induction by lamotrigine have been reported (61, 62, 63), the existence of a true causative relationship with lamotrigine therapy still requires further careful investigation.

A case of a child who died of fulminant hepatic failure associated with pulmonary embolism has been described (64).

In early trials, there was concern about the occurrence of sudden, unexpected death among patients receiving lamotrigine. Further analysis has shown, however, that the incidence of this event is within the expected range for the population at risk (65).

MANIFESTATIONS AND MANAGEMENT OF OVERDOSE

Lamotrigine overdose has been described infrequently. In one report (66), a patient inadvertently received four daily doses of lamotrigine, 2,700 mg each, after which he presented with periorbital edema and discrete and confluent blanching red macules and papules involving the face, trunk, and extremities. Laboratory tests revealed leukocytosis, hepatitis, and acute renal failure. All these clinical signs and laboratory abnormalities disappeared after discontinuation of lamotrigine. The same resolution, without any

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complication, was observed in a case of self-poisoning with lamotrigine (67). A case of lamotrigine overdose also has been described in childhood (68). After ingesting sixteen 50-mg tablets of lamotrigine, a 2-year-old boy had generalized tonic-clonic seizures, tremor of limbs, ataxia, muscle weakness, and hypertonia without any abnormality of vital signs, electroencephalogram, and laboratory tests. Treatment included midazolam and gastric lavage followed by activated charcoal and fluid loads. Symptoms resolved within 24 hours without any other complication. The patient's lamotrigine plasma concentration was 3.8 mg/L.

PREGNANCY

Clinical experience in pregnancy is limited at the time of writing. An analysis in March 2000 of 335 pregnancies during which lamotrigine was being administered (98 as monotherapy) is shown in Table 39.6 (data on file from Glaxo-Wellcome). One hundred sixty-two pregnancies went to term with births without any malformation (76 mothers on monotherapy). Most of the other pregnancies (39, of which 14 were on monotherapy) were terminated by elective abortion.

Of the three malformed neonates from mothers exposed to lamotrigine alone, one presented with an esophageal malformation corrected by surgical intervention, another one with cleft palate, and the third with talipes equinovarus. Malformations occurring in neonates from mothers treated with lamotrigine associated with other conventional antiepileptic drugs have included facial dysmorphisms, cardiac malformations, malformations of the neural tube, extra digits, and others.

Based on these limited data, there is little to suggest that lamotrigine has a major teratogenic effect, but much greater experience, running to several hundred pregnancies, will be necessary before its safety can be assured. In view of the known teratogenic effects of established antiepileptic drugs, there is no good reason for avoiding lamotrigine during pregnancy.

TABLE 39.6. PREGNANCIES OCCURRING IN PATIENTS RECEIVING LAMOTRIGINE

   

Lamotrigine Only

Lamotrigine and Antiepileptic Drugs

Births

   
 

Normal

76

186

 

Abnormal

3

14

Abortion

   
 

Spontaneous

4

9

 

Electivea

14

25

 

Abnormal

0

2

 

Fetal deathb

1

1

Total

98

237

a For causes different from ascertainment of fetal malformations.

b Without demonstrated fetal malformations.
From Glaxo-Wellcome database, March 31, 2000, with permission.

CONCLUSION

In conclusion, 10 years of marketing experience with lamotrigine indicates that the most common adverse effects of lamotrigine are on the CNS , appearing soon after lamotrigine treatment is started, and rarely requiring lamotrigine discontinuation. Skin rashes occur in approximately 5% of patients treated with the drug, but their incidence can be minimized by starting with a low dose and escalating it slowly. The rashes usually are mild, although rarely they can be serious and life threatening. Although there is no evidence of a major teratogenic effect, the safety of lamotrigine in pregnancy cannot be fully assessed by the experience to date.

REFERENCES

  1. Glaxo-Wellcome. Lamictal Advisory Board briefing document.Glaxo-Wellcome, May 1, 2000.
  2. Miller AA, Wheatley PL, Sawyer DA, et al. Pharmacological studies on lamotrigine, a novel potential antiepileptic drug: I. anticonvulsant profile in mice and rats. Epilepsy Res1986; 27:483-489.
  3. Pisani F, Nicolosi C, Macaione V, et al. Long-term lamotrigine therapy does not affect peripheral nerve function. Epilepsia1999; 40:252-253.
  4. Cohen AF, Ashby L. Crowley D, et al. Lamotrigine, a potential anticonvulsant: effects on the CNS in comparison with phenytoin and diazepam. Br J Clin Pharmacol1985;20:619-629.
  5. Hamilton MI, Cohen AF, Yuen AWC, et al. Carbamazepine and lamotrigine in healthy volunteers: relevance to early tolerance and clinical trial dosage. Epilepsy Res1993;34:166-173.
  6. Jawad S, Oxley J, Yuen WC, et al. The effect of lamotrigine, a novel anticonvulsant, on interictal spikes in patients with epilepsy. Br J Clin Pharmacol1986;22:191-193.
  7. Binnie CD, Von Emde Boas W, Kasteleijn-Nolst Trenite DGA, et al. Acute effects of lamotrigine (BW43OC) in persons with epilepsy. Epilepsia1986;27:248-254.
  8. Binnie C, Debets R, Engelman M, et al. Double-blind, crossover trial of lamotrigine (Lamictal) as add-on therapy in intractable epilepsy. Epilepsy Res1989;4:222-229.
  9. Jawad S, Richens A, Yuen AWC. Controlled trial of lamotrigine for refractory partial epilepsy. Epilepsia1989;30:356-363.
  10. Loiseau P, Yuen W, Duche B, et al. A randomized double-blind, placebo-controlled, cross-over, add-on trial of lamotrigine in patients with treatment-resistant partial seizures. Epilepsy Res1990;7:136-145.
  11. Sander J, Patsalos P, Oxley J, et al. A randomized, double-blind, placebo-controlled, add-on trial of lamotrigine in patients with severe epilepsy. Epilepsy Res1990;6:221-226.
  12. Betts T, Goodwin O, Withers RM, et al. Human safety of lamotrigine. Epilepsy Res1991;32[Suppl 2]:S17-S21.
  13. Schapel GJ, Beran RG, Vajda FJE, et al. Double-blind placebo controlled crossover study on lamotrigine in treatment resistant partial seizures. J Neurol Neurosurg Psychiatry1993:56;448-453.

P.415

 

  1. Smith D, Baker G, Davies G, et al. Outcomes of add-on treatment with lamotrigine in partial epilepsy. Epilepsia1993:34: 312-322.
  2. Schachter SC, Leppik IE, Matsuo F, et al. A multicentre, placebo-controlled evaluation of the safety of lamotrigine (Lamictal) as add-on therapy in outpatients with partial seizures. Epilepsy Res1992;33[Suppl 3]:1-19.
  3. Marson AG, Kadir ZA, Chadwick DW. New antiepileptic drugs: a systematic review of their efficacy and tolerability. BMJ1996; 313:1169-1174.
  4. Messenheimer J, Mullens EL, Giorgi L, et al. Safety review of adult clinical trial experience with lamotrigine. Drug Saf1998; 18:281-296.
  5. Cramer J, Fisher R, Ben-Menachem E, et al. New antiepileptic drugs: comparison of key clinical trials. Epilepsia1999;40: 590-600.
  6. Betts T. Safety of lamotrigine. In: Richens A, ed. Clinical update on lamotrigine: a novel antiepileptic agent.Tunbridge Wells, UK: Wells Medical, 1992:61- 68.
  7. Kilpatrick ES, Forrest G, Brodie MJ. Concentration-effect and concentration-toxicity relations with lamotrigine: a prospective study. Epilepsia1996;37:534-538.
  8. Morris RG, Black AB, Harris AL, et al. Lamotrigine and therapeutic drug monitoring: retrospective survey following the introduction of a routine service. Br J Clin Pharmacol1998;46: 547-551.
  9. Brodie MJ, Richens A, Yuen AW. Double-blind comparison of lamotrigine and carbamazepine and lamotrigine in newly diagnosed epilepsy: UK Lamotrigine/Carbamazepine Monotherapy Trial Group. Lancet1995;345:476-479.
  10. Reunanen M, Dam M, Yuen AW. A randomised open multicentre comparative trial of lamotrigine and carbamazepine as monotherapy in patients with newly diagnosed or recurrent epilepsy. Epilepsy Res1996;23:149-155.
  11. Gilliam F, Wazquez B, Sackellares JC, et al. An active-control trial of lamotrigine monotherapy for partial seizures. Neurology1998;51:1018-1025.
  12. Steiner TJ, Dellaportas CI, Findley LJ, et al. Lamotrigine monotherapy in newly diagnosed untreated epilepsy: a doubleblind comparison with phenytoin. Epilepsia1999;40:601-607.
  13. Matsuo F, Bergen D, Faught E, et al. Placebo-controlled study of the efficacy and safety of lamotrigine in patients with partial seizures. Neurology1993:43:2284-2291.
  14. Messenheimer J, Ramsay RE, Willmore U, et al. Lamotrigine therapy for partial seizures: a multicenter, placebo-controlled, double-blind, cross-over trial. Epilepsia1994:35:113-121.
  15. Reutens DC, Duncan JS, Patsalos PN. Disabling tremor after lamotrigine with sodium valproate. Lancet1993;542:185-186.
  16. Pisani F, Oteri G, Russo MF, et al. The efficacy of valproate-lamotrigine comedication in refractory complex partial seizures: evidence for a pharmacodynamic interaction.Epilepsia1999;40:1141-1146.
  17. Messenheimer A, Giorgi L, Risner ME. The tolerability of lamotrigine in children. Drug Saf2000;22:303-312.
  18. Duchowny M, Pellock JM, Graf WD, et al. A placebo-controlled trial of lamotrigine add-on therapy for partial seizures in children: Lamictal Pediatric Partial Seizure Study Group. Neurology1999;53:1724-1731.
  19. Posner J, Holdich T, Crome P. Comparison of lamotrigine pharmacokinetics in young and elderly healthy volunteers. J Pharm Med1991:1:121-128.
  20. Brodie MJ, Overstall PW, Giorgi L, et al. Multicentre, doubleblind, randomised comparison between lamotrigine and carbamazepine in elderly patients with newly diagnosed epilepsy. Epilepsy Res1999;37:81-87.
  21. Gillham R, et al. A double blind comparison of lamotrigine and carbamazepine in newly diagnosed epilepsy with health related quality of life as an outcome measure. Seizure2000;9:375-379.
  22. Guberman AH, Besag FM, Brodie, et al. Lamotrigine-associated rash: risk/benefit considerations in adults and children. Epilepsia1999;40:985-991.
  23. Yuen AWC. Safety issues. In: Richens A, ed. Clinical update on lamotrigine: a novel antiepileptic agent.Tunbridge Wells, UK: Wells Medical, 1992:69-75.
  24. Chadwick D, Shaw M, Foy P, et al. Serum anticonvulsant concentrations ad the risk of drug induced skin eruptions. J Neurol Neurosurg Psychiatry1984;47:642-644.
  25. Iannetti P, Raucci U, Zuccaro P, et al. Lamotrigine hypersensitivity in childhood epilepsy. Epilepsia1998;39:502-507
  26. Schaub N, Bircher AJ. Severe hypersensitivity syndrome to lamotrigine confirmed by lymphocyte stimulation in vitro. Allergy2000;55:191-193.
  27. Roujeau JC, Stern RS. Severe adverse cutaneous reactions to drugs. N Engl J Med1994;331:1272-1285.
  28. Faught E, Morris G, Jacobson M, et al. Adding lamotrigine to valproate: incidence of rash and other adverse effects. Postmarketing Antiepileptic Drug Survey (PADS) Group.Epilepsia1999; 49:1135-1140.
  29. Dooley J, Camfield P, Gordon K, et al. Lamotrigine-induced rash in children. Neurology1996;46:240-242.
  30. Barron TF, Hunt SL, Hoban TF, et al. Lamotrigine monotherapy in children. Pediatr Neurol2000;23:160-163.
  31. Tavernor SJ, Wong IC, Newton R, et al. Rechallenge with lamotrigine after initial rash. Seizure1995;4:67-71.
  32. Sadler M. Lamotrigine associated with insomnia. Epilepsia1999;40:322-325.
  33. Guerrini R, Dravet E, Genton P, et al. Lamotrigine and seizure aggravation in severe myoclonic epilepsy. Epilepsia1998;39: 508-512.
  34. Perucca E, Gram L, Avanzini G, et al. Antiepileptic drugs as a cause of worsening seizures. Epilepsia1998;39:5-17.
  35. Hennessy MJ, Wiles CM. Lamotrigine encephalopathy. Lancet1996;347:974-975.
  36. Sotero de Menezes MA, Rho JM, Murphy P, et al. Lamotrigine-induced tic disorder: report of five pediatric cases. Epilepsia2000;41:862-867.
  37. Pathak P, McLachian RS. Drug-induced pseudolymphoma secondary to lamotrigine. Neurology1998;50:1509-1510.
  38. Arnon R, De Vivo D, Defelice AR, et al. Acute hepatic failure in a child treated with lamotrigine. Pediatr Neurol1998;18:251-251.
  39. Fayad M, Choueiri R, Mikati M. Potential hepatotoxicity of lamotrigine. Pediatr Neurol2000;22:49-52.
  40. Nicholson RJ, Kelly KP, Grant IS. Leucopenia associated with lamotrigine. BMJ1995;310:504.
  41. Esfahani FE, Dasheiff RM. Anemia associated with lamotrigine. Neurology1997;49:306-307.
  42. De Camargo OA, Bode H. Agranulocytosis associated with lamotrigine. BMJ1999;318:1179.
  43. Tennis P, Stern RS. Risk of cutaneous disorders after initiation of use of phenytoin, carbamazepine, or sodium valproate: a record linkage study. Neurology1997;49:542-546.
  44. Richens A. Safety of lamotrigine. Epilepsia1994;35:S37-S40.
  45. Schlienger RG, Shapiro LE, Shear NH. Lamotrigine-induced severe cutaneous adverse reactions. Epilepsia1998;39[Suppl 7]: 22-26.
  46. Rzany B, Correia O, Kelly JP, et al. Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis during first weeks of antiepileptic therapy: a case-control study: Study Group of the International Case Control Study on Severe Cutaneous Adverse Reactions. Lancet1999;353:2190-2194.
  47. Yuen AWC, Bihari DJ. Multiorgan failure with disseminated intravascular coagulation in severe convulsive seizures. Lancet1992;340:618.

P.416

 

  1. Schaub JE, Williamson PJ, Barnes EW, et al. Multisystem adverse reaction to lamotrigine. Lancet1994;344:281.
  2. Chattergoon DS, McGuigan MA, Koren G, et al. Multiorgan dysfunction and disseminated intravascular coagulation in children receiving lamotrigine and valproic acid.Neurology1997;49: 1442-1444.
  3. Wadelius M, Karlsson T, Wadelius E, et al. Lamotrigine and toxic epidermal necrolysis. Lancet1996;348:1392.
  4. Makin AJ, Fitt S, Williams R, et al. Fulminant hepatic failure induced by lamotrigine. BMJ1995;311:292.
  5. Leestma JE, Annegers JF, Brodie MJ, et al. Incidence of sudden unexplained death in the Lamictal (lamotrigine) clinical development program. Epilepsia1994;35:12.
  6. Mylonakis E, Vittorio CC, Hollik DA, et al. Lamotrigine overdose presenting as anticonvulsant hypersensitivity syndrome. Ann Pharmacother1999;33:557-559.
  7. Buckley NA, Whyte IM, Dawson AH. Self-poisoning with lamotrigine. Lancet1993; 342:1552-1553.
  8. Briassoulis G, Kalabalikis P, Tamiolaki M, et al. Lamotrigine childhood overdose. Pediatr Neurol1998;19:239-242.