Lamotrigine development

A concern with the administration of lamotrigine is that it has the potential to induce the Stevens-Johnson syndrome (exfoliative dermatitis). The incidence of a serious rash in clinical trials appears to be about 0.08% with monotherapy and 0.13% with combination therapy. The rash usually resolves when lamotrigine is stopped, but all patients starting lamotrigine should be cautioned to be vigilant for the development of a rash, especially during the first 6 months of treatment. 

A maculopapular rash develops in 5%-10% of patients taking lamotrigine, usually in the first 8 weeks of treatment. Serious rashes requiring hospitalization and discontinuation of treatment may occur. The incidence of these rashes, which have included Stevens-Johnson syndrome, is approximately 0.08% (0.8 per 1,000). Stevens-Johnson syndrome is potentially fatal. Patients must be advised of this risk and of the necessity to call the office at once if they develop a rash. Development of a rash with concomitant systemic symptoms is a particularly ominous sign, and the patient should be evaluated immediately. 

Lamotrigine was developed when some investigators thought that the antifolate effects of certain antiseizure drugs (eg, phenytoin) may contribute to their effectiveness. Several phenyltriazines were developed, and although their antifolate properties were weak, some were active in seizure... 

At least three drugs are effective against absence seizures. Two are nonsedating and therefore preferred ethosuximide and valproate. Clonazepam is also highly effective but has disadvantages of dose-related adverse effects and development of tolerance. Lamotrigine and topiramate may also be useful. 

Three antiepileptic drugs have now been FDA approved as mood stabilizers for the prevention of recurring episodes of mania divalproex sodium (Depakote), extended-release carbamazepine (Equetro), and lamotrigine (Lamictal). Many of these drugs are prescribed to children for the control of epilepsy and, increasingly, for bipolar disorder. A critical question is their effect on the developing mental and emotional function of children, but there is little research on the subject (Loring, 2005). 

Two patients taking lamotrigine 225 mg/day and 200 mg/day developed forced normalization (445). Lamotrigine led to seizure control and disappearance of interictal epileptiform discharges from the electroencephalogram. However, simultaneously they had de novo psychopathology and disturbed behavior. Reduction of the dose of lamotrigine led to disappearance of the symptoms and reappearance of the spikes but not the seizures. 

A 19-year-old man with focal epilepsy took carbamazepine 1000 mg/day and lamotrigine 300 mg/day. Because his seizures persisted topiramate was added up to 200 mg/day and the dose of carbamazepine was reduced to 300 mg/day. Behavioral problems started within a week and worsened over the following months. He finally developed obsessive-compulsive disorder. Citalopram was given in doses up to 60 mg/ day and topiramate was tapered within 2 weeks. The symptoms improved. 

Lite-threatening rashes have developed in association with lamotrigine use lamotrigine should generally be discontinued at the first sign of serious rash... 

With phenytoin, carbamazepine, phenobarbital, primidone, and lamotrigine, hepatotoxicity usually occurs as part of a hypersensitivity reaction, with skin rashes and fever in the early weeks of treatment. More rarely, hepatic disease can develop after many years without signs of hypersensitivity. Once hepatotoxicity develops, mortality... 

Of the newer anticonvulsants, lamotrigine, gabapentin, tiagabine, and vigabatrin have little or no teratogenic potential in animals, whereas oxcarbazepine and topira-mate are teratogenic in rodents. However, animal studies are not necessarily apphcable to humans and chnical data are stiU insufficient to assess the effects of newer drugs on the development of the human fetus (153). 

The efficacy and safety of lamotrigine have been prospectively evaluated in 41 children and yonng adults (aged 3-25 years) with drug-resistant partial epilepsies (8). Lamotrigine withdrawal was mainly due to lack of efficacy (46%) only two patients developed a transient skin rash, which did not require withdrawal. 

The most common adverse effects of lamotrigine include dizziness, weakness, headache, diplopia, ataxia, blurred vision, and somnolence (SEDA-18, 65) (SEDA-20, 63) (19). These effects resemble those seen with carbamaze-pine and can result from an adverse pharmacodynamic interaction. Tolerability is better when lamotrigine is given as monotherapy or with drugs other than carbama-zepine however, tremor develops in some patients taking valproate in combinations (SEDA-18, 66). During monotherapy, serum lamotrigine concentrations associated with intolerable adverse effects (mostly headache, dizziness, and ataxia) were 0.4-18.5 qg/ml and overlapped widely with those tolerated in other patients (20). 

In a 5-year-old girl with benign rolandic epilepsy, the addition of lamotrigine (0.5-5 mg/kg/day) to valproate resulted in a temporary reduction in seizure frequency (23). However, her school performance deteriorated insidiously, with poor memory and concentration, clumsiness, stuttering, and emotional lability. After 4 months she developed new daily brief absence-hke episodes. 

A 9-year-old girl with Lennox-Gastaut syndrome, who had initially had an improvement in seizure frequency, insidiously developed myoclonic status epilepticus after the lamotrigine dosage was increased from 15 to 20 mg/kg (24). Withdrawal of lamotrigine resulted in rapid disappearance of status. 

Two patients (age unspecified) with severe epileptic encephalopathy who had improved on lamotrigine in combination with valproate developed continuous myoclonic jerks after 2-3 years these were ascribed to high serum concentrations of lamotrigine (65 and 69 pmol/l) (25). 

In another report, two boys aged 6 and 8 years developed severe difficulties in falling asleep and fragmented sleep (in one case associated with scary dreams) after being stabilized on lamotrigine, 8 mg/kg (27). These disturbances improved when the dosage was reduced. 

A 51-year-old man developed blepharospasm 4 months after starting lamotrigine, while taking a maintenance dosage of 500 mg/day (29). The condition cleared 4 weeks after withdrawal. 

A 29-year-old woman with Blackfan-Diamond anemia developed an erythroblastopenic crisis after taking phe-nytoin on two separate occasions and then again after taking lamotrigine (38). The proposed mechanism was inhibition of dihydrofolate reductase, and the crisis responded to treatment with folinic acid. Lamotrigine was then continued without ill effect. 

Reversible agranulocytosis developed in a 30-year-old woman who had taken lamotrigine 100 mg/day for 6 weeks and valproate 250 mg/day for 2 weeks (39). Her white cell count fell from 6.7 x 10 /1 at 4 weeks to 2.6 X 10 /1 at 6 weeks and the absolute neutrophil count was 580 x 10 /1. The white cell count recovered after withdrawal of lamotrigine the valproate was continued. 

A rash, usually urticarial or maculopapular, is the most common event leading to early withdrawal of lamotrigine. In add-on trials, rashes occurred in up to 15% of patients and led to withdrawal in 2%. Six patients who developed a rash with lamotrigine later had similar rashes after exposure to structurally unrelated anticonvulsants, such as phenytoin and barbiturates (SEDA-22, 89). In 12 patients with probable Alzheimer s disease and seizures and 16 with other neurological disorders, lamotrigine caused three cases of mild rashes (43). 

A 33-year-old woman, who had taken valproate for 3 years, developed Stevens-Johnson syndrome soon after starting to take lamotrigine 150 mg/day (46). Lamotrigine was withdrawn and prednisolone given the signs and symptoms progressively resolved over 10 days. 

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