Lamotrigine

Lamotrigine is a broad-spectrum anti-epileptic drug that has been widely accepted as a firstline drug for both partial and generalized epilepsy syndromes. Clinical trials have supported its use in partial seizures, primary generalized tonic-clonic seizures, absence seizures and seizures associated with Lennox-Gastaut syndrome [46, 47]. There is some controversy regarding the use of lamotrigine in juvenile myoclonic epilepsy. It is commonly used, but may worsen myoclonus in some patients. Lamotrigine has been the subject of a number of head-to-head studies in newly diagnosed partial and generalized epilepsy. Lamotrigine was equally effective but better tolerated than phenytoin and carbamazepine in several somewhat under-powered studies [4, 48]. Several studies indicated that lamotrigine is better tolerated than carbamazepine in the elderly [49, 50]. A recent very large, randomized open-label study indicated that lamotrigine might be the drug of choice in patients with partial epilepsy, as it was equally effective but better tolerated, but in a companion study it was substantially less effective than valproate in patients with generalized or unclassified epilepsy [16, 51]. Some studies have advocated combining lamotrigine with valproate in refractory patients, to achieve maximum efficacy through a favourable pharmacodynamic interaction [52]. However, side-effects are also enhanced when the drugs are combined. Initiation of lamotrigine is somewhat more complex than for other drugs. Slow titration is mandatory to reduce occurrence of serious rash. In monotherapy, initiation with 25 mg/day for 2 weeks, then 50 mg/day for another 2 weeks, followed by increases of 25-50 mg/week is appropriate. If the patient is receiving valproate at the time of initiation, starting doses and doses during titration should be cut in half, whereas if they are receiving enzyme-inducing AEDs such as phenytoin, carbamazepine or phenobarbital, doses can be doubled [53]. Doses can then be increased as necessary. Typical doses for patients with newly diagnosed epilepsy are 100-200 mg/day. In refractory patients, doses may be as high as 500-1000 mg/day. There is a great deal of variability in serum concentrations that produce optimal effects. Some patients may do well at serum concentrations of 2 mg/l, while others may need levels of up to 20 mg/l. Common dose-related side-effects of lamotrigine include mild tremor, double vision, headache and insomnia. Rash, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can occur. Risk is increased for children under 16, and is also more common with concomitant valproate use, and in patients who have experienced rash on other AEDs [54]. Rash almost always occurs within the first 8 weeks of therapy. Other hypersensitivity reactions, although much rarer, may be seen, including lymphadenopathy, fever, hepatic or renal failure, disseminated intravascular coagulation and arthritis [55]. Discontinuation of lamotrigine is recommended in the presence of rash or other indication of hypersensitivity, and it is very important to tell patients to call immediately with such symptoms. Rapid discontinuation can prevent a more severe, potentially life-threatening reaction. In the absence of any clinical symptoms of hypersensitivity, it is unclear that routine monitoring of liver function tests, blood counts or electrolytes is useful. Lamotrigine does not alter the metabolism of other drugs that are given concomitantly. However, other drugs may impact on the metabolism of lamotrigine (see Tables 1.1 and 1.2). One important and common drug interaction that bears noting is that with oral contraceptives, which double the clearance and halve the half-life of lamotrigine [56]. Women on lamotrigine should be told to notify their doctor of any changes in oral contraceptive pill use, something they might not otherwise think to do.

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