Phenytoin with lamotrigine

Several other therapeutic effects of sodium channel blockers have been suggested. Most of these stem from clinical activities of approved anticonvulsants and antiarrhythmics with sodium channel blocking activity. Beneficial effects of sodium channel blockers for the treatment of bipolar disease are suggested by clinical data with lamotrigine [63-67], phenytoin [68], topiramate [69], and carbamazepine [70,71]. In addition, clinical studies with lidocaine suggest efficacy in the treatment of tinnitus [72] and, as an inhaled formulation, in the suppression of cough [73,74]. 

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). 

Although serious skin rashes have been reported with traditional anticonvulsants, the risk of Stevens-Johnson syndrome and toxic epidermal necrolysis with these drugs appears to be lower than with lamotrigine. Data from the Saskatchewan Health Plan suggest that the risk of serious rashes is in the order of 0.9 1000 (1.4 1000 in children) for phenytoin, 0.6 1000 (1.4 1000 in children) for carbamaze-pine, and 0 1000 for valproate, but Stevens-Johnson syndrome constituted only a small minority of these cases (47). 

Lennox-Gastaut syndrome is a mixed seizure disorder combining the atypical absence seizures with tonic, tonic-clonic, or myoclonic motor patterns. The syndrome begins in childhood and usually Includes mental retardation. Although adequate control of the seizures rarely Is achieved, valproate, phenytoin, felbamate, lamotrigine, topiramate, and clonazepam have been... 

Unlike carbamazepine, oxcarbazepine appears not to have marked en-zyme-indueing properties so that it would not be expected to have as great an effeet on the metabolism of other antiepileptics. However, oxcarbazepine does appear to act as an inhibitor of the cytochrome P450 isoenzyme CYP2C19 at high concentrations and therefore may raise phenytoin levels (see Phenytoin + Carbamazepine , p.554, for more on this mechanism). Other antiepileptics can increase the metabolism of the active metabolite of oxearbazepine, monohydroxyoxcarbazepine. The situation with lamotrigine is not clear. In one study lamotrigine appeared to de-erease the metabolism of oxcarbazepine but another study found no phar-maeokinetie interaetion. 

Any changes in the pharmacokinetics of oxcarbazepine brought about by other antiepileptics seem to be of minimal clinical relevance. However, the clinical relevance of the increase in the active metabolite monohydroxyoxcarbazepine with lamotrigine requires further study. In addition, there is the theoretical risk that monohydroxyoxcarbazepine levels might rise to toxic levels if carbamazepine or phenytoin were withdrawn. For mention that there may be an increase in adverse effects if oxcarbazepine is used with felbamate, see Oxcarbazepine +Felbamate , p.545. 

Fluid balance A 33-year-old woman with focal epilepsy developed angioedema after starting levetiracetam. This patient had previously developed skin rashes while on both phenytoin and lamotrigine [100 ]. 

Alkhotani A, McLachlan RS. Levetiracetam induced angioedema in a patient with previous anticonvulsant hypersensitivity reaction to phenytoin and lamotrigine. Seizure June 2012 21(5) 407-8. 

One unwanted side-effect of phenytoin is its anti-folate activity. A programme of synthetic chemistry to manipulate the structure of the anti-folate compound pyri-methium to try to replace that property with anticonvulsant activity resulted in the synthesis of lamotrigine. It proved to be an effective AED in partial and generalised epilepsy but experience has found it also to be of value in absence seizures. 

Epilepsy is a clinical disorder characterized by spontaneous, recurrent seizures arising from excessive electrical activity in certain parts of the brain [51]. Currently available drugs, such as phenytoin, carbamazepine, valproic acid, lamotrigine, and topiramate (for molecular structures see Fig. 6), provide symptomatic seizure suppression in only 60-70% of those receiving treatment [52-54]. These drugs are also associated with unwanted side... 

Depression is a common problem in patients with epilepsy, with approximately 30% having symptoms of major depression at some point.34 Patients with epilepsy should be routinely assessed for signs of depression, and treatment should be initiated if necessary. Certain AEDs may exacerbate depression, for example levetirac-etam and phenytoin. Other AEDs (e.g., lamotrigine, carba-mazepine, and oxcarbazepine) maybe useful in treating depression. Changes in mood can be precipitated by addition or discontinuation of an AED. If treatment for depression is necessary, caution should be exercised in choosing an agent that does not increase seizure frequency and does not interact with AEDs. 

Studies suggest that as monotherapy for partial seizures, lamotrigine is as effective as carbamazepine and phenytoin lamotrigine may be better tolerated. Clinical data suggest that oxcarbazepine is as effective as phenytoin, valproic acid, and immediate-release carbamazepine, with perhaps fewer side effects. 

Stopping oral contraceptives - For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose of lamotrigine may need to be decreased by as much as 50% of the maintenance dose with concurrent oral contraceptives. 

II.e. 5.2. Interactions between first and second generation AEDs. Felbamate raises plasma concentrations of phenytoin, valproic acid and carbamazepine. Clearance of tiagabine, topiramate and zon-isamide is increased in the presence of an enzyme inducer. Vigabatrin reduces phenytoin concentrations after 4-5 weeks of comedication (via an unknown mechanism). For tiagabine, the elimination half-life may be reduced by 2-3 hours in the presence of an enzyme-induction AED. Lamotrigine elimination is slower if given with valproic acid. Topiramate reduces elimination of phenytoin. 

Specific myoclonic syndromes are usually treated with valproate an intravenous formulation can be used acutely if needed. It is nonsedating and can be dramatically effective. Other patients respond to clonazepam, nitrazepam, or other benzodiazepines, although high doses may be necessary, with accompanying drowsiness. Zonisamide and levetiracetam may be useful. Another specific myoclonic syndrome, juvenile myoclonic epilepsy, can be aggravated by phenytoin or carbamazepine valproate is the drug of choice followed by lamotrigine and topiramate. 

For atypical absence, tonic and clonic seizures, first line treatment is with valproate and second line with acetazolamide, carbamazepine, clobazam, clonazepam, ethosuximide, felbamate, lamotrigine, oxacarbamazepine, phenobarbitone, phenytoin, primidone or topiramate. 

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