Lamotrigine administration

Pharmacotherapy is the cornerstone of acute and maintenance treatment of bipolar disorder. Mood-stabilizing drugs are the usual first-choice treatments and include lithium, divalproex, carbamazepine, and lamotrigine. Atypical antipsychotics other than clozapine are also approved for treatment of acute mania. Lithium, lamotrigine, olanzapine, and aripiprazole are approved for maintenance therapy. Drugs used with less research support and without Food and Drug Administration (FDA) approval include topiramate and oxcarbazepine. Benzodiazepines are used adjunctively for mania. 

Introduced in clinical practice in the 1960s, lithium was the first mood stabilizer to be used in China. This was followed by carbamazepine and sodium valproate. For many years, these were the only treatment options available as mood stabilizers. Although lamotrigine was approved for maintenance treatment of bipolar I disorder in 2003 by FDA (Food and Drug Administration) in the USA, this indication has not yet been approved by the Chinese authorities. At present, only one atypical antipsychotic drug, risperidone, has been approved for treating acute mania (February 2005 by SFDA [State Food and Drug Administration]) in China (see Table 6.1). 

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. 

Administration ofchewable dispersible tablets Swallow lamotrigine chewable dispersible tablets whole, chewed, or dispersed in water or diluted fruit juice. If chewed, consume a small amount of water or diluted fruit juice to aid in swallowing. To disperse chewable dispersible tablets, add the tablets to a small amount of liquid (5 ml or enough to cover the medication). Approximately 1 minute later, when the tablets are completely dispersed, swirl the solution and consume the entire quantity immediately. Do not attempt to administer partial quantities of the dispersed tablets. 

Absorption/Distribution - Lamotrigine is rapidly and completely absorbed after oral administration. Absolute bioavailability is 98%. Peak plasma concentrations occur anywhere from 1.4 to 4.8 hours following drug administration. Lamotrigine chewable/dispersible tablets were found to be equivalent, whether they were administered as dispersed in water, chewed and swallowed, or swallowed as whole, to lamotrigine compressed tablets in terms of rate and extent of absorption. 

Metabolism/Excretion - Lamotrigine is approximately 55% bound to human plasma proteins. Following multiple administrations to healthy volunteers taking no other medications, lamotrigine induced its own metabolism resulting in a 25% decrease in half-life and a 37% increase in plasma clearance. 

Serious rashes associated with hospitalization and discontinuation of lamotrigine have been reported. It is recommended that lamotrigine not be restarted in patients who discontinued use due to rash associated with prior treatment with lamotrigine unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine, assess the need to restart with the initial dosing recommendations (See Administration and Dosage). 

Lamotrigine is almost completely absorbed after oral administration and metabolized completely in liver. 

In dogs concurrent administration of lamotrigine had no significant effect on the pharmacokinetics of carbamazepine or the plasma concentration ratio of carbamazepine epoxide to carbamazepine (97). 

Co-administration of valproate is one of the most important risk factors for skin reactions to lamotrigine valproate co-medication was present in 74 and 64% of patients with Stevens-Johnson syndrome and toxic epidermal necrolysis respectively (44). 

To date, among the newer-generation agents, only lamotrigine and oxcarbazepine have received Food and Drug Administration (FDA) approval for use as monotherapy in patients with partial seizures. Phenobarbital and primidone are also useful in partial... 

What effect does concurrent administration of valproic acid have on lamotrigine levels ... 

Phenobarbital, phenytoin, and valproic acid may increase the metabolism of carbamazepine by inducing CYP3A4 carbamazepine may enhance the biotransformation of phenytoin. Concurrent administration of carbamazepine may lower concentrations of valproic acid, lamotrigine, tiagabine, and topiramate. Carbamazepine reduces both the plasma concentration and therapeutic effect of haloperidol. The metabolism of carbamazepine may be inhibited by propoxyphene, erythromycin, cimetidine, fluoxetine, and isoniazid. 

PHARMACOKINETICS Zonisamide is almost completely absorbed after oral administration, has a long tj, ( 63 hours), and is -40% bound to plasma protein. Approximately 85% of an oral dose is excreted in the urine, principally as unmetaboUzed zonisamide and a glucuronide of the CYP3A4 metabolite, sulfamoylacetyl phenol. Phenobarbital, phenytoin, and carbamazepine decrease the plasma concentration/dose ratio of zonisamide, whereas lamotrigine increases this ratio. Zonisamide has Uftle effect on the plasma concentrations of other antiseizure drugs. 

Anticonvulsants Carbamazepine decreases the plasma concentration of bupropion to about 90% even after a single dose of 150 mg of carbamazepine. Long-term administration of valproate (a weak inhibitor of hepatic metabolism) has no effect on bupropion plasma concentration. It has been shown that bupropion does not cause clinically relevant changes in the pharmacokinetics of a single dose of 100 mg of lamotrigine. 

The anticonvulsant action of valproate may prevent ECT treatment from being effective by preventing seizure activity. This is also a theoretical/practical concern with carbamazepine, gabapentin, lamotrigine, and topiramate. As a rule of thumb, the co-administration of an anticonvulsant and ECT should be considered very cautiously ... 

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