Lamotrigine

Common indications

1. Seizure prophylaxis in epilepsy. Epilepsy is classified by seizure type which, in turn, guides antiepileptic drug choice. Lamotrigine is an option for first-line monotherapy or add-on therapy in focal seizures (with or without secondary generalisation), generalised tonic–clonic seizures and absence seizures.
2. Bipolar disorder, for depression, but not mania or hypomania.
   

 

Mechanisms of action

• The mechanism of action of lamotrigine is incompletely understood. 
• Like carbamazepine and phenytoin, it binds to voltage-sensitive neuronal Na⁺ channels, interfering with Na⁺ influx into the neuron. This impedes repetitive neuronal firing, which is a characteristic of seizure activity. 
• Additionally, it appears to have effects on synaptic function, including inhibition of a post-synaptic glutamate receptor (the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA] receptor). 
• These effects, and others, may contribute to its antiepileptic action. 
• The mechanism by which it reduces depressive symptoms in bipolar disorder is uncertain.

 

Important adverse effects

• The most common adverse effects are headache, drowsiness, irritability, blurred vision, dizziness and gastrointestinal symptoms. 
• A minority of patients develop a skin rash within a few weeks of starting lamotrigine. This is usually mild, but requires urgent review and possibly discontinuation of the drug. This is because it may be the first sign of a severe hypersensitivity reaction; although rare, this may be life threatening, and early discontinuation of the drug is of paramount importance (see Carbamazepine).

 

Warnings

• Lamotrigine should be avoided if possible in patients who have a prior history of hypersensitivity to other antiepileptic drugs, due to the risk of cross-reactivity. 
• Lamotrigine is metabolised by hepatic glucuronidation, so dosage reduction may be necessary in patients with moderate or severe hepatic impairment. 
• In general, there is no evidence that lamotrigine exposure in pregnancy increases the overall risk of congenital malformations, so it is a reasonable choice in women of child-bearing age. 
• During pregnancy, due to changes in lamotrigine metabolism, plasma concentration measurement should be considered to guide dosage adjustment.

 

Important interactions

• Lamotrigine has many interactions arising from its metabolism by glucuronidation. These are of sufficient importance to necessitate pre-emptive dosage modification. 
• Drugs that induce glucuronidation include carbamazepine, phenytoin, oestrogens, rifampicin and protease inhibitors. These can cause the lamotrigine concentration to fall, potentially leading to treatment failure. 
• Glucuronidation is inhibited by valproate, causing the lamotrigine concentration to rise, increasing the risk of toxicity. 
• Severe hypersensitivity reactions are also more common when lamotrigine is co-administered with valproate.